Metronomic Methotrexate Regimen Proposed For Platinum-Refractory Oral Cancer

Metronomic Methotrexate Regimen Proposed For Platinum-Refractory Oral Cancer
Patients with treatment-refractory squamous cell carcinoma of the oral cavity may respond to a metronomic schedule of oral methotrexate, erlotinib and celecoxib
Date: 25 Sep 2019
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Head and Neck Cancers / Anticancer Agents
medwireNews: Phase I/II trial results suggest that an oral metronomic regimen of methotrexate, erlotinib and celecoxib may have activity against platinum-refractory squamous cell cancer of the oral cavity.

The researchers describe their findings as “exciting” when compared against historical response rates of up to 13.6% and progression-free survival (PFS) of up to 2.3 months for cytotoxic chemotherapy agents and nivolumab.

The optimal biological dose of methotrexate 9 mg/m2 per week was identified in phase I and this was given once per week alongside erlotinib 150 mg/day and celecoxib 200 mg twice daily to 76 patients in phase II.

The participants had all progressed within 1 month of surgery or radiation, or within 6 months of receiving platinum-based systemic treatment, explain Kumar Prabhash and colleagues, from the Tata Memorial Centre in Mumbai, India.

After a median follow-up of 6.8 months, the median PFS was 4.6 months, with 3- and 6-month PFS rates of 71.1% and 34.5%, respectively. And at data cutoff, the median overall survival (OS) duration was 7.2 months with a 6-month rate of 61.2%.

At 2 months, 37.4% of patients achieved a response to treatment and this increased to 42.9% over follow-up. The median response durations in these two groups were 2.1 and 4.4 months, respectively.

Safety analysis of 88 patients indicated the most common adverse events were fatigue (85.2%), rash (80.7%) and anaemia (80.7%), while other less common events included grade 3–4 hyponatremia (14.8%) and elevated alanine transaminase (5.7%). Overall, 13.6% of patients required a dose reduction, most commonly for the methotrexate treatment (11.4%).

“In conclusion, the combination of erlotinib, [methotrexate], and celecoxib in platinum-insensitive oral cancer results in promising [response rates], PFS, and OS”, Kumar Prabhash and co-authors conclude in the Journal of Clinical Oncology.

And they recommend that “[i]ts activity needs to be confirmed in a phase III randomized study.”



Reference

Patil VM, Noronha V, Joshi A, et al. Phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early-failure oral cancer . J Clin Oncol; Advance online publication 20 September 2019. DOI: 10.1200/JCO.19.01076  

Third-line Cabazitaxel Benefit Demonstrated For metastatic CRPC Patients

Cabazitaxel Benefit Demonstrated For metastatic CRPC Patients
Patients with metastatic castration-resistant prostate cancer have better outcomes with third-line cabazitaxel than with receipt of a second androgen signalling-targeted agent
Date: 08 Oct 2019
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Prostate Cancer / Anticancer Agents
medwireNews: For men with metastatic castration-resistant prostate cancer (CRPC) who have progressed after docetaxel and use of enzalutamide or abiraterone, cabazitaxel offers significantly better survival than treatment with the alternative androgen signalling-targeted agent, research suggests.

The CARD trial findings were presented at the ESMO Congress 2019 in Barcelona, Spain and simultaneously reported in The New England Journal of Medicine.

After a median of 9.2 months, imaging-based progression or death had occurred in 73.6% of the metastatic CRCP 129 patients who were randomly assigned to receive cabazitaxel 25 mg/m2 every 3 weeks, alongside prednisone 10 mg/day and granulocyte colony-stimulating factor therapy at each cycle.

This rate was significantly lower than the 80.2% reported for the 126 patients who instead were randomly assigned to receive enzalutamide or abiraterone, according to which agent they had previously received, giving a significant hazard ratio (HR) for progression or death of 0.54 in favour of the taxane.

Post hoc analyses confirmed that this superior outcome with cabazitaxel was true regardless of whether the second androgen signalling-targeted inhibitor was enzalutamide or abiraterone, reported presenting author Ronald de Wit, from Erasmus Medical Center in Rotterdam, the Netherlands, and co-workers.

Patients using cabazitaxel also achieved a significantly longer duration of overall survival than those given a second androgen signalling-targeted agent (median 13.6 vs 11.0 months, HR=0.64) as well as better progression-free survival when including prostate-specific antigen (PSA) and pain progression (median 4.4 vs 2.7 months, HR=0.52).

These benefits with cabazitaxel were accompanied by higher rates of PSA response (35.7 vs 13.5%) and tumour response (36.5 vs 11.5%), the researchers say.

Of note, there was a comparable incidence of serious adverse events (AEs) in the cabazitaxel and second androgen signalling-inhibitor trial arms (38.9 vs 38.7%), although cabazitaxel was associated with a higher rate of discontinuation because of AEs (19.8 vs 8.9%).

Cabazitaxel-treated patients were more likely than those given enzalutamide or abiraterone to experience grade 3 and more severe asthenia/fatigue (4.0 vs 2.4%), diarrhoea (3.2 vs 0%), peripheral neuropathy (3.2 vs 0%), and febrile neutropenia (3.2 vs 0%), but were less likely to develop renal disorders (3.2 vs 8.1%), musculoskeletal pain (1.6 vs 5.6%), cardiac disorders (0.8 vs 4.8%) and spinal cord or nerve root disorders (2.4 vs 4.0%).

“The results of the CARD trial are in agreement with those of previous studies that have shown poor outcomes with a second androgen-signaling–targeted inhibitor”, de Wit and co-workers note.

“This is probably due to the fact that these agents target the same pathway and thus share common mechanisms of resistance” whereas “taxanes, owing to their different mechanism of action, are able to overcome several mechanisms of resistance to androgen-signaling-targeted inhibitors”, they hypothesise.



References

de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer . N Engl J Med; Advance online publication 30 September 2019. DOI: 10.1056/NEJMoa1911206

de Wit R, Kramer G, Eymard J-C, et al. CARD: Randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). ESMO Congress 2019 ; Barcelona, Spain: 27 September–1 October. LBA13

Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer

Enzalutamide Could Have Pivotal Role in Metastatic Hormone-Sensitive Prostate Cancer
Ellie Leick
Published: Friday, Jul 12, 2019
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Christopher J. Sweeney, MBBS
Christopher J. Sweeney, MBBS Results of the ENZAMET trial showed that enzalutamide (Xtandi) significantly improved overall survival (OS) when added to the standard of care for patients with metastatic hormone-sensitive prostate cancer, although the benefits were lower for those slated to receive early docetaxel, explained Christopher Sweeney, MBBS.

In the phase III study, investigators randomized 1125 patients to receive testosterone suppression plus either enzalutamide or a nonsteroidal antiandrogen, such as bicalutamide (Casodex), nilutamide (Nilandron), or flutamide (Eulexin).

Interim findings showed that the 3-year OS rate was 80% in patients with metastatic hormone-sensitive prostate cancer who received the enzalutamide regimen compared with 72% of those who received a standard nonsteroidal antiandrogen agent.

Additionally, a subgroup of patients received early doses of docetaxel or abiraterone acetate (Zytiga) with testosterone suppression. In this group, the OS rates were similar between the 2 arms (HR, 0.90; 0.62-1.31).

The addition of enzalutamide, however, did exacerbate docetaxel-related adverse events (AEs). Docetaxel-related AEs in the enzalutamide versus nonsteroidal antiandrogen arms included neutropenic fever (14% vs 13%, respectively), grade 2 sensory neuropathy (9% vs 3%), nail discoloration (10% vs 5%), grade 1 or 2 watery eyes (20% vs 6%), and grade 2 fatigue (20% vs 14%).

“We need longer follow-up, but it is possible we will see that adding enzalutamide to docetaxel will have a clinical benefit. We can't say that yet because we've got to do the quality-of-life analysis to see if delaying progression improves the patient's quality of life. There were some extra side effects with adding the enzalutamide to docetaxel,” said Sweeney, a medical oncologist at Dana-Farber Cancer Institute.

In an interview with OncLive, Sweeney discussed the results of the ENZAMET trial and the next steps for researching the efficacy of enzalutamide in the treatment of patients with metastatic hormone-sensitive prostate cancer.

OncLive: Could you provide an overview of the ENZAMET trial design?

Sweeney: This is a study in the metastatic hormone-sensitive setting of prostate cancer. It's asking whether enzalutamide, which we know improved the survival of men with castration-resistant disease, is more effective when given at the start of hormonal therapy—testosterone suppression. In this hormone-sensitive setting, patients with a high volume of disease also benefit from getting docetaxel. That result came out in the CHAARTED study, which was not too long after we wrote, designed, and activated the ENZAMET study. We quickly activated an amendment that allowed patients to receive docetaxel based on physician and patient choice. The patients could either get testosterone suppression with a standard nonsteroidal—either bicalutamide, nilutamide, or flutamide—as an active control or enzalutamide. Then, patients were stratified by whether they received docetaxel. What ultimately happened is 50% of the patients received docetaxel, many of them with high-volume disease. Half of the patients received enzalutamide and half were treated with the nonsteroidal antiandrogen.

We saw that enzalutamide prolonged OS in both patients with high-volume and low-volume disease. We also saw that patients had a longer time to progression; the study was very positive. We get the readout early from the interim analysis, [but] we need longer follow-up.

Although early enzalutamide prolonged the time to progression for those who got docetaxel, there is not a big treatment effect yet. We will hopefully see a bigger treatment effect soon with longer follow-up. It's possible to do sequential therapy as long as patients get docetaxel and enzalutamide at some stage.

On the other hand, patients who did not get docetaxel had a clear improvement in time to progression and a significant improvement in OS—a very clear treatment effect. However, we've got a lot of work to do. We often need the longer follow-up to see if it translates into longer survival. Hopefully patients who have a longer time to progression get other agents and compound the early cancer control, resulting in a longer survival, but we haven't seen it yet at the early analysis.

Could you expand upon the safety findings with enzalutamide?
It's very important when we counsel patients on the efficacy benefits and the AEs. There is the same degree of enzalutamide-associated AEs that we expected; there is fatigue, increased concentration impairment, and falls. About 5% of patients experienced falls as an AE, which is a low number but more than we saw with patients who got the standard nonsteroidal. That's something we need to be careful about. There was also a 1% incidence of seizures in patients who received enzalutamide, despite excluding patients who had a predisposition to seizures.

