ASCO GU 2020: Pembrolizumab Plus Enzalutamide for Enza-Resistant Metastatic Castration-Resistant Prostate Cancer: KEYNOTE-199 Cohorts 4-5

San Francisco, CA ( During the Rapid Abstract Session, A: Prostate Cancer session at the Annual ASCO GU 2020 meeting in San Francisco, CA, results for KEYNOTE-199 Cohort 4 and 5 were presented by Nicole Graff, MD. Pembrolizumab monotherapy has demonstrated durable activity in PD-L1 positive mCRPC. KEYNOTE-199 is an open-label multicohort phase 2 study of pembrolizumab looking at the antitumor activity and acceptable safety in mCRPC previously treated with next-generation hormone agents and docetaxel.

Cohort 4 (RECIST-measurable disease) and Cohort 5 (bone-predominant disease) consist of chemotherapy-naive patients with mCRPC treated with enzalutamide plus pembrolizumab after progression with enzalutamide.

Patients with or without prior Abiraterone had clinically meaningful response/benefits to Enzalutamide, followed by disease progression. Patients received Pembrolizumab 200 mg Q3W with the continuation of Enzalutamide for up to 35 cycles or until progression/intolerable toxicity. The primary endpoint was overall response rate (ORR) by RECIST 1.1 per blinded independent central review (Cohort 4). Secondary endpoints were disease control rate (DCR), PSA response rate (≥50% reduction), radiographic progression-free survival (rPFS), overall survival (OS), and safety (Cohort 4 and 5); duration of response (DOR) (Cohort 4).

Dr. Graff then highlighted the results of this study. Of 126 pts (Cohort 4, n= 81; Cohort 5, n=45), 107 discontinued, primarily due to progression. Median follow-up was 15.3 months in Cohort 4 and 19.1 months in Cohort 5.


ORR (95% CI) for patients with measurable disease was 12% in Cohort 4; DCR for all patients was 51% in Cohort 4 and 51% in Cohort 5. In Cohort 4, 53% experienced a reduction in target lesion size, and 24% experienced greater than 30% reduction. The median duration of response was 6.3 months, and 60% had a durable response greater than six months in Cohort 4.



PSA decrease from baseline was noted in 40% of the patients, and greater than 50% decrease was seen in 14% of the patients.


Median rPFS was 4.2 months in Cohort 4 and 4.4 months in Cohort 5. OS in Cohort 5 was 18.8 months.


Any grade/grade 3-5 treatment-related adverse events occurred in 73%/25% of all patients.  Any grade/grade 3-5 immune-mediated adverse events occurred in 29%/15% of all patients. Two patients in Cohort 4 died of immune-related adverse events (Miller Fisher syndrome and myasthenia gravis). The incidence of any grade/grade 3-4 rash (regardless of treatment relatedness) was higher than previously reported for individual agents (33%/6%). All except one patient (grade 3 treated with IV steroids) were treated with oral/topical steroids or had no intervention.


Dr. Graff concluded her talk by summarizing that the addition of pembrolizumab to enzalutamide following enzalutamide resistance showed modest antitumor activity and durable response in patients with RECIST-measurable and bone-predominant mCRPC. The combination had manageable safety and is being evaluated in a phase 3 trial (KEYNOTE-641, NCT03834493).

Presented by: Julie Nicole Graff, MD, Associate Professor of Medicine, School of Medicine, Oregon Health & Science University, Portland, OR 

Written by: Abhishek Srivastava, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia, PA, Twitter: @shekabhishek, at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California.

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