CCTG IND 232: A phase II study of durvalumab with or without tremelimumab in patients with metastatic castration resistant prostate cancer (mCRPC)

Abstract

Background: PD-L1 is overexpressed by dendritic cells of mCRPC patients (pts) progressing on androgen receptor antagonist therapy. Anti-PD-1 agents lead to infrequent but durable responses. We tested the hypothesis that dual checkpoint blockade of CTLA-4 with tremelimumab (T) and PD-L1 with durvalumab (D) enhances immune mediated activity in mCRPC. Methods: In this multicenter randomized phase II study, mCRPC pts (measurable disease, prior abiraterone and/or enzalutamide, nomore than one taxane formCRPC) were randomized toD1500mg IV Q4weeks+/- 4 doses of T 75mg IV. The primary endpoint was ORR (RECIST1.1 and iRECIST) using a Simon 2-stage design. Key secondary endpoints were PSA response rate (RR) and time to progression (TTP). A treatment arm would be considered of interest if ≥4 ORs (null5% or less, alt 20%or more). Correlative testing was done for PD-L1/CD8 IHCon mandatory tumour biopsies and 74-gene panel (∼1Mb) sequencing of plasma cell-freeDNA(cfDNA) both collected at baseline. Results: 52 pts were enrolled: median age 70 yrs (50-83), ECOG 0/1 (13/39 pts), taxane for CRPC (25 pts/48%). Table below shows details of responses. In stage 1, 13 pts were randomized to D with 0% ORR. D+T advanced to stage 2 with a total of 39 pts enrolled who received a median of 3 cycles (1-27). D+T related AEs were mainly grade 2 or less: fatigue (46%), anorexia (28%), rash (24%), diarrhea (23%), nausea/vomiting (21/ 18%) and thyroid dysfunction (15%). Most common grade 3/4 AEs: LFTs (8%) and diarrhea (8%). Six pts discontinued treatment due to AEs. There were no grade 5 AEs. There were six ORs (16% (95% CI: 6-32); OR median duration not reached, longest ongoing 25mos+ with PSA <0.2 ng/ml); all six remain on D, and pain improved in three of four pts. Correlation with full cfDNA panel to be presented. Conclusions: Based on prespecified criteria, Ddid not show sufficient clinical activity, but further studies incorporating patient selection by biomarkers are warranted forD+T. (Table Presented) .