The other very interesting thing is enzalutamide increased some of the AEs of docetaxel. There was the same grade of neutropenic fever, but there was also grade 2 sensory neuropathy at about 9%; there was only 3% who experienced sensory neuropathy with the standard nonsteroidal. We also saw some increasing eye tearing and nail discoloration—AEs we have learned to see with docetaxel. Enzalutamide seemed to increase their frequency.

What can you share regarding the quality-of-life (QoL) analysis for enzalutamide?

Stay tuned for the QoL analysis. The ENZAMET team who worked with the clinical trial center based in Sydney, Australia has done an amazing job of getting these data out and getting the publication within 3 months of the interim analysis, which is unheard of. We focused on the efficacy endpoints and the AE endpoints. The next part is to focus on the QoL analysis because it is important for us to describe the total patient experience.

What is your takeaway message for those who are treating patients with metastatic hormone-sensitive prostate cancer?

I look at their risk category: do they high-volume or low-volume [disease]? Are they fit? Are they fit enough for chemotherapy? Then, I'll lay out the options: hormone suppression and docetaxel; hormone suppression and enzalutamide, abiraterone, or apalutamide (Erleada). [The docetaxel/hormone suppression option is] based on the different side effect profiles and if the patient has some problems being on enzalutamide for 3 years or longer. [In that case], you can get the docetaxel out of the way and maybe you add the other agents at progression until we find out that there is a clear benefit for doing it all concurrently. That is to be determined.

Otherwise, if the patient is not fit for chemotherapy and has low-volume disease, they can choose from testosterone suppression with abiraterone, enzalutamide, or apalutamide.


Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. J Clin Oncol. 2019;37(suppl; abstr LBA2).

First CDK4/6 Inhibitor to Improve Survival in Metastatic Breast Cancer

First CDK4/6 Inhibitor to Improve Survival in Metastatic Breast Cancer
'Striking, Wonderful' Result
Nick Mulcahy

CHICAGO — It's not often that a systemic oral therapy significantly improves overall survival (OS) in the setting of metastatic cancer.

And, in the case of CDK4/6 inhibitors for breast cancer, it was looking like one might not do so, as multiple previous trials were limited to a significant improvement in progression-free survival.


Sara Hurvitz, MD

So, understandably, there were some smiles among experts discussing the results of the MONALEESA-7 trial in premenopausal women with advanced breast cancer (abstract LBA1008) here during a press conference at the 2019 American Society of Clinical Oncology Annual Meeting.


The CDK4/6 inhibitor ribociclib (Kisqali, Novartis) plus standard-of-care endocrine therapy significantly improved OS for younger women with advanced hormone receptor-positive (HR+) breast cancer compared with endocrine therapy alone, reported lead study author Sara Hurvitz, MD, director, Breast Cancer Clinical Research, UCLA Jonsson Comprehensive Cancer Center, Los Angeles.

It is the first time that a CDK4/6 inhibitor — or any targeted therapy — has been shown in combination with endocrine therapy to significantly improve OS among women with HR+/HER2-negative metastatic disease, she told reporters.

The estimated OS rate at 42 months was 70.2% for women in the combination therapy group vs 46% for women in the endocrine therapy-only group (hazard ratio for death, 0.71; P = .009)

The new findings will be presented in an ASCO session and simultaneously published online June 4 in The New England Journal of Medicine.


The overall survival result, which was part of a planned analysis, crossed the prespecified stopping boundary for superior efficacy.

Advanced breast cancer in this younger population is a "terrible disease" due to its often aggressive nature, said Hurvitz in a meeting press statement.

Harold Burstein, MD, of Dana Farber Cancer Institute, Boston, and an ASCO expert not involved with the study told reporters that "the golden age of clinical research in oncology continues."

A theme seen in the new study and others, he added, is "that with mature and robust data, we are now seeing substantial improvements in survival with innovative drugs that are coming to market."


At a pre-meeting press event, Monica Bertagnolli, MD, chief of surgical oncology, Dana Farber Cancer Institute, and ASCO president called the results "striking and wonderful" and observed that the 42-month data amount to 3.5 years, which is "a lot" of time in advanced breast cancer.

Previously, ribociclib was approved in 2017 by the US Food and Drug Administration for use in advanced HR+ breast cancer in post-menopausal women and, in 2018, for similar use in premenopausal women on the basis of earlier progression-free survival results from this same MONALEESA-7 trial.

Charles Shapiro, MD, director of translational breast cancer research and cancer survivorship, Tisch Cancer Institute at Mount Sinai, New York City, commented on the new results: "This is going to represent a new standard of care for metastatic premenopausal women with hormone receptor-positive breast cancers."

Shapiro, who was not involved in the study, told Medscape Medical News that it is "an excellent question whether there any differences between the three CDK 4/6 inhibitors. Thus far there are no direct comparisons among them." This was a reference to palbociclib (Ibrance, Pfizer) and abemaciclib (Verzenio, Lilly) , the other members of this class of drugs.

Combination therapy in this premenopausal setting "will likely work" with other CDK 4/6 inhibitors, he added.

Agreed, said Dawn Hershman, MD, leader of the breast cancer program at Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York City, who was asked for comment.

All of the drugs in this class would probably have a similar effect "if studied using the same criteria and length of time," said Hershman, who was not involved in the study. "It's hard to believe they wouldn't," she told Medscape Medical News.

This was, in part, a reference to the fact that palbociclib was shown to improve overall survival in the PALOMA-3 trial but not significantly so. But PALOMA-3 included both post- and pre-menopausal women, who were more heavily pretreated than the women in the current trial. Indeed, in MONALEESA-7, all of the women were receiving initial endocrine therapy and only 15% had received previous chemotherapy.

However, Hurvitz defended ribociclib's newly established status in this setting during the press conference.

She said that medical oncologists have generally been "comfortable using these drugs [CDK 4/6 inhibitors] interchangeably" with these patients but, with the overall survival improvement now seen with ribociclib, other agents will have to demonstrate the same.

Study Details
MONALEESA-7 is the first trial to focus exclusively premenopausal women (< age 59 years) with advanced breast cancer who had not received prior endocrine therapy. In the trial, investigators randomly assigned 672 women to the oral therapy ribociclib or to a placebo pill. All women also received the injectable endocrine therapy goserelin, and one of three other endocrine therapies: the aromatase inhibitors letrozole or anastrozole or the selective estrogen receptor modulator tamoxifen. After a median follow-up of 34.6 months, 173 (26%) continued to receive treatment, but with 116 (35%) of the women still receiving ribociclib vs only 57 (17%) still receiving the placebo. In addition, the investigators broke down the survival data by the two types of oral endocrine therapies used in the trial. They report survival rates of 71% and 70% for women who took ribociclib in combination with tamoxifen or an aromatase inhibitor, respectively, compared with a survival rate of 55% and 43%, respectively, for women who received placebo in combination with tamoxifen or aromatase inhibitors only. No new safety signals were observed during the median of 2 years of treatment exposure in the combination therapy group, said the study authors. The study also serves another purpose for clinicians and patients, said Dana Farber's Burstein. "One of the myths that this study helps suppress is that younger [women] with ER+ breast cancer have a fundamentally different outcome than older women — actually their outcomes look very similar," he said, referring to earlier ribociclib research among postmenopausal women, including PALOMA-3 trial.

The study was funded by Novartis, makers of ribociclib. Study authors including Hurvitz have financial ties to the company and include Novartis employees. Shapiro, Hershman, and Burstein have disclosed no relevant financial relationships.

2019 American Society of Clinical Oncology (ASCO) Annual Meeting: Abstract LBA1008. Presented June 4, 2019.

N Engl J Med. Published online June 4, 2019. Abstract

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Personalized Eating: The 'New' Diet?

Heidi Nelson, MD

Perspective > Medscape
Personalized Eating: The 'New' Diet?


We have long assumed that the same "healthy" diet was healthy for everyone. But what if the food you are eating is all wrong for your body?

Welcome to personalized nutrition, an emerging field using a mix of science and technology that determines what foods are good or bad for you by designing an individualized diet. In just the past few years, the research has overturned conventional wisdom surrounding nutrition and may soon entirely collapse the monolithic dietary guidance upon which we've relied to date.

Although the definition of "personalized nutrition" is still evolving, it has been concisely described as "an approach that uses information on individual characteristics to develop targeted nutritional advice, products, or services."[1] Those "individual characteristics" can include physiologic features (eg, age, gender), fluctuating environmental factors (eg, sleep patterns, physical activity), more cutting-edge insights obtained by assessing a person's genetic or microbiome profile, or some combination thereof.

On its own, this information may not seem to have much disruptive power. Yet, using "big data" collected from thousands of people around the world to create algorithm-based prediction models has revealed surprising disparities in how individuals respond to different foods.


Eran Elinav, MD, PhD

We are only in the early stages of understanding how individuals respond to specific foods, with the best available data focusing on glycemic outcomes, yet there is considerable optimism that personalized nutrition will become an invaluable tool for helping patients decide what to include and exclude from their plates to maintain overall health and manage or prevent disease.

"We envision that in 5-10 years, one-size-fits-all diets would become obsolete and be replaced by diets that will be based on a combination of individual host and microbiome features, the medical condition to be treated, and personal preferences," said Eran Elinav, MD, PhD, a professor of immunology at the Weizmann Institute of Science in Israel, and a pioneer in the field.


State of Personalized Nutrition Science
So far, the most compelling data on the promise of personalized nutrition have come from studies incorporating the gut microbiome profile. These raise the tantalizing possibility that the information gleaned from a simple stool sample can help predict responses to specific foods.

Elinav and colleagues tested this theory in a watershed three-part study focusing on postprandial glycemic responses (PPGRs).[2] First, they enrolled 800 participants from Israel and tested glucose after every meal they consumed, confirming that PPGRs varied considerably among them, even when they ate identical foods. Next, they incorporated all the information they obtained from this cohort into an algorithm, along with other factors, such as age, weight, and microbiome profiles, and validated the algorithm's ability to accurately predict PPGRs in a separate, smaller cohort. Finally, they confirmed the algorithm's real-world value in a blinded, randomized study, in which microbiomes and clinical information were used to create customized diets for each participant based on that person's predicted PPGR to foods. The algorithm-designed diets resulted in significantly lower PPGRs. Thus, the study made a compelling case for proof of concept, validity, and applicability, all in one publication.

