ORLANDO, FL, USA (UroToday.com) - Joseph W. Kim, MD highlighted 3 prostate cancer journal articles of the past year addressing the treatment of metastatic castration-resistant prostate cancer (mCRPC).
- PREVAIL trial – Beer TM, Armstrong AJ, Rathkopf DE, et al. NEJM (2014) 371(5): 424-33.
Dr. Kim discussed the published results of the PREVAIL trial which looked at the use of enzalutamide in asymptomatic chemotherapy-naïve mCRPC patients. The study randomized 1 717 patients to receive either enzalutamide or placebo. Enzalutamide was shown to result in an 81% reduction in radiographic progression as well as a 29% reduction in death, with a median overall survival of 32.4 months compared to 30.2 months for placebo. All secondary endpoints of the trial demonstrated improved outcomes with enzalutamide treatment including delay to initiation of chemotherapy, increased time to initial skeletal-related event, larger declines in PSA from baseline, and prolonged time to PSA progression. Dr. Kim highlighted the fact that enzalutamide is a prime example of successful drug development, from bench to bedside. As a segue to his second article he also discussed that despite the success seen with newer agents like enzalutamide and abiraterone acetate, treatment resistance is inevitable. The discovery of mechanisms of resistance will help to better assign patients to appropriate and effective therapies. -
AR-V7 and abiraterone/enzalutamide resistance – Antonarakis ES, Lu C, Wang H, et al. NEJM (2014) 371(11): 1028-38.
Dr. Kim then moved on to a discussion of AR-V7, a splice variant of the androgen receptor (AR) that possesses a truncated C-terminus, resulting in a lack of the ligand-binding domain which is targeted by abiraterone and enzalutamide. As a result, the presence of AR-V7 results in resistance to both of these agents. This study by Antonarakis et al. examined whether detection of AR-V7 mRNA in circulating tumor cells (CTCs) could be used as a biomarker of resistance to abiraterone and enzalutamide. In total 19% of abiraterone patients and 39% of enzalutamide patients were AR-V7 positive. AR-V7-positive patients in both groups had worse PSA response rates, shorter PSA, clinical and radiographic progression-free survival, as well as shorter overall survival. Dr. Kim discussed the notion of “conversion” of AR-V7 as 6 of 42 patients changed status from negative at baseline to positive following therapy. He also warned that AR-V7 is only part of the story of resistance as only 22% of patients who were AR-V7 negative and had previously received abiraterone ultimately responded to enzalutamide. This data points to additional mechanisms of resistance, which are yet to be elucidated. -
Ipilimumab and mCRPC – Kwon ED, Drake CG, Scher HI, et al. Lancet Oncol (2014) 15(7): 700-12.
Dr. Kim then moved onto the phase III randomized, double-blind, placebo-controlled trial of ipilimumab versus placebo following radiotherapy in patients with mCRPC, published by Kwon et al. This study enrolled 799 patients with mCRPC who had previously received docetaxel. The study participants underwent a single dose of bone-directed radiation therapy in order to release tumor antigens to improve immune response, and subsequently were randomized to receive either ipilimumab or placebo. In this trial ipilimumab administration did not result in a significant improvement in overall survival compared to placebo. In examining overall survival outcomes stratified by subgroups however, Dr. Kim explained that patients without visceral disease did experience a significant 27% reduction in death (HR 0.73, 95% CI 0.59-0.89) whereas no reduction was seen in those with visceral disease. Dr. Kim pointed to the fact that to date there has been no evidence that immunotherapy is effective in mCRPC patients with visceral metastases, given sipuleucel-T and other immunotherapy trials have excluded these patients. Dr. Kim outlined the biologic rationale behind resistance to immunotherapy in patients with visceral metastases, which occurs due to an upregulation of anti-apoptotic pathways as well as immune checkpoint molecules, increased secretion of immunosuppressive chemokines, and increased prevalence of immunosuppressive cells. Dr. Kim discussed that the results of this trial confirm that CTLA-4 blockade is not adequate to overcome the immunosuppression induced by mCRPC visceral metastases, and due to this, did not result in a significant difference in overall survival.
Presented by Joseph W. Kim, MD at the 2015 Genitourinary Cancers Symposium - "Integrating Biology Into Patient-Centric Care" - February 26 - 28, 2015 - Rosen Shingle Creek - Orlando, Florida USA
Yale School of Medicine, New Haven, CT USA
Reported by Timothy Ito, MD, medical writer for UroToday.com