ASCO GU 2020: KEYNOTE-365 Cohort A Updated Results: Pembrolizumab Plus Olaparib in Docetaxel-Pretreated Patients with mCRPC

San Francisco, California ( Therapeutic options for patients with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC) patients are limited to next-generation hormone agents. Pembrolizumab has been shown to have antitumor activity as monotherapy in patients with heavily pretreated PD-L1-positive advanced prostate cancer and PD-L1-negative patients previously treated with docetaxel who received ≥1 next-generation hormone agent.1 Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor that has shown antitumor activity in patients previously treated for mCRPC. TOPARP-B confirmed composited response was achieved by 25 of 46 patients with previously treated mCRPC who received 400 mg of olaparib twice daily.2 Presenting at the Prostate Cancer Session at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Evan Yu and colleagues shared updated results of Cohort A (pembrolizumab plus olaparib) from KEYNOTE-365, which is a Phase 1b/2 study evaluating pembrolizumab + other agents in mCRPC.

Cohort A of KEYNOTE-365 included docetaxel-pretreated, molecularly unselected patients with mCRPC who had progression within six months of screening per prostate-specific antigen (PSA) or radiologic bone/soft tissue progression. Patients may have received one other chemotherapy and ≤2 2nd-generation hormone therapies. These patients then received pembrolizumab 200 mg IV Q3W + olaparib 400 mg PO BID. The primary endpoints for this analysis included safety, PSA response rate (confirmed PSA decline ≥50%), and ORR per blinded independent central review.

Among the 84 patients included in the analysis, 42 discontinued, primarily due to radiographic progression (n=20). The median age was 71 years (range, 47-83 years), 26% were PD-L1+, 26% had visceral disease, and 57% had RECIST-measurable disease. The median follow-up was three months for all patients (n=81) and 14 months for patients with ≥27 weeks of follow-up (n=41). The confirmed PSA response rate was 8.5% in the overall population, including 10.6% among patients with RECIST measurable disease and 5.7% among patients with RECIST nonmeasurable disease. The overall PSA decrease from baseline was 36.6%, including 11.0% of patients having a >50% decline. Time to PSA progression based on the burden of disease is as follows:

kaplan meier estimate of confirmed time to psa progression

Median radiographic progression-free survival (rPFS) was 4.3 months (95% CI 3.4-7.7 months) and median overall survival (OS) was 14 months (95% confidence interval [CI] 8-19 months). Treatment-related adverse events occurred in 70 (83%) patients, most frequently (≥30%) were nausea (33%) and anemia (31%). Grade 3-5 treatment-related adverse events occurred in 29 (35%) patients and three patients died of adverse events (two treatment-related [one myocardial infarction, one unknown cause]).

Dr. Yu concluded this updated analysis of KEYNOTE-365 with the following concluding points:

  • With additional follow-up, pembrolizumab plus olaparib continued to show activity in docetaxel-pretreated, molecularly unselected patients who previously received hormone therapy for mCRPC
  • The safety and tolerability profile of pembrolizumab plus olaparib is consistent with the individual profiles of each agent
  • Confirmed PSA response rate was 8.5% in the total population and 10.6% in the population with RECIST-measurable disease
  • In the total population, the median rPFS was 4.3 months and median OS was 14.4 months
  • Future analyses will be performed to evaluate biomarkers associated with response to combination therapy of pembrolizumab plus olaparib

Clinical trial information: NCT02861573

Presented by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine, Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California 


1. Hansen, A. R., C. Massard, P. A. Ott, N. B. Haas, J. S. Lopez, S. Ejadi, J. M. Wallmark et al. "Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study." Annals of Oncology 29, no. 8 (2018): 1807-1813.

2. Mateo, Joaquin, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus et al. "Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial." The Lancet Oncology 21, no. 1 (2020): 162-174.