"Although the concept of interpersonal differences in response to food has been previously described, we believe that formulating individual host and microbiome features into dietary recommendations in a large cohort in an evidence-based manner was unprecedented and revolutionized the outlook on nutrition," Elinav said.
This is particularly important, according to Heidi Nelson, MD, who leads the Center for Individualized Medicine Microbiome Program at the Mayo Clinic in Rochester, Minnesota, and is one of the authors of this study, because it replaces the relatively uninformative averages on which nutritional advice is based with precise variable-derived predictions.


"We want to know whether someone is a low or high responder to various foods, because you can substitute high-response foods with another food, or avoid those foods entirely. We've also shown that in some cases, combining foods lowers the glycemic response. Sometimes a few almonds added into a certain food mitigated the glycemic response," she said.

Commercialization Before Validation Raises Concerns
Although these forays into personalized nutrition have garnered significant attention, concern remains that expectations for its actual application may be unrealistic at present. But commercial entities aren't waiting for more data; they have already begun marketing these tools to the general public.

DayTwo, Inc., is using the technology to provide personalized nutrition recommendations that predict a person's glycemic response to various foods. It's as simple as buying a kit and mailing in a stool sample. After testing the stool, DayTwo claims to provide access to dietary advice that can help modify outcomes ranging from weight loss and gastrointestinal symptoms (eg, bloating, constipation) to mental and immunologic health. Other companies offer broadly comparable services, but their prediction tools haven't been vetted in the peer-reviewed literature to the same level.[2]

Several personalized nutrition companies—for example, Habit, GenoPalate, Nutrogenomix, and Profile—focus on DNA testing. Though they differ in their offerings, the basic pitch is the same. Consumers purchase a kit, either through the mail or at a brick-and-mortar location, which they use to provide blood samples and/or cheek swabs. The kits are sent to the companies, which then analyze the person's genotype and phenotype and compare them against established genetic markers. Consumers are informed what foods are right for them based on their predicted ability to metabolize them, which nutrients they should be seeking and avoiding, and what is likely to result in the most weight loss. Advice comes in printed reports or on digital apps, right down to personalized recipes.

These kits range in price from $150 to $350, although add-on features (memberships, extended coaching sessions with dietitians, and foods and supplements offered by the companies) are also available. These companies are doing more than selling a one-time curiosity product; they are establishing relationships with consumers to provide long-term health advice. The model is some combination of genetic information providers, such as 23andMe or Ancestery.com, and popular weight-loss institutions, such as Jenny Craig or Weight Watchers. It's easy to envision why this would be intriguing to both consumers and investors. However, their websites are often vague about what they can provide or the science underlying their services.
"My discomfort is that these proprietary methods have gone into full commercialization before any real validation has occurred," said Alexander Khoruts, MD, a scientific advisory board member for the American Gastroenterological Association Center for Gut Microbiome Research & Education and medical director of the Microbiota Therapeutics Program at the University of Minnesota in Minneapolis.

Other researchers are similarly dismayed by the claims some companies are making in the absence of large-scale validation studies.

"Personalized nutrition services should be scrutinized," said Elinav. "Constituents other than glucose, such as fat, protein, vitamins, and minerals, should be taken into account in dietary planning. Food allergies and other individual considerations shouldn't be overlooked. Blindly following automated reports is never advisable."

They are also largely in agreement about the key limitations of personalized nutrition research to date. Khoruts identified one of the lingering issues to be the lack of standardization among testing kits. Elinav agreed with this characterization, noting that whereas standardization has been achieved in his own model, it is a bigger concern with more inadequately studied direct-to-consumer kits.

How Personalized Nutrition Can Realize Its Potential
Nonetheless, Khoruts acknowledges that because of these direct-to-consumer services, physicians are likely to encounter more patients asking about them.

"Gastroenterologists are seeing patients who bring in these reports to the office, because the companies are marketing directly to consumers. They have pretty websites that promise a lot," he said.

The trouble is that the reports are difficult to explain to patients, even for an expert such as Khoruts. For those incorporating microbiome analyses, patients are often told whether their profiles are within ranges considered normal, when in fact sufficient analyses have not yet been provided to establish these ranges convincingly. This means these reports offer little actionable advice for physicians to work with, although Khoruts does see their value in simply generating productive interactions with patients.

"If patients are engaged and are doing some of this research on their own to seek answers, it is also an opportunity for a physician to engage in conversation with the patient."

Elinav added that reports generated by a personalized nutrition company should never replace common sense. "They should be integrated into the armamentarium of physicians and medical personnel as an auxiliary evidence-based means to enhance precision in dietary planning," he said.

Regardless of these current limitations, the potential to use this research to inform diagnosis and treatment is considerable, given the microbiome's hypothesized role in so many elements of human health, such as cancer progression, infection susceptibility, inflammatory bowel disease, neurologic disorders, and metabolic conditions, said Elinav.

Nelson added that perhaps the most important thing to remember is that this is a young field of science that will take time to sort out.

To fulfill its promise, more well-designed studies of the type conducted by Elinav, Nelson, and others are needed, and perhaps a little less of the hype coming from the commercial side of this field.

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Dr. Rubens Riotorto Bellomo Medical Oncologist CV

Dr. Rubens Riotorto Bellomo
Medical Oncologist

Medical Oncologist
Compassionate and dedicated professional with extensive experience diagnosing and treating cancer across hospitals and clinical settings. Well-versed in improving patient’s lives, delivering palliative care, interfacing with radiotherapy team, and recommending effective medical oncology treatments regarding bowel, breast, and lung cancer. Proficient in meeting co-ordination, budgeting, consultancy services, case, personnel, and project management. Possess multi-lingual proficiencies in Spanish, English, French, Italian, and Portuguese.

Professional Experience
CHU UCL Louvain, Dinant
Medical Oncologist, 2018
Headed departmental functions at the Day Medical Hospital to accomplish bottom-line results. Assisted four multi-disciplinary meetings regarding breast, gynaecology, colon, and dermatology with St. Elizabeth and Mt. Godinne centres.
Provided robust consultancy services to patients.
Managed patients’ medical oncology treatments.
Genesis Care Group, Spain
Medical Oncologist, 2015–2018
Recommended treatments to cancer patients at Algeciras Clinic in Radon Clinic Algeciras. Discussed patients’ condition with radiotherapy team and proposed RT treatment by interfacing with radiotherapist specialist at Algeciras Clinic.
Conducted follow up visits to oncologic outpatients with all solid tumours and newly cancer patients at Quore Clinic.
Attended weekly MDT meeting and mentored admitted oncologic patients across Clinica La Salud Cadiz.
Clinica Diagonal, Barcelona, Spain
Medical Oncologist, 2012–2015
Delivered solid tumours and chemotherapy services to newly diagnosed cancer patients. Controlled toxicity management. Participated in multi-disciplinary meeting and discussed oncologic patients’ history with general surgeon, radiologist, pathologist, internal medicine, psycologist, and nurse.
Managed solid tumours service with follow up visits.
Hospital Santos Reyes, Aranda de Duero, Burgos
In charge - Tumor Registry, 2010–2011
Gathered and upheld appropriate diagnostic, therapeutic, and survival data on patients with neoplastic diseases while attending regular meetings of the central Tumor Registry in Burgos.
Technical Commission, Spanish Association against Cancer, Melilla, Spain
President, 2008–2009
Provided expert opinion to board of directors on technical aspects of actions of Association.
Hospital Comarcal de Melilla, Spain
Medical Oncologist, 2006–2009
Saw patients with all solid tumors at a Day Hospital to give all medical oncology treatments available at Hospital on a daily basis. Administered patients with follow up visits and newly diagnosed cancer patients. Managed all the patients with an oncologic diagnosis admitted at Hospital and supervised inpatient chemotherapy, toxicity, and palliative care. Oversaw admissions and review of internal medicine patients admitted to Hospital with all internal medicine pathology. Managed all kind of emergency patients including children.
Credited for providing oncology service to about 85K inhabitants within a city.
Additional Experience:
Consultant Assistant, USP Dexeus University Institute, Barcelona | Hospital of Barcelona, Assistencia Sanitaria
Committee Member, Tumor Committee, Hospital Santos Reyes, Aranda de Duero, Burgos
Member of the Breast Pathology Unit, Hospital Santos Reyes, Aranda de duero
Medical Oncologist, Hospital Santos Reyes, Aranda de Duero, Burgos, Spain
Secretary, Tumor Registry Commission, Hospital Comarcal de Melilla, Spain
Medical Oncologist, Asociación Española Primera de Socorros Mutuos, Montevideo, Uruguay
Director, National Institute of Oncology, Ministry of Public Health, Montevideo Uruguay
Committe Member, Comisión Honoraria de Lucha contra el Cancer, Montevideo, Uruguay
Head of Department, Department of Medical Oncology, Instituto Nacional de Oncología, Montevideo Uruguay
Commitee Member, Central Tumor Comittee, (Dirección General de la Administración de Servicios de Salud del Estado), Ministry of Public Health, Montevideo, Uruguay
Committee Member, Advisor Committe for purchases of Antitumor medications, Instituto Nacional de Oncología, Montevideo, Uruguay
Medical Advisor, Anti- tumor National medication Bank, Instituto Nacional de Oncología, Montevideo Uruguay
Advisor, Technical education for Professionals, Comisión Honoraria de Lucha contra el Cáncer, Montevideo, Uruguay
Committee Member, Climateric Commission Ministry of Public Health, Montevideo, Uruguay
Head of Department, Chemotherapy Service, Instituto Nacional de Oncologia
Designed Medical Doctor, Instituto Nacional de Oncología

