BY BRUCE ROTH, MD
Professor of Medicine
Washington University School of Medicine
The past few years have seen a groundswell of activity resulting in a number of new therapeutic alternatives in the treatment of advanced carcinoma of the prostate, and 2011 was no exception. The year will be remembered for the approval of one new drug (abiraterone acetate), the presentation of data that will likely result in the approval of another agent in the next 12 months (MDV-3100), and remarkable initial results with an agent targeting a novel pathway in prostate cancer (cabozantinib). To round out the year, the U.S. Preventive Services Task Force released a draft recommendation statement on screening for prostate cancer that unleashed a firestorm of controversy.
Over the past decade there has been increasing evidence of the importance of the androgen-signaling pathway, even in so-called “castrate-resistant” disease. Whether that continued growth stimulation was the result of circulating levels of relatively weak adrenal androgens or from autocrine/paracrine synthesis of testosterone/dihydrotestosterone by prostate cancer tissue, it became the standard of care to add second- or even third-line hormonal therapies to the castrate patient, including androgen-receptor antagonists such as bicalutamide or nilutamide, or relatively crude androgen synthesis inhibitors such as high-dose ketoconazole. Clinical trials have now brought us an additional agent from each of the classes of drugs.
The Food and Drug Administration in April approved abiraterone acetate (Zytiga) in combination with prednisone, for use in patients with castrate-resistant metastatic disease who had received prior docetaxel-based therapy. Abiraterone is a CYP-17 lyase inhibitor, and by doing so blocks the synthesis of androgens in the adrenals, the testicles, and in the tumor itself. The drug’s approval was based on the initial results of a randomized trial in 1195 metastatic, castrate-resistant prostate cancer patients who had not responded to one or two prior chemotherapy regimens.
Patients were randomized in a 2:1 fashion to receive either 1000 mg/day of abiraterone orally or placebo, both combined with prednisone. In the initial report, the median overall survival in those receiving abiraterone was 3.9 months longer than those receiving placebo. A second preplanned analysis was presented at the 2011 ASCO Annual Meeting, and this survival benefit has increased to 4.6 months.
Toxicity with this drug is minimal, the median duration of response is in excess of 10 months, and the finding of overall survival benefit in this heavily pretreated population is remarkable. A trial of the drug in patients prior to receiving chemotherapy has completed accrual, but the results are not yet available.
The main problem with the drug to date has been cost, and, as with other oral agents, much of that cost is frequently born by patients. The cost of the drug is approximately $6100/month, with wide fluctuations in insurance coverage. Some patients in my practice have been told they have a co-pay as little as $1.50/month, while others have been told they would have to pay in excess of $5900/month out-of-pocket. Sadly, this drug is currently out of financial reach for many patients.
MDV-3100 is an androgen-receptor signaling inhibitor (ARSI) -- for those of you still using the term “antiandrogen,” you are SO 2011 -- which in preclinical studies appeared to be superior to current agents such as bicalutamide, and in early clinical trials demonstrated responses even in patients who had received prior chemotherapy.
A phase III trial (AFFIRM) randomized (2:1 randomization) 1199 castrate-resistant, metastatic patients to receive MDV-3100 at 160 mg/day orally versus placebo. Patients could have received up to two prior chemotherapy regimens. Late in 2011, the Data Safety and Monitoring Board for this trial recommended unblinding the study after finding a significant overall survival benefit (4.8 months) in the MDV-3100 patients.
The data were presented at the 2012 ASCO GU meeting this month (Abstract LBA1), and it is likely that the FDA will review the data this calendar year. A similar trial (PREVAIL) in castrate-resistant metastatic patients who have not received chemotherapy completed accrual late in 2011 and we await the results.
Some of the most exciting data presented this year involved the multi-targeted kinase inhibitor cabozantinib. At the ASCO Annual Meeting, data were presented from a large, multi-disease randomized discontinuation phase II trial. While activity was observed in a number of disease types, including ovarian cancer and melanoma, the most impressive results were seen in patients with castrate-resistant, metastatic prostate cancer, with activity in this population likely related to the drug’s inhibition of c-MET and VEGFR2.
Of 171 patients with prostate cancer on the trial, only a few (4%) achieved a RECIST-defined partial response at 12 weeks of therapy. However, in 108 patients with bone scan evaluable disease, the results were remarkable. In these patients, 19% achieved a complete response by 12 weeks of therapy, and an additional 56% had improvement in their bone scan over that interval, with only 3% of patients progressing on therapy. These were not merely radiographic anomalies, but were accompanied by improvement in pain and reduction in narcotic usage. A planned phase III trial of this compound in patients previously treated with chemotherapy will begin accrual shortly.
Prostate Cancer Screening
No year-end review would be complete without a little controversy. This year it was provided by the U.S. Preventive Services Task Force, which issued a draft recommendation statement on screening for prostate cancer. Based on a review of data from two large screening trials (the Prostate, Lung Colorectal, and Ovarian -- PLCO; and the European Randomized Study of Screening for Prostate Cancer -- ERSPC) which failed to detect a significant reduction in prostate cancer-specific mortality associated with PSA screening of the adult male population, the Task Force “downgraded” PSA as a screening tool (to a “D”), concluding that the risk of utilizing it outweighed the benefits.
There were the expected vehement outbursts from the usual suspects who are intolerant of any negative comments about the usefulness of PSA as a screening tool, but even more measured observers commented on the lack of new data to warrant a downgrade to a “D.” The level of controversy AFTER the publication of two large randomized trials unfortunately probably indicates that a definitive answer regarding usefulness will likely not come from additional clinical trials, but will continue to be hotly debated in the court of public opinion.