Background: AR-V7 is an AR splice variant present in ~20% of men with mCRPC, and is associated with poor responses to abiraterone and enzalutamide. Developing effective treatments for AR-V7+ mCRPC is an unmet medical need, and combined immune checkpoint blockade may be a fruitful approach in such pts. Previous studies have shown benefits using ipilimumab in a subset of mCRPC pts. Given that treatment of prostate cancer cells with potent anti-androgens may induce PD-L1 expression, and given that the AR-V7+ phenotype may be associated with DNA repair defects (mismatch repair, homologous recombination), we hypothesize that the addition of nivolumab in AR-V7+ mCRPC men will improve the response rates seen with ipilimumab, and that the combination will be safe and tolerable. We also hypothesize that successful treatment with this combination may correlate with conversion of AR-V7 from positive to negative, and with baseline PD-L1 expression in CTCs and tumor biopsies. Methods: STARVE-PC is a single-arm open-label phase 2 trial (NCT02601014) of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 wks x 4 doses, followed by nivolumab 3 mg/kg every 2 wks. Treatment will continue until wk 48, radiologic progression, or unmanageable toxicity. The target population (N = 15) is men with mCRPC and detectable AR-V7 using our CTC-enriched RT-PCR–based assay performed in a CLIA lab. CTCs will be collected for AR-V7 analysis at baseline, at wk 12, and at progression, to allow dynamic evaluation of AR-V7 status. The primary endpoint is PSA₅₀ response rate; the trial will meet its endpoint if ≥ 3/15 men achieve a PSA₅₀ response. Additional clinical endpoints include PSA progression free survival (PSA-PFS), clinical/radiologic PFS, objective responses, overall survival, and frequency/intensity of adverse events. We will prospectively assess baseline PD-L1 status in CTCs and metastatic tumor biopsies, and DNA repair defects will also be examined in an exploratory fashion. If this study shows preliminary evidence of clinical activity and reasonable safety, our future goal will be to compare the efficacy of combined checkpoint blockade versus taxane chemotherapy in AR-V7+ mCRPC. Clinical trial information: NCT02601014