KEYNOTE-365 cohorts G and H: Phase 1b/2 study of pembrolizumab + vibostolimab combination therapy in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC (t-NE).

Abstract

TPS204 Background: Treatment options are limited for patients with mCRPC that progresses after treatment with next-generation hormonal agents (NHAs)—such as enzalutamide and abiraterone acetate—or docetaxel. Approximately 20% of patients with adenocarcinoma mCRPC that progresses on androgen deprivation therapy develop t-NE mCRPC, which is associated with shortened overall survival (OS). The PD-1 inhibitor pembrolizumab showed antitumor activity as monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC in the phase 2 KEYNOTE-199 trial. The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor vibostolimab showed antitumor activity when combined with pembrolizumab in pretreated patients with several tumor types in a phase 1 dose-escalation study. Combining PD-1 and TIGIT inhibition might have enhanced benefit in mCRPC, potentially both adenocarcinoma and t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate the efficacy and safety of several pembrolizumab combination therapies in patients with mCRPC. Patients enrolled in cohort G will have confirmed adenocarcinoma of the prostate without small cell histology, per the investigator. Cohort H will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Enrollment in cohort H requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score 0 or 1. Both cohorts will receive MK-7684A, a coformulation of pembrolizumab 200 mg and vibostolimab 200 mg, IV every 3 weeks. Treatment will continue until disease progression, withdrawal of consent, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and OS. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.