Emerging Agents for Metastatic Prostate Cancer: Galeterone, Selinexor, and ARN-509
I. Galeterone is an oral, small-molecule drug that disrupts androgen receptor signaling via multitargeted mechanisms of action, combining androgen receptor degradation and antagonism with cytochrome P17 suppression. Taplin and colleagues reported the results from phase 2 ARMOR2 study to confirm the optimal dose of galeterone and to assess the safety and efficacy of a daily dose of 2550 mg of the drug in 4 different cohorts of patients with castration-resistant prostate cancer (CRPC)—treatment-naïve patients with nonmetastatic disease, treatment-naïve patients with metastatic disease, abiraterone refractory patients, and enzalutamide refractory patients (Taplin M, et al. ESMO 2014: Abstract 757O).
As shown in the Table, at 3 months, 71% of galeterone-treated treatment-naïve patients with nonmetastatic disease and 89% of treatment-naïve patients with metastatic disease achieved a prostate-specific antigen (PSA) decline of ?30% (PSA30), and 64% and 81%, respectively, of the same cohorts achieved a PSA decline of ?50% (PSA50). Galeterone was not as effective in abiraterone-refractory patients or enzalutamide-refractory patients. Galeterone was well-tolerated, with grade 1 or 2 treatment-related adverse events occurring in 57% of patients, which were most frequently nausea, fatigue, and pruritus. Grade 3 or 4 treatment-related adverse events were noted in 21% of patients. Based on these results, ARMOR2 will continue to accrue additional patients, including those with progression after abiraterone and/or enzalutamide and chemotherapy.
II. Selinexor is an oral, selective inhibitor of nuclear export that activates ?10 tumor suppressor proteins, and has been shown to induce apoptosis in CRPC cell lines and in patient-derived tumors in vitro. Mahaseth and colleagues presented the preliminary results of 11 heavily pretreated patients with CRPC (5.5 median previous regimens) who were treated with selinexor across 3 dose levels: 33 to 65 mg/m2 (Mahaseth H, et al. ESMO 2014: Abstract 758O).
All patients had received taxanes, abiraterone, and/or enzalutamide before receiving selinexor. Of 8 evaluable patients, 7 achieved prolonged stable disease (range, 114-300+ days), with reductions in PSA and pain; 1 patient progressed despite treatment.
The most common treatment-related adverse events (grades 1-3) were fatigue, nausea, anorexia, and thrombocytopenia, but supportive care with dexamethasone, appetite stimulants, and antiemetics improved the constitutional symptoms. One patient developed grade 4 leukopenia. On the basis of these results, further studies with selinexor are planned.
III. ARN-509 is a novel antiandrogen that selectively binds the androgen receptor. The ARN-509-001 study evaluated the activity of this agent in patients with high-risk, nonmetastatic CRPC, chemotherapy-naïve metastatic CRPC, and metastatic CRPC after abiraterone acetate. Smith and colleagues reported the updated results for the nonmetastatic CRPC cohort, which consisted of 47 patients with CRPC and no radiographic evidence of metastases (Smith M, et al. ESMO 2014: Abstract 761PD).
The patients were considered high risk for disease progression based on having PSA levels of ?8 ng/mL within 3 months of enrollment and/or a PSA doubling time of ?10 months. All patients were treated with ARN-509 240 mg daily, with a primary end point of a PSA50 response at 12 weeks according to Protocol-Specific Prostate Working Group 2 criteria (?50% decline in PSA from baseline), with secondary end points including safety, time to PSA progression, and metastasis-free survival.
At a median follow-up of 20.2 months, 91% of the patients had a PSA50 response, which was maintained by 87% of the patients at 24 weeks and by 48% of the patients at 36 weeks. The median time to PSA progression and the median metastasis-free survival were not reached during the course of the study. The most common treatment-related adverse events were fatigue, diarrhea, nausea, dysgeusia, arthralgia, and weight loss.
Smith and colleagues concluded that ARN-509 is well-tolerated in patients with high-risk nonmetastatic CRPC, with robust and durable activity based on PSA responses and disease control.