Education & Credentials
Medical Oncology
Graduate School of Facultad de Medicina de la República Oriental del Uruguay – Montevideo Uruguay
homologation diplomes In Spain, UK and Belgium
Degree of Medical Doctor
Universidad de la República Oriental del Uruguay –Montevideo Uruguay
homologation diplomes In Spain, UK and Belgium
Professional Development Program for Goverment Employees of Oficina Nacional del Registro Civil
Honorary Collaborator, Immunology Department, Facultad de Química, Montevideo Uruguay under the Supervision of Fernando Goñi in the area of Immunoglobulins & Cancer
Aguarded with a scholarship by Insituto Nacional de Oncología and Comisión Honoraria de Lucha contra el Cáncer at the INSTITUT CURIE of Paris reporting to Prof. Dr. Pierre Pouillart
Courses & Conferences Attended
European Congress 2018 Munich, Germany; European Cancer Congress 2017, Madrid, Spain; ESMO Congress, Copenhagen, Denmark; VI Symposium SOGUG (Spanish Genitourinary Group); Vienna, European Cancer Congress 2015 (ECC 2015); V Symposisum SOGUG; Madrid. ESMO Congress; Madrid, IV Symposium SOGUG; 15th World Congress On Gastrointestinal Cancer, Barcelona; Praga, Prostate Cancer up to date. AGUCC Congress; Updates on Cancer. Dr. Díaz Rubio, Madrid; Intrernational Meeting in Cambridge: Advances on Brest Cancer, UK; 5th EAN- EGFR Advisors Network Meeting, Netherlands

Professional Associations
Member: Spanish Oncology Genitourinary Group, European Society of Medical Oncology, Sociedad Española de Oncología Médica

Publication
1. 1995 ASCO Annual Meeting Abstract N: 730. Authors: E Lasalvia, S Cuchi, T Carlevaro, J Vazquez, R Riotorto, L Fierro, Antimetastatic effect of a blood fraction from cancer patients (Meeting Abstract). 2006.
2. Phase II, open-label, randomized study (SIGN) of single agent Gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) nbon-small-cell lung cancer. Cufer T; Vrdoljak E; Gaafar R; Erensoy I; Pemberton K; on behalf of the SIGN study proup, Principal resercher for Uruguay. Fase II Gefitinib.
3. Anales de Otorrinolaringología del Uruguay, Tomo LXXXI-2004-29 Importancia del Factor de Crecimiento Epidérmico en Oncología. Caso Clínico. Authors: Falconi E; Riotorto R, García E.
4. Communication in the 57 Congress of the National Society of Spanish Hospital Pharmacy. “Usefulness of Cystatin C for Therapeutic Drug Monitoring of Amikacin in an Oncologic Patient”. Authors: Rebollo Díaz N; Moreno Gómez AM; Revilla Cuesta N; Riotorto Bellomo RE; Cepeda Piorno J.Rubens Riotorto Bellomo
Anhée
ruriotorto@gmail.com  +32460977053
Personal Details:
March 3rd, 1955  Montevideo  Spain
4. Male  Spanish Citizenship

IBM Watson Oncology: Not Living Up to Expectations

IBM Watson Oncology: Not Living Up to Expectations
Roxanne Nelson, BSN, RN

August 15, 2018

If it sounds too good to be true, then maybe it is.

Such seems to be the case with IBM Watson, which has been aggressively marketed as a tool to assist oncologists in selecting the optimal treatment regimen for their patients.

However, some of its recommendations for cancer treatment have been questionable, according to a new investigative report by STAT, which suggests it is not yet ready for prime time. Internal IBM documents, which STAT had access to, showed that Watson often gave erroneous cancer treatment advice and that company medical specialists and customers identified "multiple examples of unsafe and incorrect treatment recommendations" at the same time that IBM was promoting its supercomputer to hospitals and physicians across the globe.

The report certainly gives oncologists pause for thought, and maybe second thoughts before enlisting the help of Watson.

With an almost never ending series of new biomarkers and mutations being detected and a dazzling array of new therapies pouring out of the pipeline, choosing a cancer treatment regimen can take an arduous amount of time.

In a recent report, the supercomputer was shown to significantly speed up the process of analyzing whole-genome sequencing, which is a "key bottleneck in cancer genomics." It took IBM Watson 10 minutes to come up with conclusions that were similar to those reached by a team of experts after 160 hours of analysis.

However, when implemented in real-world oncology settings, Watson fares less well, according to the STAT report. Part of the problem appears to stem from how the system was trained. IBM's internal documents largely blame the problems on the training of Watson by IBM engineers and oncologists at Memorial Sloan Kettering Cancer Center in New York City, who had been tapped to train Watson in 2012. The resulting software was drilled with a small number of "synthetic" cancer cases, or hypothetical patients, instead of real patient data. Thus, Watson was trained on the basis of the expertise of a few specialists for each cancer type, rather than from guidelines or evidence.

STAT also noted that product information posted on the IBM website implies that Watson is continuing to be trained using real patient data and says that the supercomputer "analyzes patient data against thousands of historical cases and insights gleaned from thousands of Memorial Sloan Kettering MD and analyst hours." However, the number of cases for each of the eight cancers that are covered is a small fraction of the grand total, which ranges from 635 cases for lung cancer to 106 for ovarian cancer.


Gloom and Doom?
The Wall Street Journal recently issued its own report about IBM Watson, saying that despite the initial promise and hype, "six years and billions of dollars later, the diagnosis for Watson is gloomy."

Echoing some of the concerns brought up in the STAT articles, the Wall Street Journal notes that in many cases, the tools did not add much value, and in other cases, Watson was inaccurate. Some problems were that Watson could be "tripped up" by a lack of data for rare or recurring cancers and that treatments were evolving faster than Watson's human "trainers" were able to update the supercomputer. They also pointed out that thus far, there is no published research demonstrating that Watson has improved patient

Watson for Genomics has been piloted at a number of US cancer centers, but according to the Wall Street Journal, physicians at several centers have reported that results were not always accurate, and when they were, it was often information that oncologists already knew.

"The discomfort that I have — and that others have had with using it — has been the sense that you never know what you're really going to get...and how much faith you can put in those results," Lukas Wartman, MD, of the McDonnell Genome Institute at the Washington University School of Medicine in St. Louis, Missouri, told the newspaper. He also said that even though he has complimentary access to Watson, he rarely uses it.

IBM Responds
IBM has taken issue with the negative media reports that were published recently. It singled out the Wall Street Journal article specifically.

In an article entitled "Watson Health: Setting the Record Straight" posted on the company website, John E. Kelly III, MD, IBM senior vice president, Cognitive Solutions and IBM Research, writes that the media reports distort and ignore facts when they suggest that IBM has not made "enough" progress in bringing the benefits of artificial intelligence (AI) to healthcare.


"It is true, as the article reports, that we at IBM have placed a big bet on healthcare," Kelly writes. He says that IBM has done this for two reasons: "AI can make a big difference in solving medical challenges and supporting the work of the healthcare industry," he writes, and also there is an "enormous business opportunity in this area as the adoption of AI increases." IBM has built three distinct cancer tools, Kelly notes:

Watson for Oncology, which offers treatment recommendations/options that can augment an oncologist's own expertise,

Watson for Clinical Trial Matching, which helps match patients to clinical trials, and

Watson for Genomics, which uses genetic sequencing to provide information that can be used to personalize treatment for cancer patients.

"Together, they are now in use at 230 hospitals and health organizations globally and have nearly doubled the number of patients they've reached in the first six months of the year to 84,000," he writes.

Kelly also addresses the allegation that there has been no benefit to patients. "To suggest there has been no patient benefit is to ignore both what we know the Wall Street Journal was told by a number of physicians around the world and these institutions' own public comments — which we believe speak for themselves," he writes.

These were the examples that Kelly listed to support this statement:

Mayo Clinic physicians presented a poster at the annual meeting of the American Society of Clinical Oncology in which they reported that Watson for Clinical Trial Matching boosted enrollment in breast cancer trials by 80%, to 6.3 patients/month, up from 3.5 patients/month, during an 18-month period following its implementation.

Thaddeus Beck, MD, and colleagues at the Highland Oncology Group in Arkansas reported that Watson Clinical Trial Matching reduced the time for clinical trials matching by 78%.

Mark Kris, MD, and oncologists at the Memorial Sloan Kettering Cancer Center have helped to train Watson for Oncology regarding 13 cancers that represent 80% of global cancer incidence and prevalence.

S. P. Somashekhar, MBBS, and Manipal Hospital, Bangalore, India, reported a 93% concordance rate in breast cancer for their multidisciplinary tumor board in an article published in the Annals of Oncology earlier this year. They recently stated that their multidisciplinary tumor board uses Watson for Oncology for all of their complex cases and that it is changing their treatment recommendations in 9% to 11% of cases.

Michael Kelley, MD, and the Department of Veterans Affairs recently extended their contract for Watson for Genomics. Thus far, nearly 3000 veterans with stage IV cancer have been supported by this tool.

William Kim, MD, and the University of North Carolina Lineberger Cancer Center, Chapel Hill, reported that Watson for Genomics found new, actionable mutations in 32% of patients.

Oncologist Dilemma
So what should oncologists do with the extra information provided by the supercomputer?

Approached for comment, Nigam Shah, MBBS, PhD, associate professor of medicine and biomedical data science at Stanford University, California, said that he doesn't think there is much to debate about, given that the system is not being trained using real patient data.

"If I was an oncologist, I'd want to see their system validated in the same way we validate other interventions in medicine, such as with a prospective study, either with or without randomization, depending on the nature of the intervention," Shah told Medscape Medical News.

As an example, he suggested that a medical center could run IBM Watson in silent mode. The computer would be asked to assess and opine on every case the medical center sees. Its recommendations would be recorded, but not acted upon. The center would then assess how often Watson's recommendations corresponded with what the physicians did. "If that test establishes safety, then I'd start showing the recommendations and acting on them," Shah said, "then follow patients over time to see if those that got a Watson-generated recommendation did better than those who didn't."

But for now, he reiterated that if he were a practicing oncologist, "I'd just ignore the noise and chatter and wait for more proof points."


Shah added that IBM Watson should clearly disclose the data upon which the system is trained. "Any AI system is only as good as the data it gets to train on," he explained. "If the system is trained on idealized patient records generated by a small set of doctors, it is improper to say it is trained from real patient data at Sloan Kettering."

Michael Hogarth, MD, a professor in the Division of Biomedical Informatics, Department of Internal Medicine, the University of California, San Diego, said that although he is not a legal expert, he believes that there is a fair amount of case law that indicates that the physician using such a system is fully responsible for its use (ie, the system itself is not culpable).

