148 Background: More efficacious treatment options are needed to extend survival and disease control for pts with mCRPC whose disease progressed after treatment with docetaxel. The PD-1 inhibitor pembro has shown manageable safety and limited antitumor activity in pts with mCRPC. Preclinical evidence suggests the VEGF/TKI inhibitor lenva inhibits angiogenesis and cell proliferation in prostate cancer. In cohort E of the phase 1b/2 KEYNOTE-365 study (NCT02861573), the safety and efficacy of pembro + lenva was evaluated in pts with docetaxel-pretreated mCRPC. Methods: Eligible pts were aged ≥18 years with confirmed mCRPC, an ECOG PS of 0 or 1, and prior treatment with docetaxel for mCRPC. Prior treatment with 1 other chemotherapy for mCRPC and ≤2 next-generation hormonal manipulations were allowed. Pts received pembro 200 mg IV Q3W for up to 35 cycles plus lenva 20 mg PO QD continuously from day 1 of cycle 1, unless specific withdrawal or discontinuation criteria were met. Primary end points were prostate-specific antigen (PSA) response rate, objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR), and safety. Secondary end points included duration of response (DOR) and disease control rate (DCR: CR and PR of any duration and SD or non-CR/non-PD of ≥6 months) per RECIST v1.1 by BICR, radiographic progression-free survival (rPFS) per PCWG3-modified RECIST v1.1 by BICR, and overall survival (OS). Results: Of 39 treated pts, median age was 67 years (range, 55-84), 64% had RECIST v1.1–measurable disease per BICR, and 59% had an ECOG PS of 1. At data cutoff (January 25, 2023), 64% pts had discontinued study treatment, 31% due to PD; 36% pts had ongoing treatment. Median time from first dose to data cut-off was 9.7 months (range, 7.4-15.2). Confirmed PSA response was 34% (95% CI, 20-51 [13/38 pts]) for pts with a baseline PSA measurement. ORR for pts with RECIST v1.1–measurable disease was 36% (95% CI, 18-58 [9 PR]). Median DOR was not reached (NR; range, 2.1+ to 6.9+ months); 3 pts had a response duration of ≥6 months. DCR for all pts was 51%. Median rPFS was 7.9 months (95% CI, 4.1-NR); estimated 12-month rPFS rate was 35%. Median OS was 9.4 months (95% CI, 8.4-NR); estimated 12-month OS rate was 37%. Treatment-related AEs (TRAEs) occurred in 92% of pts; most common (≥30%) were hypertension (51%), hypothyroidism (44%), fatigue (38%), diarrhea (36%), dysphonia (31%), and weight decreased (31%). Grade 3-5 TRAEs occurred in 62% of pts and most common (≥20%) were hypertension (36%) and fatigue (21%). Two pts died of AEs (acute kidney failure and death), but neither were treatment related. Conclusions: Pembro + lenva demonstrated promising and durable antitumor activity in selected pts with docetaxel-pretreated mCRPC. Safety was generally consistent with the individual profiles and for the combination of these agents. Clinical trial information: NCT02861573 .
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