ASCO 2019: Pembrolizumab plus Enzalutamide in Abiraterone-Pretreated Patients with Metastatic Castrate-Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study

Chicago, IL ( Pembrolizumab has activity as monotherapy in patients with heavily pretreated advanced metastatic castrate-resistant prostate cancer (mCRPC). The mechanism of action of pembrolizumab and enzalutamide might be synergistic, leading to increased antitumor activity, compared with either agent alone. Preliminary results of a small study (n=28) have shown the activity of pembrolizumab when given in patients with mCRPC whose disease progressed on enzalutamide.1 KEYNOTE-365 was conducted to assess the safety and efficacy of pembrolizumab combination therapies in patients with mCRPC. Dr. Peter Fong and colleagues presented data from KEYNOTE-365 cohort C (pembrolizumab plus enzalutamide), a phase 1b/2 umbrella study for men with mCRPC.

Patients were included in this study if they were unsuccessful with or became intolerant to ≥4 weeks of abiraterone in the pre-chemotherapy mCRPC state, with either prostate-specific antigen (PSA) or radiologic progression within 6 months before screening. Patients received pembrolizumab 200 mg IV every three weeks with enzalutamide 160 mg/day orally. The primary endpoints were safety and PSA response rate (confirmed PSA decrease ≥50%) and key secondary endpoints were investigator-assessed ORR (RECIST v1.1), disease control rate (CR+PR+SD for ≥6 months), time to PSA progression, radiographic progression-free survival (rPFS), and overall survival (OS).  A summary of the study design is as follows:

ASCO 2019 KEYNOTE 365 study design

There were 69 patients that began treatment, of which the median age was 69 years (range 43-87), 26% that had visceral disease, and 30% that were PD-L1 positive. Over a median follow-up of 8.9 months (IQR 6.5-13.0 months), 22 patients were still on treatment; of the 47 patients that discontinued treatment, 32 did so for progressive disease. PSA response was noted in 26% of the total population (40% in RECIST measurable disease), the objective response rate was 20%, and the disease control rate was 33%.

ASCO 2019 KEYNOTE 365 PSA response rate

The median time to PSA progression among men with measurable disease was 18.4 weeks (95%CI 15.4-48.3).

ASCO 2019 KEYNOTE 365 PSA progression

Median OS was not reached at the time of analysis. Treatment-related adverse events occurred in 63 (91%) patients, most frequent (≥20%) fatigue (30%), rash (23%), and nausea (22%). Grade 3/4 treatment-related adverse events occurred in 28 (41%) patients, most commonly rash (10%); there were no deaths were from treatment-related adverse events.

In summary, the results from KEYNOTE-365 cohort C show that pembrolizumab plus enzalutamide combination therapy is generally well tolerated and has promising activity in patients with mCRPC previously treated with abiraterone acetate. Generally, the safety and tolerability profile of pembrolizumab plus enzalutamide combination therapy was consistent with the individual profile of each agent, however, there was an increased incidence of all-grade rash (23%) and grade 3 rash (10%), which resolved with standard-of-care treatment. Confirmed PSA response rate was 26% in the total population and 40% among patients with RECIST-measurable disease. Results from the study support further evaluation of pembrolizumab plus enzalutamide combination therapy in patients with mCRPC previously treated with abiraterone acetate; enrolment in cohort C was increased to 100 patients and is now complete. A randomized phase 3 study of enzalutamide with or without pembrolizumab in patients with mCRPC that progressed with ADT with or without abiraterone acetate but who have not received prior chemotherapy is open to enrollment (KEYNOTE-641).

Clinical trial information:  NCT02861573

Speaker: Peter C.C. Fong, FRACP, Auckland City Hospital, Auckland, New Zealand  

Written By: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

  1. Graff JN, Alumkal JJ, Thompson RF, et al. Pembrolizumab (Pembro) plus enzalutamide (Enz) in metastatic castration resistant prostate cancer (mCRPC): Extended follow up. J Clin Oncol 2018;(Suppl):5047.