With the high rate of [prostate-specific antigen (PSA)] decline, the study of enzalutamide (Xtandi) reported by Dr. Smith and colleagues appears to be a positive study,” said formal discussant Michael A. Carducci, MD, AEGON Professor in Prostate Cancer Research at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. “We still need to know about the durability of PSA decline and the long-term clinical benefits.” The side-effect profile of enzalutamide is more favorable than that of androgen deprivation therapy, he noted.
“The way forward is novel uses and sequencing of androgen-inhibiting drugs for prostate cancer that improve survival—enzalutamide being one of them,” said Dr. Carducci. “With six new drugs approved for the treatment of metastatic castration-resistant, it is a no-brainer to study them earlier in the course of disease, in sequence and in combination.”
Recent paradigm shifts in prostate cancer research include a focus on enhanced therapy at the time of local management and drug development for biochemical recurrence, Dr. Carducci said. “However, studies thus far suggest that monotherapy with a noncastrating drug will not be enough to slow the course of disease and improve survival,” he pointed out.
“Biology tells us combination therapy will be the next advance, treating patients earlier in the course of disease. The problem is that when we move to the adjuvant setting, it will take a decade to show cure rates. Drugs approved for advanced disease are currently used sequentially, but this may not be the best way to treat patients in the adjuvant setting,” he said.
Dr. Carducci said that since the optimal sequence for these new drugs is not known, combination studies should be conducted, and he listed several that are underway or in the planning stages, including the following:
The ALLIANCE A031201 study in men with metastatic castration-resistant prostate cancer who have not received docetaxel is evaluating enzalutamide vs enzalutamide plus abiraterone (Zytiga). The primary endpoint is overall survival, and the study will include 1,400 patients.
The Southwest Oncology Group (SWOG) 1216 trial is being conducted in men with newly diagnosed metastatic disease, treating them with a luteinizing hormone-releasing hormone (LHRH) antagonist and bicalutamide vs an LHRH antagonist plus the investigational androgen synthesis inhibitor orteronel. The study will enroll 1,600 men and assess overall survival.
The Prostate Cancer Clinical Trials Consortium’s AbiCure study is one example of several studies investigating biochemical recurrence. This study includes patients with short PSA doubling times who are randomly assigned to degarelix (Firmagon) alone vs degarelix plus abiraterone vs abiraterone alone. The primary endpoint is proportion of men with an undetectable PSA at 18 months.
The Radiation Therapy Oncology Group (RTOG) 1115 trial is enrolling men with high-risk prostate cancer, who are undergoing standard dose-escalated radiotherapy plus 2 years of standard androgen deprivation therapy vs androgen deprivation therapy plus orteronel. Planned enrollment is 900 men, and the primary endpoint is overall survival.
A proposed adjuvant prostatectomy trial by the ECOG-ACRIN Cancer Research Group—the merger of the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network—will compare placebo plus an LHRH antagonist vs an LHRH antagonist and enzalutamide. The study will enroll men at the highest risk, ie, those with Gleason score > 8, lymph node–positive, seminal vesicle–positive prostate cancer. The standard use of adjuvant radiation for such high-risk men will be incorporated into this study as well. The proposed primary endpoint will be 8-year biochemical relapse-free survival. ■
Disclosure: Dr. Carducci reported no potential conflicts of interest.
Enzalutamide (Xtandi) monotherapy induced striking declines in prostate-specific antigen (PSA) in a majority of patients with hormone-naive prostate cancer in a phase II trial, and this oral agent appears to have little effect on bone mineral density. If these findings are confirmed in a phase III...