Background: Androgen deprivation therapy (ADT) combined with novel hormonal agents +/- docetaxel is a standard of care treatment for mHSPC. The combination of tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) is FDA approved in renal cell carcinoma, and shows promising efficacy in preclinical models of prostate cancer by favorably altering the tumor immune microenvironment. There are currently ongoing trials of TKI + ICB in metastatic castration resistant prostate cancer. Here we present interim safety results from an ongoing phase Ib single-arm trial of cabozantinib + nivolumab + abiraterone/prednisone (cabo, nivo, abi/pred) in pts with newly diagnosed mHSPC (NCT04477512). Methods: Eligible pts had de-novo or recurrent mHSPC with up to 12 weeks ADT prior to enrollment, ECOG 0-1, and adequate organ function. Prior abi and docetaxel were excluded. Pts received cabo 20 mg or 40 mg daily (3+3 dose escalation in 2 cohorts) combined with nivo 480mg IV q4 weeks, and abi/pred 1,000mg/5mg daily until progression or unacceptable toxicity. The primary endpoint is safety and tolerability. Secondary endpoints include overall response rate (ORR) by RECIST 1.1, overall survival (OS), progression free survival (PFS), and PSA response. Exploratory analyses include CyTOF of peripheral blood and serum cytokine ELISA. Results: As of 19DEC2022, 17 pts were enrolled, 3 at 20mg and 14 at 40mg cabo with no dose-limiting toxicity (DLTs) observed. Median age was 65 yrs, 4/17 pts are Black, 11 had de-novo and 6 recurrent disease, with median baseline PSA 78ng/mL. Most had bone (n=16), lymph node (6), or lung (1) mets, and 11 (64.7%) had high-volume disease. With median follow-up 12.8 months, 9 pts (53%) remain on study. 1 withdrew, 3 discontinued due to disease progression (with 1 death), and 4 stopped due to toxicity. Grade ≥ 3 adverse events (AEs) include encephalitis (n=1, grade 4 likely nivo-related after 1yr on therapy), diarrhea (n=2), elevated AST/ALT (n=4), wound infection/dehiscence, adrenal insufficiency, hypertension, elevated lipase, and proteinuria (grade 3, n=1 each). No other AEs were reported outside the current safety labels for the study agents. Of 15 response evaluable pts, 7 had RECIST-measurable lesions; 4 had partial response and 3 had stable disease as best response at data cutoff. 9/14 (64.3%) evaluable had PSA <0.2ng/mL at 7 months. Immune correlative studies are ongoing. Conclusions: Here we present the initial safety and preliminary efficacy results of the first trial of cabo + nivo in mHSPC patients receiving SOC ADT + abi. To date, the combination has a safety profile consistent with known AEs for these agents, no DLTs, and evidence of clinical benefit. Further follow up will be required to fully assess clinical safety, efficacy and immune responses. Future, larger studies could compare this combination to SOC ADT + abi. Clinical trial information: NCT04477512.