"This is no different than a physician relying on a reference textbook that has misprinted or wrongly characterized something and using that information and having a bad patient outcome as a result," he explained. "Ultimately, the treating physician is 'always' responsible for the decision making — they can't blame a computer, journal article, or book for making them do the wrong thing."

Hogarth noted that he and many others in his discipline of health informatics were a bit skeptical of IBM when the company claimed Watson could improve oncologist decision making. Essentially, the reason is that specialists such as oncologists are experts in their fields, and some are "super experts" regarding specific conditions within their discipline and treat only patients with those conditions.

Such specialization has become very common in healthcare. It has been shown that clinical decision support systems tend to offer the most assistance to physicians who are not specialists of the condition at hand. "The more 'general' the physician, the more a clinical decision support system focused on specialized content — like IBM Watson Oncology — might surface up information that is not known by that physician," explained Hogarth. "When it comes to specialists, the amount of relevant knowledge is less overwhelming for the specialist, who has less to retain, since they don't have to know everything about every health condition and only need to know about the conditions they see in their specialty."

Hogarth added that the most concerning thing is that there is much talk about "machine learning" tools being used at the bedside for diagnosis and treatment decision making. "That's fine, but they still need to be validated," he emphasized. "Many of them are built using data from EHRs [electronic health records], and a lot of that data is incomplete in terms of knowing everything about a patient, since many patients get care in multiple health systems, so nobody has a complete record on them."

The notion of validating machine learning–based diagnostic aids is just starting to be discussed. "The question is whether it should be regulated as a medical device," he said.

Another physician who was approached for comment cautioned that oncologists need to be aware of where Watson's data are coming. "One thing that has to be emphasized is that Watson's output suffers a huge bias related to the fact that it's all Memorial Sloan Kettering doctors who are training Watson," David H. Gorski, MD, PhD, professor and chief, Breast Surgery Section, Wayne State University School of Medicine, Detroit, Michigan, told Medscape Medical News.

"That means Watson is basically the MSKCC way, which might or not be the right way in every case," he explained. "Remember, academic physicians approach the medical literature with their own biases and interpret it in light of them, and that's why we can see differing recommendations coming from different institutions."

He added that that is also why he wishes that there was a much broader base of physicians training Watson and feeding it studies. "In the end, Watson is a tool, nothing more," said Gorski. "It's a recommendation for treatment that suffers all the flaws of the medical literature and the specific doctors who taught it how to derive recommendations from that literature.


"If a doctor keeps that in mind and isn't afraid to overrule Watson when he or she thinks it's wrong," he added, "it certainly can be potentially useful."

Not Ready for Prime Time
STAT published an article in September 2017 about some of the problems that IBM was having with Watson. It reported that Watson was "still struggling with the basic step of learning about different forms of cancer. Only a few dozen hospitals have adopted the system, which is a long way from IBM's goal of establishing dominance in a multibillion-dollar market."

For that article, STAT conducted numerous interviews with various stakeholders, including physicians, IBM executives, and experts in AI. It also assessed its use, marketing, and performance in hospitals across the globe. The interviews suggested that "IBM, in its rush to bolster flagging revenue, unleashed a product without fully assessing the challenges of deploying it in hospitals globally," and as a result, "its flaws are getting exposed on the front lines of care by doctors and researchers who say that the system, while promising in some respects, remains undeveloped."

"Watson for Oncology is in their toddler stage, and we have to wait and actively engage, hopefully to help them grow healthy," said Taewoo Kang, MD, a South Korean cancer specialist who has used the product and was quoted in the STAT article.

Earlier this year, IBM confirmed rumors of company layoffs, but denied that the cuts affected 50% to 70% of the workforce at its Watson Health operation, as had been reported. IBM has not reported the actual number of layoffs.

"IBM is continuing to reposition our team to focus on the high-value segments of the IT market, and we continue to hire aggressively in critical new areas that deliver value for our clients and IBM. This activity affects a small percentage of our Watson Health workforce, as we move to more technology-intensive offerings, simplified processes, and automation to drive speed," IBM told Medscape Medical News in a statement earlier this year.

Hogarth commented in an interview with Medscape Medical News: "I understand that IBM Watson has laid off/moved many technical staff that were working on IBM Watson Health, so I think they discovered it was not as easy as they thought, plus actually improving decision making is not a trivial maneuver.... It involves many factors beyond just supplying summarized information."

Hogarth believes that had IBM put its sights on a more modest goal, it could have achieved it. The bar that IBM set Watson Health, as well as its expectations, were quite high and were perhaps misplaced or mistargeted. "Instead of creating a system for oncologists, they probably should have focused on a system that can assist general internists, family physicians, and other midlevel extenders and focused its help on patients with enigmatic diagnoses or patterns of symptoms and signs that are not frequently seen by generalists," he said. "That is where an engine like IBM Watson can potentially provide significant value."

IBM recently reported that it will be modifying its Watson software to better reflect geographic differences in cancer treatment, according to the most recent article from STAT about this topic. To date, Watson Oncology has made the most headway in Asia, and most of the hospitals currently using Watson are based outside of the United States. Some physicians have complained that Watson's "decisions" do not reflect treatment protocols in their country and have expressed dissatisfaction with its American bias, that article reports.

At an internal meeting for Watson Health employees worldwide, IBM announced that it would begin using data from real patients for the first time, and it recommended that treatments incorporate more localized treatment advice.

Metformin in cancer prevention and therapy

Ann Transl Med. 2014 Jun; 2(6): 57.
doi: 10.3978/j.issn.2305-5839.2014.06.01
PMCID: PMC4200668
PMID: 25333032
Metformin in cancer prevention and therapy
Jacek Kasznicki,corresponding author Agnieszka Sliwinska, and Józef Drzewoski

Abstract
The prevalence of diabetes is dramatically increasing worldwide. The results of numerous epidemiological studies indicate that diabetic population is not only at increased risk of cardiovascular complications, but also at substantially higher risk of many forms of malignancies. The use of metformin, the most commonly prescribed drug for type 2 diabetes, was repeatedly associated with the decreased risk of the occurrence of various types of cancers, especially of pancreas and colon and hepatocellular carcinoma. This observation was also confirmed by the results of numerous meta-analyses. There are however, several unanswered questions regarding the exact mechanism of the anticancer effect of metformin as well as its activity against various types of cancer both in diabetic and nondiabetic populations. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin and preclinical and clinical data suggesting its anticancer effect in different populations.


The prevalence of diabetes is dramatically increasing worldwide reaching epidemic proportion. Landmark of diabetes, chronic hyperglycemia leads to the development and progression of life-treating complications, predominantly cardiovascular. The results of several studies indicate that people with diabetes (mainly type 2, T2DM) are also at substantially higher risk of cancer of the pancreas, liver, endometrium, breast, colon, rectum and urinary bladder compared to individuals without this chronic disease (1).

However, the incidence of other types of cancer (e.g., lung, kidney, non-Hodgkin lymphomas) does not seem to be strongly associated with diabetes or the evidence is inconclusive (2). Interestingly enough, it has been suggested that diabetes is associated with a lower risk for prostate cancer (2,3). According to the American Diabetes Association and the American Cancer Society consensus report the relative risks imparted by diabetes are greatest (about two fold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (about 1.2-1.5 fold) for cancers of the colon and rectum, breast, and bladder (2).

Clinical observations indicate that the prevalence of diabetes in newly diagnosed cancer patients ranges from 8% to 18%, suggesting bidirectional association between these two disease (4,5). The association of diabetes and cancer was first reported as an incidental finding in 1932 (6). Nowadays, this coexistence is well recognized, however in spite of the intensive studies its mechanism still remains unclear. There is a general agreement that T2DM and cancer share several common potential risk factors (e.g., aging, sex, obesity, physical inactivity, diet, alcohol, and smoking).

In T2DM, insulin resistance and hyperinsulinemia (either endogenous due to insulin resistance or induced by administration of exogenous insulin formulations) are considered to be independent risk factors for cancer development (1,2). In addition, hyperglycemia-related oxidative stress, accumulation of advances glycation end products as well as low-grade inflammation may also enhance the risk of malignant transformation (7,8).

Recent publications have also suggested the link between hypoglycemic medications and cancer (8-11). The results of numerous preclinical, epidemiological and clinical studies suggested that metformin use is associated with inhibition of cancer cell growth and proliferation and reduction in all-cancer incidents in comparison with users of other hypoglycemic drugs. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin as well as preclinical and clinical data suggesting this beneficial effect.


Molecular action of metformin in cancer cell
The current proposed anticancer molecular action of metformin is mainly associated with the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). The mTOR pathway plays a pivotal role in metabolism, growth and proliferation of cancer cell (12). Metformin is thought to inhibit mTORC1 pathway (Figure 1).

It is believed that systemic effect of metformin manifested by the reduction of circulating level of insulin and insulin-like growth factor 1 (IGF-1) might be associated with anticancer action (13).

Insulin/IGF-1 is involved not only in regulation of glucose uptake but also in carcinogenesis through upregulation of insulin/IGF receptor signaling pathway (14).
The excessive food consumption (insulin) leads to increased liver production of IGF-1 that binds to IGF-1 receptor and insulin receptor.
Then, through insulin receptor substrate (IRS) the signal is transmitted to phosphoinositide 3-kinase (PI3K), and Akt/protein kinase B (PKB) that indirectly activates (not phosphorylates) mTORC1.
Additionally, insulin receptor through growth factor receptor-bound protein 2 (GRB2) propagates signal to Ras/Raf/ERK pathway that drives cell growth. Evidences indicate that these pathways play important role in changes of cellular metabolism that are typical feature of tumor cells (15).
Increased levels of circulating insulin/IGF1 and upregulation of insulin/IGF receptor signaling pathways were demonstrated to be involved in the formation of many types of cancer.
Metformin was found to reduce insulin level, inhibit insulin/IGF signaling pathways, and modify cellular metabolism in normal and cancer cells (16).

