Johann S. de Bono, MBChB, PhD, MSc

Disclosures

June 13, 2012

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Introduction

Hello, I am Johann de Bono. I am Professor of Experimental Cancer Medicine at the Institute of Cancer Research and Honorary Consultant at the Royal Marsden Hospital, in the Department of Medical Oncology, in Sutton in the United Kingdom.

Welcome to this edition of Medscape Oncology Insights on prostate cancer. Today I want to share with you some of the exciting data we have been hearing about on prostate cancer, presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO®).

Unprecedented Number of New Drugs

This is truly an unprecedented time in prostate cancer drug development, a real renaissance in our development of the therapeutic armamentarium for treatment of this common disease. Prostate cancer is the most common cancer in men, the second most common killer from cancer in men in the Western world, and as men live longer, this is an increasingly common disease.

What has really changed our understanding of the disease is the increasing evidence, both preclinical and clinical, that this cancer remains hormone driven and dependent on androgen receptor signaling, despite the cancer progressing through androgen deprivation by treatment with luteinizing hormone-releasing hormone (LHRH) analogs or chemical castration, and the established antiandrogens, including bicalutamide, flutamide, and nilutamide.

Impressive Results With Abiraterone

We heard today from my colleague Chuck Ryan[1] in his presentation of an abstract (on which I am a coauthor) of a phase 3 trial showing that the CYP17 inhibitor abiraterone acetate improves radiologic progression-free survival (rPFS) in patients in the prechemotherapy, predocetaxel setting. This study was halted early by the independent data monitoring committee at the first interval for survival because, with 40% of the death events reported, because the coprimary endpoints of rPFS and overall survival favored the abiraterone arm.

Although further data and stronger statistical evidence for the benefit of this drug given as prechemotherapy are necessary, these data robustly support the use of abiraterone in this setting. At some point this year the abiraterone data will be submitted to the regulatory authorities for oversight to try to get this drug available to our patients in the prechemotherapy setting.

What we have seen today in the phase 3 trial for this COU-AA-302 trial from the Cougar and Johnson & Johnson group is that this drug improves not only overall survival and radiologic PFS, but also a number of other secondary endpoints, including response endpoints and clinical benefit endpoints.

Neoadjuvant Abiraterone

Another important presentation today was the study of abiraterone in the neoadjuvant setting, before prostatectomy. Work presented by Mary Ellen Taplin and colleagues[2] has shown that abiraterone added to chemical castration in the preprostatectomy setting in patients with high-grade, poor prognosis, locally advanced prostate cancer and a Gleason score of 8-10 significantly increases the pathologic complete response (CR) rate (and the endpoint that she described as "near pathologic CR") to more than 30%, which is unprecedented. This raises hope that our ongoing trials in Europe and the United States with abiraterone in the high-risk, locally advanced disease setting will show increased cure rates by giving this drug neoadjuvantly. Those data are awaited eagerly for us to further influence outcomes in this disease, although currently abiraterone remains approved only for the postchemotherapy setting.

Enzalutamide: Well Tolerated, Low Risk for Seizure

The data I presented today at the same session on prostate cancer was on enzalutamide (or MDV3100).[3] This compound was discovered and developed by the group at the University of California in Los Angeles. Charles Sawyers and Michael Jung described this compound in a seminal paper in Science by Tran and colleagues.[4]These data led to a phase 1-2 study led by Howard Scher[5] that was published in The Lancet, which described impressive, single-agent, antitumor activity in patients in both prechemotherapy and postchemotherapy settings. Unlike abiraterone, this drug does not require the concurrent administration of prednisone, which may be an advantage in some settings in this disease. Today I presented that this agent, enzalutamide, not only improves overall survival, but it also improves all the secondary endpoints that were a preplanned part of this trial, including time to PSA progression, time to radiologic progression, and all the detailed quality-of-life measures, including time to first skeletal-related event, as well as the well-being of the patient as measured by the FACT-P [Functional Assessment of Cancer Therapy-Prostate] questionnaire, which measures personal, family, and social well-being, as well as prostate cancer-specific symptoms. Of importance, enzalutamide improved outcome across the board in all the endpoints studied.

