Two-Year KEYNOTE-365 Update Continues to Show Promise of Pembrolizumab Plus Abiraterone in mCRPC Naïve to Chemo


Antitumor activity and safety of pembrolizumab plus abiraterone acetate appears to be sustained in chemotherapy-naïve castration-resistant prostate cancer.

Follow-up data at 2 years for the multicohort phase 1b/2 KEYNOTE-365 trial (NCT02861573) presented at the 2022 European Society for Medical Oncology Congress (ESMO) support earlier findings that revealed promising antitumor activity and an acceptable safety profile of pembrolizumab (Keytruda) plus abiraterone acetate (Zytiga) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC).

At a median follow-up of 28.2 months (range, 20.2-37.6), the objective response rate was 16.2% among patients with RECIST-measurable disease. The objective response rates (ORRs) comprised 1 complete response and 5 partial responses. Across the overall population, 56.3% of patients had a confirmed prostate-specific antigen (PSA) response and 78.6% achieved a PSA reduction from baseline—either confirmed or unconfirmed.

The ongoing open-label, nonrandomized KEYNOTE-365 trial is exploring various combinations of pembrolizumab with other therapies in men with mCRPC. The pembrolizumab plus abiraterone/prednisone arm is cohort D of the study. Cohort D included 103 chemotherapy-naïve men with mCRPC who had an ECOG performance status of 0 or 1 and disease progression within 6 months of screening.

Patients had no prior next-generation hormonal agents (NHAs) for mCRPC or had received the NHA enzalutamide (Xtandi) for mCRPC but had progressed on or were intolerant to the drug. Of the 103 patients treated in cohort D, 75 (72.8%) had no prior NHAs and 27 (26.2%) had prior enzalutamide. (There was 1 patient had prior enzalutamide and abiraterone.)

Patients received 200 mg of pembrolizumab intravenously every 3 weeks in addition to oral doses of 1000 mg of abiraterone daily and 5 mg of prednisone twice daily.The primary study end points were PSA response (≥50% decrease from baseline), confirmed ORR per RECIST v1.1 by blinded independent central review (BICR), and safety. Secondary end points included radiographic progression-free survival (rPFS), disease control rate (DCR), duration of response (DOR), and overall survival (OS).

The cutoff date for the data shared at ESMO was February 14, 2022. The 16.2% ORR among patients with RECIST-measurable disease (37 patients) comprised an ORR of 21.7% in patients with no prior NHAs and an ORR of 7.7% in patients with prior enzalutamide. Of note, there were 2 patients with RECIST non-measurable disease who had a CR. The median DOR for all responders was not reached (range, 2.1+ to 24.4+). The DCR was 44.7% across all patients, 58.7% in those with no prior NHAs, and 7.4% in the prior enzalutamide group.

The median OS was 29.7 months and the 36-month OS rate was 49.5%. The median rPFS was 15.1 months and the 24-month rPFS rate was 33.3%.

Regarding safety, 91.3% of patients experienced a treatment-related adverse event (TRAE). Grade 3/5 TRAEs occurred in 38.8% of patients. Across the population, 18.4% had grade 3/4 ALT elevation and 12.6% had grade 3/4 AST elevation. One patient died of treatment-related myasthenic syndrome.

The FDA approved abiraterone plus prednisone in 2012 for the treatment of patients with mCRPC who had not received prior chemotherapy. Pembrolizumab does not currently have a specific FDA-approved indication for prostate cancer; however, the PD-1 inhibitor does have a tumor-agnostic approval for patients with microsatellite instability high or mismatch repair deficient solid tumors.


Linch M, Ferrario C, Stoeckle M, et al. Two-year follow-up of KEYNOTE-365 cohort D: Pembrolizumab (pembro) plus abiraterone acetate (abi) and prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2022;33(suppl 7):1389O. doi:10.1016/annonc/annonc1070

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