A phase II trial of abemaciclib (abema) and atezolizumab (atezo) in unselected and CDK12-loss metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rao Arpit , Kwak Lucia , Reimers Melissa Andrea , Reichert Zachery R , Thyagarajan Bharat , Fernandez Kaylah , Bretta Katherine , Pfaff Kathleen L. , Rodig Scott J. , Alva Ajjai Shivaram , Shapiro Geoffrey , Ryan Charles J. , Choudhury Atish Dipankar 
Published: February 2022

TPS213 Background: Alterations in the cell cycle signaling pathway are common in mCRPC and may contribute to resistance to AR-targeted therapies. Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) have revolutionized the therapeutic landscape in ER+ breast cancer and have demonstrated robust anti-tumor activity in multiple pre-clinical mCRPC models such as enzalutamide-resistant cell lines, including those with the androgen-receptor splice variant 7 (AR-V7). Pre-clinical synergy has also been seen in multiple studies of CDK4/6i and anti-programmed death 1 (PD-1) or PD-ligand-1 (PD-L1). Additionally, loss of function alterations of CDK12, found in 5-7% of mCRPC, may confer vulnerability to anti-PD-L1 agents. Methods: This multi-center study will enroll 54 unselected mCRPC patients (pts), randomized 1:1 to abema (arm A) or abema + atezo (arm B); and 21 pts with known loss of function mutations in CDK12 (arm C) treated with atezo (n = 5) or abema + atezo (n = 16). All pts will undergo on-treatment (6-week) tumor biopsy. Treatment will be continued until disease progression and crossover is prohibited. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-1, biopsy-proven prostate adenocarcinoma, progressive metastatic disease per Prostate Cancer Working Group 3 (PCWG3), progression/intolerance to ≥ 1 novel antiandrogen in hormone-sensitive or CRPC setting, ineligible for docetaxel/cabazitaxel (progression within 12 months of taxane, pt refusal, investigator discretion), no uncontrolled comorbidity or history of pneumonitis/ILD. Arms A & B will use two stage design for co-primary endpoints of progression-free survival at 6 months using PCWG3 (6m-PFS) and objective response rate (ORR). If ≥ 1/12 pts meet either co-primary endpoint, 2nd stage will open to enroll 15 more pts in that arm. Treatment will be deemed to have meaningful clinical activity (MCA) if ≥ 6/27 meet 6m-PFS or ≥ 5/27 have an ORR. This will provide 86% power for 6m-PFS (34% vs. 12%) and 85% power for ORR (30% vs. 10%) at a one-sided α = 0.08. For MCA in arm C, 16 patients treated with abema+atezo will provide 80-85% power for 6m-PFS (34% vs. 12%) at a one-sided α = 0.05 using a one-sample log-rank test. Primary safety endpoint is the incidence of dose-limiting toxicities in pts receiving abema+atezo. Key secondary endpoints are clinical benefit rate (ORR + stable disease), duration of response and overall survival in arms A and B, and safety events in all arms. Primary exploratory endpoint is comparison of tumoral FoxP3+/CD8+ ratio in pts treated with abema vs. abema + atezo. Additional exploratory endpoints will evaluate association between response and genomic alterations identified from tissue or circulating tumor-derived exosomes. Enrollment began in July 2021 and projected enrollment goal is 3 years (NCT04751929). Clinical trial information: NCT04751929.