This compound is very well tolerated, but it does have a very small risk of increasing the tendency to seizures, as has been described with other antiandrogens. However, of the patients on the study (this was a 1200-patient trial), only 5 patients were reported to have a seizure during the study. Two of these patients actually had intracerebral metastatic prostate cancer. One of these patients had a large, 5 x 4 cm mass, and the other patient had multiple intracranial metastases. It would therefore seem that at least in these 2 out of 5 patients, the prostate cancer probably had some part to play in causing these seizures, which were focal in nature. One of these 5 patients was on drugs for weeks to months and developed a seizure immediately after an inadvertent intravenous lidocaine injection. Lidocaine is well known to induce seizures. This patient was also on a flecainide analog, propafenone. So, in this third patient you have this clear confounding factor, which may have predisposed this patient -- or even caused this patient -- to have a seizure. Although there were no seizures in the control arm (and that is an important statement), I do think that as we move this drug forward, the risk for seizures will be dependent primarily on other confounding factors.

In the enzalutamide prechemotherapy setting, the PREVAIL study[6] is still ongoing and we hope to have those data available in the not-too-distant future. These drugs are very likely to influence outcomes, particularly in the high-risk, locally advanced setting.

More Exciting Agents

Moving forward at this meeting we also had the privilege of hearing data on 2 other agents that are particularly exciting for the field. The first agent, radium 223, also known as alpharadin, was presented by my colleague Chris Parker[7] from the Royal Marsden Hospital. This agent is an intravenous injection given once a month with really minimal toxicity. The different mechanism of action of this drug is that it is taken up by osteoblasts. It's a heavy metal, such as calcium, and the osteoblasts take it up and it emits alpha radiation, which causes double-strand DNA breaks that are lethal to the prostate cancer cell at the site of increased bone turnover induced by the cancer. We have seen minimal myelosuppression with this agent. It is very well tolerated and shows an impressive overall survival benefit of almost 4 months. We now look forward to combining this agent with the endocrine agents abiraterone and enzalutamide and making this agent more broadly available.

The other agent I'm particularly enthused about is cabozantinib. Data at this meeting are being presented by Matthew Smith,[8] from Massachusetts General Hospital in Boston, who has shown us that this agent has impressive antitumor activity, even at doses where the drug is well tolerated. Initial studies presented last year by Maha Hussain[9] at this meeting showed that this drug has impressive antitumor activity. However, there were concerns that the dose taken forward into phase 3 trials had significant toxicity, particularly fatigue. However, at the lower dose of 40 mg/day, this drug is not only well tolerated but is still impressively active. Patients had significant resolution of pain, decreasing circulating tumor cells associated with survival benefit, and other measurable improved outcomes, including improved quality of life. The agent is now in randomized phase 3 trials, and it is our hope that it will become another part of our armamentarium for treating this common disease.

How Best to Sequence the Drugs?

I have shared with you data on several new agents that will have an impact on the treatment of this common disease. A significant challenge for us now is how do we best sequence these drugs? What do we give first? Currently what we have available to give are LHRH analogs plus the established antiandrogens, such as bicalutamide, and then move forward beyond those drugs, perhaps to giving sipuleucel-T, after which docetaxel is currently the standard of care. I envision that abiraterone will become available in the prechemotherapy setting at some point in the not-too-distant future, on the basis of these COU-AA-302 data I have presented to you today.[1]

Cabazitaxel is being studied in the first-line chemotherapy setting and it is possible that it could replace docetaxel in that setting. However, at the present time, cabazitaxel is approved primarily in the postdocetaxel setting and has important antitumor activity in these men with advanced prostate cancer. We also now have alpharadin. The alpharadin phase 3 data[7] involve patients both in the pre- and postchemotherapy settings, although most of the patients were in the postchemotherapy setting. This drug would be useful pre- and post-chemotherapy if approved by the regulatory authorities. Finally, cabozantinib, if the phase 3 trials are positive, may have a role to play, certainly initially post-chemotherapy but eventually earlier in the disease, as will be the case with enzalutamide, the data for which have been submitted to the regulatory authorities.

It is hopeful that enzalutamide will become available and maybe even used in combination with abiraterone eventually. We have recent published data suggesting and supporting the study of these 2 drugs, enzalutamide and abiraterone, in combination to address resistance to each drug alone. This truly is a golden age in prostate cancer drug development.

Thank you for your attention. I am Johann de Bono, reporting from the 2012 ASCO® meeting in Chicago. Thank you so much for joining me on this edition of Medscape Oncology Insights.

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