Phase 1b/2 KEYNOTE-365 cohort I: Pembrolizumab (pembro) plus carboplatin and etoposide chemotherapy (chemo) or chemo alone for metastatic neuroendocrine prostate cancer (NEPC).

5059 Background: Patients with NEPC are often treated with platinum-based chemotherapy but novel therapies with favorable efficacy and safety profiles are needed. Cohort I of the phase 1b/2 KEYNOTE-365 study (NCT02861573) was designed to evaluate the safety and efficacy of adding pembro to chemo in participants (pts) with NEPC. Preliminary data are presented. Methods: Adultpts with pathologically (morphology and immunohistochemistry) confirmed treatment-emergent (t-NE) or de novo metastatic NEPC (small cell, large cell, or mixed morphology per central review), disease progression ≤6 mo before screening, and ECOG PS of 0 or 1, with or without prior androgen deprivation therapy, are included. Enrollment is ongoing. Prior treatment (Tx) with ≤2 chemo regimens for metastatic castration-resistant prostate cancer and ≤2 next-generation hormonal agents are allowed. Prior Tx with platinum-containing regimens is not permitted. Pts are randomly assigned 1:1 to receive 4-6 cycles of carboplatin AUC 5 IV on day 1 Q3W + etoposide 100 mg/m 2 IV on days 1-3 Q3W with or without pembro 200 mg IV Q3W for ≤35 cycles. Primary end points are safety, ORR per RECIST v1.1 by blinded independent central review (BICR), and confirmed prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [BL] measured twice ≥3 wk apart). Secondary end points include rPFS per PCWG3-modified RECIST v1.1 by BICR and OS. No formal hypothesis testing was performed. Results: As of August 26, 2024, 40 pts have been randomized; 19 pts received ≥1 dose of pembro + chemo and 18 pts ≥1 dose of chemo. Of treated pts, 29 (78%) had t-NE. Median follow-up was 11.7 mo (range, 0.5-28.7); 7 and 2 pts remain on Tx with pembro + chemo or chemo, respectively. For pts with RECIST-measurable disease, confirmed ORR was 33% (6/18; 95% CI, 13-59; 6 partial responses [PRs]) with pembro + chemo versus 6% (1/16; 0-30; 1 PR) with chemo. For pts with a BL PSA measurement, confirmed PSA response rate was 37% (7/19; 95% CI, 16-62) versus 18% (3/17; 4-43). In all treated pts, median rPFS was 5.1 mo (95% CI, 3.9-8.1) with pembro + chemo versus 4.0 mo (2.0-4.3) with chemo; 6-mo rPFS rate was 49% versus 21%. Median OS was 11.4 mo (95% CI, 5.1-not reached) versus 7.8 mo (3.6-8.5); 6-mo OS rate was 80% versus 65%. Grade 3 or 4 Tx-related AEs (TRAEs) occurred in 58% of pts with pembro + chemo versus 78% with chemo, most commonly anemia (32% vs 39%); no grade 5 TRAEs occurred. Immune-mediated AEs and infusion reactions occurred in 32% of pts with pembro + chemo versus 11% with chemo, most commonly hyperthyroidism (16% vs 6%) and infusion reactions (16% vs 6%). Conclusions: Based on these preliminary data in pts with NEPC, the addition of pembro to chemo is associated with promising efficacy outcomes compared with chemo alone and does not result in new or unexpected safety signals. Updated data from cohort I will be presented at the meeting. Clinical trial information: NCT02861573 .