ASCO GU 2019: Keynote-365: Pembrolizumab Plus Olaparib in Docetaxel Pretreated Patients with Metastatic Castrate-resistant Prostate Cancer

San Francisco, CA ( It has been previously shown that treatments for metastatic castrate-resistant prostate cancer (mCRPC) such as docetaxel and enzalutamide may increase programmed death ligand 1 (PD-1) expression. Pembrolizumab (pembro) is an anti-PD-1 antibody that has produced antitumor responses in previously treated patients with mCRPC. Olaparib is a PARP inhibitor that has shown activity in mCRPC with DNA-repair defects. KEYNOTE-365 is a non-randomized, open-label phase 1b/2 umbrella trial evaluating the safety and efficacy of three treatment combinations in patients who have progressed on second-generation hormonal therapy and chemotherapy: Cohort A: pembro + olaparib, Cohort B: pembro + docetaxel + prednisone, Cohort C: pembro + enzalutamide. The study start date was in 2016 and it is projected to come to completion in 2022. Here, Dr. Yu presented the early results from Cohort A combining pembro + olaparib.

Patients in Cohort A were all previously treated with docetaxel (treatment with 1 other chemotherapy and <=2 second-generation hormonal treatments allowed). Once treatment with pembro commenced, it was continued until progression or a maximum of 35 treatment cycles (up to 2 years); treatment with olaparib is continued until progression. If patients discontinue treatment in one cohort due to adverse events (AE), they may continue the study with the other combination drugs. Some notable inclusion criteria include adenocarcinoma of the prostate without small cell histology, available biopsy tissue from a metastatic lesion within 1 year of screening and after developing mCRPC, cancer progression within 6 months prior to screening, castrate testosterone level and ECOG 0 or 1. The primary outcome measures include the percentage of patients with a decrease of >=50% in prostate-specific antigen (PSA), number of patients with AE, number of patients discontinuing the study due to AEs and objective response rate (ORR) based on RECIST 1.1.

With a median follow-up of 11 months, 41 patients started treatment. The median age was 69 years, 27% were PD-L1 +, 42% had visceral disease, 68% had RECIST-measurable disease, 0% had a homologous recombination repair mutation (HRR). Treatment-related AEs occurred in 39 (95%) with the most frequent being anemia (37%), fatigue (34%), and nausea (34%). Grade 3-5 treatment AEs occurred in 21 (51%). There were two deaths, one of which was treatment-related (cause unknown). 

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KEYNOTE-365: Yu, E.Y. et al. European Urology Supplements, Volume 16, Issue 3, e360

In conclusion, a combination of pembro + olaparib in HRR wild-type patients previously treated with docetaxel for mCRPC is under present investigation, with early results as summarized above.

Presented by: Evan Y. Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center, Clinical Trials Core Director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

Written by: Selma Masic, MD, Urologic Oncology Fellow (SUO), Fox Chase Cancer Center, @selmasic at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA