Cabozantinib (C) ± atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Expansion cohorts from the open-label phase 1b COSMIC-021 study.
Authors: Neeraj Agarwal, Ulka N. Vaishampayan, Jingsong Zhang, Xavier Artignan, Begoña Mellado, Shirley S. Wong, Omi Parikh, Daniel Castellano, Joaquina Celebre Baranda, Denise Williamson, Lavanya Gunachandran, Xiang Guo, Prachi Nandoskar, Bradley Alexander McGregor, Sumanta Kumar Pal
Journal: Journal of Clinical Oncology (2025)

145 Background: The phase 3 CONTACT-02 study significantly improved PFS and showed a trend in OS benefit with C+A vs a second novel hormone therapy (NHT) in mCRPC pts with soft tissue metastases (mets). We report outcomes from similar pts in the randomized mCRPC expansion cohorts of COSMIC-021 evaluating the contribution of adding A to C vs C alone. Methods: Pts with mCRPC with extrapelvic visceral or nodal mets who progressed on one prior NHT were randomized to receive C (60 mg QD), A (1200 mg IV Q3W), or C (40 mg QD) + A (1200 mg IV Q3W). Cohort A (n=10) was terminated early (lacked objective responses). The primary and secondary endpoints were investigator-assessed ORR per RECIST v1.1 and safety, respectively. Efficacy outcomes by blinded independent radiology committee (BIRC) were also assessed. Flow cytometry and proteomic profiling were performed on baseline and on-treatment samples. Results: A total of 101 pts were randomized to C (n=51) and C+A (n=50); median age was 70 y in both groups, 75%/72% had bone mets, 20%/24% had liver mets, and 31%/24% received docetaxel for mCSPC. ORR by BIRC (Table) and investigator (C: 20%, 95% CI, 10–33; C+A: 22%, 95% CI, 12–36) were similar between groups. Although PFS by BIRC was similar (Table, HR, 0.96; 95% CI, 0.59–1.58), the KM estimate of pts without events at 12 mo was higher with C+A (25.8% vs 14.0%). Compared with C, C+A group had longer DOR (~2-fold), fewer pts with progressive disease (PD) as best response, a numerically higher median OS (HR, 0.91; 95% CI, 0.57–1.46), more pts with PSA response with longer duration of response (median mo [95% CI], NE [6.24, NE] vs 6.93 [4.63, NE]), and prolonged time to PSA progression (Table). In the liver mets subgroup, median PFS and OS were longer with C+A vs C (PFS: HR, 0.44; 95% CI, 0.15–1.34, 5.7 vs 2.5 mo; OS: HR, 0.25; 95% CI, 0.08–0.77, 14.7 vs 5.0 mo). Grade 3–4 treatment-related adverse events occurred in 51% and 58% in C and C+A, respectively; no grade 5 events occurred. Differential regulation of activated CD8 T cells, myeloid-derived suppressor cells, and immune response and apoptosis-related proteins were observed with C+A vs C or A. Conclusions: C and C+A demonstrated clinical activity in pts with mCRPC and extrapelvic soft tissue mets, with no new safety signals. These exploratory data from randomized cohorts suggest an additive effect of A to C with a prolonged DOR in C+A vs C; additive clinical benefits were noted in pts with liver mets. Clinical trial information: NCT03170960 . Efficacy outcomes by BIRC. C (n=51) C+A (n=50) ORR, % (95% CI) 12 (4–24) 14 (6–27) Complete / partial response, n (%) 0 / 6 (12) 0 / 7 (14) Stable disease / PD, n (%) 33 (65) / 9 (18) 31 (62) / 6 (12) DCR, n (%) 39 (76) 38 (76) Median DOR (95% CI), mo 4.3 (2.8–NE) 10.6 (6.7–NE) PSA response, n (%) 5 (12%) 8 (20%) Median time to PSA progression (95% CI), mo 3.5 (1.7–5.7) 5.6 (2.7–NE) Median PFS, mo 6.7 5.5 Median OS, mo 13.8 15.6 NE, not evaluable for KM estimates.