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Background: Pts who have progressed on a prior NHT and have mCRPC with extrapelvic nodal or visceral metastasis have a poor prognosis with limited, broadly available treatment options beyond chemotherapy. C promotes an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors (ICIs). Methods: Pts randomized 1:1 to C+A (C [40 mg PO QD] + A [1200 mg IV Q3W]) or control (ctrl) (abiraterone [1000 mg PO QD] + prednisone [5 mg PO BID] or enzalutamide [160 mg PO QD]) were stratified by liver metastasis (yes/no), prior docetaxel for mCSPC (yes/no), and prior NHT for mCSPC/M0CRPC/mCRPC. Key eligibility criteria: mCRPC with disease progression on one prior NHT, measurable extrapelvic nodal or visceral disease, ECOG PS ≤1, ongoing androgen deprivation therapy. Docetaxel was allowed for mCSPC. Dual primary endpoints are radiographic PFS by blinded independent radiology committee (BIRC) per RECIST 1.1 in the first 400 randomized pts (PITT) and OS in all randomized pts (ITT). Secondary endpoint is ORR by RECIST 1.1 per BIRC. Results: At the data cutoff (Feb 28, 2023), 507 pts (ITT) were randomized to receive C+A (n=253) or ctrl (n=254). Baseline and clinical characteristics were balanced between C+A and ctrl arms: 25% and 26% had liver metastasis, 21% and 20% received docetaxel for mCSPC, and 72% and 74% received first NHT for mCRPC. Median follow-up was 12.0 mo for ITT and 14.3 mo for PITT populations. Median PFS was significantly longer with C+A vs ctrl (6.3 vs 4.2 mo; HR 0.65, 95% CI 0.50-0.84; P=0.0007) including in subgroups with liver metastasis (6.0 vs 2.1 mo; HR 0.47 [95% CI 0.30- 0.74]) or prior docetaxel treatment for mCSPC (8.8 vs 4.1 mo; HR 0.55 [0.32-0.96]). ORR was higher in C+A vs ctrl in pts with follow-up ≥6 mo in ITT (13.6% [23/169] vs 4.2% [7/165]). Median DOR was 9.7 mo for C+A vs not reached for ctrl, and time to response was 2.3 vs 4.6 mo. DCR was 72.8% (123/169) vs 54.5% (90/165). OS data are immature. Treatment-emergent adverse events (TEAE) occurred in 97% in C+A vs 87% in ctrl (grade 3/4 events, 48% vs 23%). Grade 5 TEAEs occurred in 9% vs 12% and no grade 5 treatment-related AEs occurred in either arm. TEAEs led to the discontinuation of all treatment components in 16% in C+A and 15% in ctrl. Conclusions: C+A significantly improved PFS vs second NHT in pts who had progressed on a prior NHT and have mCRPC with extrapelvic nodal or visceral disease, a population with high unmet medical need. These PFS benefits were particularly notable in pts with liver metastasis and those who previously received docetaxel for mCSPC. Toxicities reported with each treatment arm were manageable. CONTACT-02 is the only phase 3 study of an ICI-based regimen to show a significant and clinically meaningful improvement in PFS in prostate cancer with visceral metastasis. Follow-up for OS is ongoing. Clinical trial information: NCT04446117.