Evidences suggest that the inhibition of mTOR pathway by metformin proceeds dependent and independent on AMP-activated protein kinase (AMPK) activation.
AMPK phosphorylates tuberous sclerosis complex protein 2 (TSC2) that inhibits mTORC1 leading to decrease in protein synthesis and cell growth (17).
Among the first studies that showed the participation of AMPK activation in antitumor action of metformin were researches performed on breast cancer cells (18,19). Dowling et al. showed that compound C, an inhibitor of AMPK, reversed inhibition of initiation of translation evoked by metformin (18).
More recently, Mohammed et al. showed reduction of carcinoma spread in pancreas of transgenic mice fed with metformin (20). Additionally, pancreatic tissue of mice fed with metformin revealed a significant inhibition of mTOR, and an increase of phosphorylated AMPK and TSC2 (20). However, Gwinn el al. demonstrated that inhibition of mTOR could be independent on TSC2, since AMPK directly phosphorylates the rotor compartment of mTOR (21).

Several studies identified that liver kinase B1 (LKB1), a major upstream kinase of AMPK, may be involved in anticancer action of metfromin associated with inhibition of mTOR. In vitro and in vivo studies revealed that deletion of LKB1 function accelerated proliferation of tumor cell and sensitized them to activators of AMPK such as biguanide (22-24).
Due to the fact that p53 expression and phosphorylation is regulated by AMPK and p53 is involved in cell metabolism and control of cell cycle its participation in metformin action is discussed.
Growing evidences from in vivo and in vitro studies of various cancers revealed that metformin blocked cell cycle in G0/G1 phase with a significant decrease expression of G1 cyclins (including cyclin D1) without changes in p53 status (25-27).
However, others researches indicated that inhibitory effect on cancer cell growth of metformin was associated with p53 activity (28-31).
Taking together the results of preclinical studies are inconclusive whether antitumor action of metformin is associated with p53. Some investigators hypothesize that the dose of metformin may determine the effect of metformin. Yi et al. demonstrated on hepatoma cells that low concentration of metformin induced p53-dependent senescence, whereas higher doses induced apoptotic cell death (32).

Inhibition of mTOR by metformin independent on AMPK activation was demonstrated by Memmott et al. in mice lung cancer cells (16). Metformin evoked inhibition of mTOR pathway with accompanied decreasing activation of IGF-1/insulin receptor, Akt, extracellular signal-regulated kinase (ERK) without AMPK activation (16).
Kalender et al. demonstrated in Drosophilla cells that inhibition of mTOR signaling induced by metformin occurred in the absence of AMPK. They reveal the existence of an alternative TSC1/2-mTOR AMPK-independent pathway mediated by RAG GTPase (33).
Metformin was found to inhibit breast carcinoma cell growth through decreasing level of epidermal growth factor receptor 2 (HER2). This effect was mediated by inhibition of the mTOR effector, p70S6K1 (34).
p70S6K is responsible for the phosphorylation of S6 ribosomal protein and thereby protein synthesis at the ribosome (35). Antiproliferative action of metformin related to enhancement of DNA-damage-inducible transcript 4 protein (DDIT4, REDD1) expression, a negative regulator of mTOR, was reported in prostate cancer cells by Ben Sahra et al. (36).
This effect of metformin was also independent on AMPK activation (36).

The results of preclinical studies undoubtedly confirm the efficacy of metformin to inhibit cancer cell growth in vitro and to reduce tumor spread in animal models of various cancers. However, it should be stressed that molecular action of metformin is still investigated and seems to be affected by the type of tumor cell line.

Vitamin D Does Not Prevent Cancer

Medscape Medical News > Oncology News
Vitamin D Does Not Prevent Cancer: Study
Kristin Jenkins

July 24, 2018


The latest study on whether vitamin D can prevent cancer is negative, but there have been many such trials, and the findings have been contradictory.

The latest results come from New Zealand and are based on a post hoc analysis of the Vitamin D Assessment (ViDA) study, which involved 5108 community participants. The primary purpose of the ViDA study was to investigate cardiovascular outcomes.

It found that taking high doses of vitamin D for up to 4 years without calcium was not associated with reductions in cancer incidence or cancer mortality.

The cumulative incidence of cancer during a median follow-up of 3.3 years was 6.5% for those who received 100,000 IU of vitamin D3 each month. By comparison, the cumulative incidence of cancer during the same period was 6.4% among participants who received placebo (adjusted hazard ratio [HR], 1.01; P = .95).


"Monthly high-dose vitamin D supplementation may not be associated with cancer prevention and should not be used for this purpose," say Robert Scragg, MBBS, PhD, of the University of Auckland, and colleagues.

The report was published online July 19 in JAMA Oncology.

Scragg and colleagues note that other randomized clinical trials of vitamin D supplementation have provided inconsistent results. They point out that these latest results on cancer incidence are consistent with findings from previous randomized clinical trials of community samples from the United States and the United Kingdom, and they are also consistent with the results from a recent meta-analysis of vitamin D supplementation trials.

Considerable Interest
Approached for comment, Carolyn Y. Fang, PhD, coleader of Cancer Prevention and Control at Fox Chase Cancer Center in Philadelphia, Pennsylvania, said that in spite of the current study's null findings, "there is still considerable interest in the possible connection between vitamin D and cancer."


Clinicians should talk to patients who have vitamin D deficiency about how they can make healthy dietary or behavioral changes and whether taking a vitamin D supplement is warranted, Fang told Medscape Medical News.

"However," she added, "from a population health perspective, key questions regarding the appropriate 'dosage' of vitamin D for cancer prevention and how long one might need to take this dose in order to positively impact health remain to be addressed."

Conflicting Results
Results of previous studies on whether vitamin D can reduce cancer risk are conflicting.


In the largest and most comprehensive observational study to date, an international research group concluded that vitamin D was unlikely to provide primary prevention of lung cancer, even in nonsmokers.

Prior to that, the SUNSHINE study showed that high-dose vitamin D supplementation significantly improved progression-free survival in patients with advanced colorectal cancer who were receiving chemotherapy.

Last month, results from an international collaborative meta-analysis indicated that higher vitamin D levels in the blood may protect against colorectal cancer, especially in women.


In 2016, a literature review that included 28 new meta-analyses and 100 trials published between 2013 and 2017 revealed evidence that 10 to 20 μg daily of vitamin D can reduce death from any cause and death from cancer in middle-aged and older adults.

Study Details
The ViDA trial was a randomized, double-blind, placebo-controlled clinical trial that was conducted from March 1, 2011, to July 31, 2015. The primary outcome was the effect of vitamin D supplementation on the incidence of cardiovascular disease, but it also assessed possible effects related to acute respiratory infection, falls, and nonvertebral fractures.

Scragg and colleagues comment that findings from an earlier meta-analysis suggested that vitamin D supplements were "associated with a reduction in cancer mortality, but not cancer incidence."


The ViDA study participants were recruited from 55 family practices in Auckland. The mean age of the participants was 66 years, 58% were male, and 83% were of European or other race/ethnicity. The rest of the participants were of Polynesian or South Asian descent.

Of the participants, 320 (6.3%) used tobacco, and 2173 (42.5%) reported that they had formerly been smokers.

Some 1214 (23.8%) participants said they had been previously diagnosed with cancer. Cancer cases were evenly distributed between the two arms — of 2558 participants in the vitamin D group, 622 (24.3%) had been previously diagnosed with cancer, compared to 592 of 2550 (23.3%) patients in the placebo group.


Participants in the vitamin D group received an initial bolus of 200,000 IU of oral vitamin D3 followed by monthly doses of 100,000 IU. All participants were followed for up to 4.2 years.

At baseline, the mean concentration of deseasonalized 25-hydroxyvitamin D (25[OH]D) was 26.5 ng/mL. At follow-up, the mean concentration in a random sample of 438 participants was consistently higher than 20 ng/mL in participants taking vitamin D compared to those taking placebo.

The study showed that in 375 participants who were diagnosed with cancer after randomization, there were no differences in the percentage taking vitamin D vs placebo. The most common cancers included melanoma in situ, which was diagnosed in 71 participants, and malignant melanoma, which was diagnosed in 55 participants. Prostate cancer was diagnosed in 64 participants, colorectal cancer in 38, breast cancer in 36, and lymphoid and hematopoietic cancers in 36.

There were no significant differences between men and women, between participants with serum concentrations of 25(OH)D higher than 20 ng/mL vs lower than 20 ng/mL, or in the time to diagnosis after randomization. Similar results were seen for all secondary outcomes. These were defined as all malignant neoplasms reported from more than 12 months after randomization until the study medication was discontinued on July 31, 2015.

The fact that 25% of study participants had vitamin D deficiency may have limited the statistical power in that subgroup, the researchers indicate.

Funding for the study was provided by the Health Research Council of New Zealand. Dr Scragg and study coauthors have disclosed no relevant financial relationships.

JAMA Oncol. Published online July 19, 2018. Abstract

Nivolumab: EMA Extension of Indications

EMA Recommends Extension of Indications for Nivolumab

New indication concerns the treatment of locally advanced unresectable or metastatic urothelial carcinoma after failure of prior platinum-containing therapy
Date: 24 Apr 2017
Topic: Genitourinary cancers / Cancer Immunology and Immunotherapy
On 21 April 2017, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for the medicinal product nivolumab (Opdivo).

The marketing authorisation holder for this medicinal product is Bristol-Myers Squibb Pharma EEIG.

The CHMP adopted a new indication as follows:

“Opdivo as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy.”

For information, the full indications for Opdivo will be as follows:

“Melanoma
Opdivo as monotherapy or in combination with ipilimumab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.

Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression.

Non-Small Cell Lung Cancer (NSCLC)
Opdivo as monotherapy is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer after prior chemotherapy in adults.

Renal Cell Carcinoma (RCC)
Opdivo as monotherapy is indicated for the treatment of advanced renal cell carcinoma after prior therapy in adults.

Classical Hodgkin lymphoma (cHL)
Opdivo as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin.

Squamous Cell Cancer of the Head and Neck (SCCHN)
Opdivo as monotherapy is indicated for the treatment of squamous cell cancer of the head and neck in adults progressing on or after platinum-based therapy.

Urothelial Carcinoma
Opdivo as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy.”

Summaries of positive opinion are published without prejudice to the Commission decision, which will normally be issued 67 days from adoption of the opinion.

Detailed recommendations for the use of this product will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report, and will be available in all official European Union languages after a decision on this change to the marketing authorisation has been granted by the European Commission.

