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

摘要: 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 CTLA-4 with tremelimumab (T) and durvalumab (D) enhances immune mediated activity in mCRPC. Methods In this multicenter randomized phase II study, pts (measurable disease, prior abiraterone and/or enzalutamide, no more than one taxane for mCRPC) were D 1500mg IV Q4 weeks +/- 4 doses T 75mg IV. The primary endpoint was ORR (RECIST1.1 iRECIST) using a Simon 2-stage design. Key secondary endpoints PSA response rate (RR) time progression (TTP). A treatment arm would be considered interest if ≥ 4 ORs (null 5% or less, alt 20% more). Correlative testing done PD-L1/CD8 IHC mandatory tumour biopsies 74-gene panel (∼1Mb) sequencing plasma cell-free DNA (cfDNA) both collected at baseline. Results 52 enrolled: median age 70 yrs (50-83), ECOG 0/1 (13/39 pts), CRPC (25 pts/48%). Table below shows details stage 1, 13 0% ORR. D+T advanced 2 total 39 enrolled who received 3 cycles (1-27). related AEs mainly grade less: fatigue (46%), anorexia (28%), rash (24%), diarrhea (23%), nausea/vomiting (21/18%) thyroid dysfunction (15%). Most common 3/4 AEs: LFTs (8%) (8%). Six discontinued due AEs. There 5 six (16% (95% CI: 6-32); OR duration not reached, longest ongoing 25mos+ . LBA51 Durvalumab + Tremelimumab CI, 0-25%) 0/13 16% 6-32%) 6/37 ≥1% 0/3 5/13 (38%) 0/9 1/19 (5%) TMB , 11 mts/Mb ctDNA ≥ 1/2 (50%) 0/8 4/30 (13%) CD8 density 0/5 5/16 (31%) 0/7 1/14 (7%) RR (0-25%) (6-32%) TTP, CI), mos 2.1 (1.4, 2.6) 2.6 (1.8, 2.8) Conclusions Based prespecified criteria, did show sufficient clinical activity, further studies incorporating patient selection biomarkers are warranted D+T. Clinical trial identification NCT02788773. Legal entity responsible study Canadian Cancer Trials Group (CCTG). Funding AstraZeneca. Disclosure S.J. Hotte: Research grant / (institution): E. Winquist: Honoraria (self): K.N. Chi: Advisory Consultancy: S. Sridhar: U. Emmenegger: C. Canil: A.R. Hansen: L.K. Seymour: All other authors have declared conflicts interest.