Sequencing Challenges in Kidney Cancer

Agarwal Addresses Sequencing Challenges in Kidney Cancer
Caroline Seymour
Published: Tuesday, Jun 19, 2018
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Neeraj Agarwal, MD
Neeraj Agarwal, MD The FDA approval of cabozantinib (Cabometyx) in December 2017 and the subsequent approval of nivolumab (Opdivo) and ipilimumab (Yervoy) in April 2018 for the frontline treatment of patients with renal cell carcinoma (RCC) has broadened available therapeutic options for patients.

The challenge, said Neeraj Agarwal, MD, is, “sequencing and using these agents in a timely fashion, so as to optimize benefit and minimize the risk of disease progression.”

In an interview during the 2018 OncLive® State of the Science Summit™ on Genitourinary Cancers, Agarwal, associate professor, Division of Oncology, Department of Medicine, University of Utah School of Medicine, Huntsman Cancer Institute, discussed his preferred sequencing strategies for treating patients with kidney cancer, and ongoing immunotherapy research in the field.

OncLive: Can you speak to the importance of sequencing agents in kidney cancer?
Agarwal: Over the last 10 years, especially the last 3 years, multiple agents have been approved in the treatment of patients with metastatic RCC. This is great news for patients, but it also creates a lot of challenges for clinicians and oncologists.

What are the patient factors that you take into consideration in determining first- and second-line therapy?
The most important resource I use for treatment decision-making is the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors. In my view, those are presently the most commonly recognized risk factors for prognostication and drug selection. I use them for first line, second line, or later lines of therapy.

What are some unanswered questions in kidney cancer?
Until last year, the first-line agents were sunitinib (Sutent) or pazopanib (Votrient) and, for some patients, the mTOR inhibitor temsirolimus. Within the last 5 months, the FDA approved the combination of ipilimumab and nivolumab, as well as cabozantinib as a single agent, in the first-line setting. Cabozantinib was previously approved in the second-line setting.

I wouldn't be surprised if bevacizumab (Avastin) in combination with atezolizumab (Tecentriq) gets approved in the next few months. This is just a start. We are going to have more approvals in the next 2 years by combining novel checkpoint inhibitors with VEGF tyrosine kinase inhibitors (TKIs).

The field continues to evolve very quickly, which is great for patients. However, this leaves sequencing questions unanswered with so many new drugs in the first-line setting. If you look at cabozantinib, nivolumab, or axitinib (Inlyta), which are currently approved for use in the second-line setting, they have never been tested after disease progression on immunotherapy, for example.
If patients get nivolumab and ipilimumab, or bevacizumab with atezolizumab in the first-line setting, we don't know what their efficacy is in the second-line setting.
Not knowing how these agents will pan out in the second-line setting is a challenge we are facing.

How do you decide between nivolumab plus ipilimumab or cabozantinib in the first-line setting?
The combination of nivolumab and ipilimumab was superior to sunitinib in intermediate- and poor-risk patients with newly diagnosed metastatic RCC in a randomized phase III trial.
There is stronger evidence favoring nivolumab and ipilimumab in these patients.
However, if you delve deeper into the data, you’ll see that favorable-risk patients benefit more from sunitinib. Progression-free survival was highly superior to nivolumab and ipilimumab.
For those patients, a VEGF TKI remains the drug of choice.
Since cabozantinib beat sunitinib in a randomized phase II trial, cabozantinib is my drug of choice for those patients.

Let's go beyond the risk categorization. Most of the patients who had 1% or greater PD-L1 expression in their tumors seemed to derive the most benefit from the combination of nivolumab and ipilimumab.

The majority of patients’ tumors in that trial did not have high PD-L1 expression. Most of the benefit in the trial with nivolumab and ipilimumab seemed to be driven by PD-L1–expressing tumors.
In some patients, whose tumors do not express PD-L1, I do not expect to see a progression-free survival benefit with [the immunotherapy combination]. I would strongly consider cabozantinib in those patients.
Cabozantinib is already an established drug with superior efficacy to most contemporary drugs in patients with bone metastases. If I see a patient with bone metastasis, I likely give them cabozantinib.

Can you highlight some of the emerging combinations?
Within the next 2 years, we are going to see the efficacy and approval of newer combinations. Some of these include axitinib with pembrolizumab (Keytruda), in which the overall response rate has exceeded 70% or 75%. Lenvatinib (Lenvima) with pembrolizumab and axitinib with avelumab (Bavencio) are additional combinations [being explored]. We are also testing cabozantinib with atezolizumab. Dr Sumanta Kumar Pal is leading the trial, and we are fortunate to have that combination available for our patients in our clinic.

What is a key challenge that remains?
We have so many drugs and good combinations that are increasing survival with each passing year. That is fantastic news for us and our patients, but the problem is the selection of these drugs for a given patient at a given time point. We can always compare the clinical data across trials. However, there are problems with cross-trial analyses because populations can be different.

What we really need are biomarkers. We need biomarkers to predict who is going to respond, and, more importantly, who is not going to respond to a given therapy. If we have them, and we will have them in the next few years, they will allow us to optimize personalized medicine in a better fashion

Apalutamide (ARN-509),in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort

Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort
Matthew R. Smith,a,* Emmanuel S. Antonarakis,b Charles J. Ryan,c William R. Berry,d Neal D. Shore,e Glenn Liu,f Joshi J. Alumkal,g Celestia S. Higano,h Edna Chow Maneval,i Rajesh Bandekar,j Carla J. de Boer,k Margaret K. Yu,l and Dana E. Rathkopfm
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The publisher's final edited version of this article is available at Eur Urol

Abstract
Background
Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. Objective: To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).

Design, setting, and participants
We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo).

Intervention
Patients received 240 mg/d apalutamide while continuing on androgen-deprivation therapy.

Outcome measurements and statistical analysis
Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS).

Results and limitations
A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤ 7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo–not reached [NR]); median MFS was NR (95% CI, 33.4 mo–NR). Most of the patients discontinued study treatment (n = 33) due to disease progression (n = 11 [22%]) or adverse events (AEs) (n = 9 [18%]). The most common AE was fatigue (any grade, n = 31 [61%]) although grade ≥3 fatigue was uncommon (n = 2 [4%]). These represent the first apalutamide nmCRPC patient clinical data.

Conclusions
In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control.

Patient summary
Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting.

Trial registration
ClinicalTrials.gov identifier NCT01171898

Keywords: Antitumor activity, Apalutamide, Castration-resistant prostate cancer, Safety

1. Introduction
Androgen-deprivation therapy (ADT) is the standard first-line treatment for patients with metastatic prostate cancer (PCa) and a routine part of management for many men with nonmetastatic PCa. Initial ADT achieves responses in nearly all patients, although most patients progress to castration-resistant disease within a few years [1]. In men with nonmetastatic castration-resistant prostate cancer (nmCRPC), higher prostate-specific antigen (PSA) and shorter PSA doubling time (PSA DT) are associated with high risk for metastases and death [2–4]. Examining patients at regular intervals is important because patients with a short PSA DT are often found with occult metastases. National Comprehensive Cancer Network PCa clinical practice guidelines recommend more frequent bone imaging for patients with a PSA DT ≤ 8 mo [5]. To date, there are no approved treatments for nmCRPC.

Apalutamide is a potent antagonist of the androgen receptor (AR) in development for the treatment of men with CRPC as well as earlier disease including localized PCa and metastatic hormone-sensitive PCa [6]. Apalutamide selectively binds to the ligand-binding domain of AR and blocks AR nuclear translocation or binding to androgen response elements. Unlike bicalutamide, apalutamide antagonized AR-mediated signaling in AR overexpressing human CRPC cell lines [7]. In mice bearing human CRPC xenografts, apalutamide produced dose-dependent tumor regressions superior to those achieved with bicalutamide or enzalutamide [6].

On the basis of these promising preclinical results, a first-in-human phase 1/2 study was conducted (ARN-509-001) in patients with CRPC. The 18F-fluoro-α-dihydrotestosterone positron emission tomography/computed tomography imaging analysis in 16 patients with metastatic CRPC (mCRPC) indicated an optimal biologic dose of 240 mg/d of apalutamide; the phase 1 portion of the study in 30 mCRPC patients determined that a phase 2 dose of 240 mg/d was safe and well tolerated [8]. The phase 2 portion of the study evaluates apalutamide activity in three distinct patient cohorts: nmCRPC, abiraterone acetate–naive mCRPC, and post–abiraterone acetate mCRPC. We report the phase 2 results for patients in the nmCRPC cohort.


2. Patients and methods
ARN-509-001 (NCT01171898) is a phase 1/2 multicenter open-label study. Phase 1 was completed in May 2012 and the results were published [8]. Patients were enrolled into the phase 2 expansion cohorts from November 2011 to June 2012, and the study is ongoing. The review boards at all participating institutions approved the study that was conducted according to the Declaration of Helsinki, the International Conference on Harmonisation, and the Guidelines for Good Clinical Practice. All patients gave written informed consent.

2.1. Patients
All patients had histologically or cytologically confirmed PCa and had received ongoing ADT with a gonadotropin-releasing hormone analog or inhibitor, or orchiectomy (ie, surgical or medical castration). Patients in the nmCRPC cohort had no radiographic evidence of distant metastases (central nervous system [CNS], vertebral, or meningeal) as determined by central review (pelvic lymph nodes <3 cm below the iliac bifurcation were allowed). They met the following inclusion criteria: castrate levels of serum testosterone ≤50 ng/dl within 4 wk of study enrollment, an Eastern Cooperative Oncology Group performance status of 0–1, a life expectancy ≥3 mo, a corrected QT interval ≤450 ms, and adequate cardiac, renal, hepatic, and bone marrow function. The patients had a high risk for developing metastases, defined as either a PSA value ≥8 ng/ ml obtained within 3 mo prior to enrollment or PSA DT ≤10 mo. Patients were excluded if they had been treated previously with enzalutamide, abiraterone acetate, or ketoconazole, or had a history of seizures or conditions that predispose to seizures or concurrent treatment with medications known to have seizure potential.
2.2. Study design
Patients were enrolled in three cohorts: nmCRPC, chemotherapy/ abiraterone acetate–naive mCRPC, and mCRPC post–abiraterone acetate, as shown in Figure 1 [8]. This study focuses on the high-risk nmCRPC expansion cohort. Patients received apalutamide 240 mg/d based on the biologically efficacious dose established in the phase 1 study [8]. Patients with nmCRPC received continuous daily dosing until disease progression defined as evidence of PSA progression and radiographic progression as described below, or clinical progression alone (skeletal-related event or pain progression requiring intervention). Dose modifications (eg, short treatment breaks or dose reduction) were allowed in case of treatment-related adverse events (AEs).


2.3. End points
PSA response was assessed using the Prostate Cancer Working Group 2 (PCWG2) criteria [9]. Imaging evaluations were performed every 16 wk. The primary end point was the posttreatment percentage change in PSA relative to baseline at 12 wk (or earlier for those who discontinued therapy) and maximal change at any time on the study. The secondary efficacy end points included time to PSA progression (TTPP), measured from the start of treatment until the criteria for PSA progression were met, according to the modified PCWG2 (≥25% and >2 ng/ml above PSA nadir confirmed ≥3 wk later or >2 ng/ml above baseline PSA after 12 wk), and metastasis-free survival (MFS), measured from the start of treatment until new metastatic lesions were seen on computed tomography/magnetic resonance imaging scans by modified Response Evaluation Criteria in Solid Tumors [10] and/or 99m-technetium-methylene diphosphate bone scans (after repeat imaging ≥6 wk later), independently verified by central imaging.

2.4. Safety
Safety was assessed on an ongoing basis from the first dose until 30 d after the last dose or until the resolution of any drug-related AE.

2.5. Statistical analysis
The sample size was based primarily on clinical judgment. A combined 12-wk PSA response rate of at least 20% in the nmCRPC cohort was considered of clinical interest to warrant further development of apalutamide in nmCRPC. If 22 of 70 patients (including a chemotherapy/abiraterone acetate cohort not described here) achieved a 12-wk PSA response of at least 50%, the lower exact 95% confidence interval (CI) was 20.9% with the upper limit of 43.6%. All patients who received at least one dose of apalutamide were included in the efficacy (excluding four patients who had baseline metastases) and safety analyses. Summary statistics were reported for demographics, baseline characteristics, AEs, vital signs, and clinical laboratory evaluations. The change in PSA at 12 wk relative to baseline and the maximal change in PSA at any time on the study relative to baseline are presented in waterfall plots and descriptively summarized. The Kaplan-Meier method was used to estimate the median time to events and 95% CIs.


3. Results
3.1. Patients
The high-risk nmCRPC cohort enrolled 51 patients from November 2011 to June 2012. The data cut-off for database lock and primary analysis was December 31, 2014. Median patient age was 71 yr (range: 51–88); most patients were white (47 of 51 [92%]). Median baseline PSA was 10.7 ng/ml (Table 1). Patients were enrolled with a PSA ≥8 ng/ml (21 of 51 [41%]) or PSA DT ≤10 mo (23 of 51 [45%]), with seven patients having both criteria met (14%). Most patients (80%) had received prior treatment with a first-generation anti-androgen (ie, bicalutamide, flutamide, or nilutamide) (Table 1). Four patients had metastatic disease and were excluded from the efficacy analysis because they later were determined to have metastases on their screening scans (Fig. 2). At a median follow-up of 28.0 mo, 18 of 51 patients (35%) remained in the study. Most who went off the study did so either for disease progression (11 of 51 [22%]) or AEs (9 of 51 [18%]). The median treatment duration was 26.9 mo (range: <1–37.8). An external file that holds a picture, illustration, etc. Object name is nihms895646f2.jpg Fig. 2 Patient disposition. PSA = prostate-specific antigen. *Patients may have discontinued due to more than one type of progression. 3.2. Prostate-specific antigen outcome
The median change in PSA from baseline to week 12, per PCWG2 criteria, was −85% (range: −99.9 to 52.2). The median maximal change in PSA from baseline to any point during the study was −93% (range: −99.9 to 47.5). This corresponded to a PSA response (≥50% decline in PSA after baseline) at 12 wk of 89% (Table 2 and Fig. 3A). The maximal PSA response (maximal percentage reduction [≥50%] after baseline at any time) was reported in 94% of patients (Table 2 and Fig. 3B).


3.4. Safety
The most common treatment-emergent adverse events (TEAEs) regardless of relationship to the study drug were fatigue (61%), diarrhea (43%), and nausea (39%) (Table 3). Most TEAEs were grade 1 or 2. Grade ≥3 TEAEs reported in more than one patient each were fatigue (n = 2 [4%]), hypertension (n = 2 [4%]), and malignant melanoma (n = 2 [4%]). The most common TEAEs related to study treatment were fatigue (45%), diarrhea (29%), and nausea (25%); no serious TEAEs were considered related to study treatment. No seizures, amnesia, or visual disturbance were reported. Headache and dizziness were reported in seven patients (14%) and six patients (12%), respectively. TEAEs of a fall (all grade 1 or 2) were reported in five patients (10%) with a resultant grade 1 contusion in one patient. Another patient had several TEAEs (all grade 1 or 2) including a contusion secondary to a fall not reported as an AE. TEAEs that led to permanent treatment discontinuation were fatigue (n = 2 [4%]); abdominal adhesions, bone marrow tumor cell infiltration, brain cancer, colorectal cancer, decreased appetite, drug hypersensitivity, dysphagia, esophageal cancer, nerve root compression, and macular rash (n = 1 [2% each]); it was possible for patients to experience more than one TEAE leading to treatment discontinuation. TEAEs that led to dose modification were fatigue (n = 2 [4%]); choking, contusion, erythematous rash, and vomiting (n = 1 [2% each]). TEAEs that led to dose interruption were observed in 15 patients (29%); the only TEAE leading to dose interruption that was observed in more than one patient was diarrhea in two patients (4%).

4. Discussion
In this phase 2 study of apalutamide, we confirm the safety and tolerability profile of the previously established biologically efficacious dose of 240 mg/d [8] in the nmCRPC cohort. This study used several measures to determine the antitumor activity of apalutamide including declines in PSA level per PCWG2 criteria [9], TTPP, and MFS. With apalutamide treatment, 89% of patients (42 of 47) with high-risk nmCRPC experienced a ≥50% decline in PSA level after 12 wk on the study, with a maximal PSA response (≥50% after baseline at any time) reported in 94% of patients (44 of 47). At 28.0 mo of follow-up, the median TTPP and MFS were 24 mo and NR, respectively. Grade 3 and 4 TEAEs were infrequent. The most common treatment-related TEAEs were fatigue (45%), diarrhea (29%), and nausea (25%); these were mostly grade 1 and 2. Collectively, these data support the continued clinical development of apalutamide in future efficacy and safety studies of men with nmCRPC.

The most common grade 3 and 4 TEAEs were fatigue (n = 2 [4%]), hypertension (n = 2 [4%]), and malignant melanoma (n = 2 [4%]). Grade 3 secondary malignant melanomas were observed after 2.5 yr in one patient and 1 yr in a second. They were considered unrelated to the study drug and were not associated with dose reductions or interruptions. The most common treatment-related TEAEs were fatigue (45%), diarrhea (29%), and nausea (25%); these were mostly grade 1 and 2. Overall, apalutamide was safe and well tolerated.

Risk of seizures has been identified with AR antagonists as a class and is thought to be mediated via CNS-based γ -aminobutyric acid A receptors [11]; this represents an exclusion criterion in studies of enzalutamide [12–14] as in the current study with apalutamide. No seizures were reported in the current study, consistent with the safety data from the phase 1 clinical trial of apalutamide [8]. Falls have been reported to be more frequently observed with enzalutamide compared with placebo [12] and may also represent an AR antagonist class risk related to CNS effects. In the current study, five patients experienced grade 1 and 2 falls, but these falls were not reported as serious and did not result in discontinuation of the study drug.

Safe and effective treatment to delay or prevent the development of metastatic disease in nmCRPC is an important unmet medical need. The results of phase 3 metastasis prevention studies of zoledronic acid, denosumab, clodronic acid, and atrasentan did not support the regulatory approval of these agents for treatment of patients with nmCRPC [15–18]. The results of these phase 3 studies, however, have helped define the natural history of nmCRPC and facilitate the description of high risk based on PSA kinetics.

Strengths of this phase 2 study include the multicenter design and relatively long follow-up interval. The pre-specified definition of the high-risk nmCRPC cohort is also a substantial strength. Limitations include the nonrandomized nature of the study and the modest sample size.

The results of this phase 2 study informed the design of the global SPARTAN study (NCT01946204). SPARTAN is a multicenter double-blind placebo-controlled phase 3 trial to evaluate the efficacy and safety of apalutamide in patients with nmCRPC at high risk for progression, defined as a PSA DT ≤10 mo. The primary end point is MFS. Key secondary end points are overall survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy, radiographic progression-free survival, and time to metastasis. SPARTAN is ongoing [19]. Additional phase 3 trials in the high-risk nmCRPC patient population are also under way for the AR inhibitors enzalutamide (NCT02003924 [20]) and ODM-201 (NCT02200614 [21]).

In the absence of comparative studies of apalutamide, enzalutamide, and ODM-201, it is not possible to draw conclusions about the relative efficacy and safety of the different AR antagonists in the treatment of patients with nmCRPC. Nevertheless, AR antagonists appear promising in exerting clinical benefit in the nmCRPC population based on the results of this study as well as those of the STRIVE study [13].

Overall, apalutamide was well tolerated in this cohort of patients with high-risk nmCRPC, with a safety profile consistent with the previous phase 1 study. No serious TEAEs or seizures were reported.

5. Conclusions
Apalutamide was safe and well tolerated in patients with high-risk nmCRPC in the phase 2 portion of the study. Apalutamide exhibited robust activity in patients with high-risk nmCRPC based on durable PSA responses and disease control. These results support further clinical development of apalutamide in nmCRPC.

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Acknowledgments
Writing assistance was provided by Ira Mills of PAREXEL and Patricia Pelton of Janssen Research & Development.

Funding/Support and role of the sponsor: This study was funded by Aragon Pharmaceuticals, Inc. and supported by Janssen Research & Development. The sponsors were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Janssen Research & Development, LLC, is performing work on behalf of Aragon. Writing assistance was funded by Janssen Global Services, LLC.