Phase 2 multicenter trial of chemoimmunotherapy for patients with neuroendocrine or aggressive variant metastatic prostate cancer (CHAMP).

5016 Background: Platinum-doublet chemotherapy is effective in pts with neuroendocrine small cell neuroendocrine or aggressive-variant prostate cancer (NEPC/AVPC), but responses have limited durability. PD-1/PD-L1 inhibition in small cell lung cancer with chemotherapy is standard of care, but chemoimmunotherapy has not been tested in patients with NEPC/AVPC. Methods: We conducted a multicenter, phase II trial evaluating cabazitaxel, carboplatin, ipilimumab, and nivolumab (NCT04709276) in patients with metastatic NEPC/AVPC defined by histologic, clinical, or molecular features. Ipilimumab was dosed at 1 mg/kg q6w and nivolumab 360 mg q3w w/ongoing ADT. Cabazitaxel 20-25 mg/m2 + carboplatin AUC4 with GCSF was given q3w up to 10 cycles but could be stopped early for response or toxicity, followed by maintenance immunotherapy. Primary endpoint was immune modified iRECIST/PCWG3 radiographic progression-free survival (rPFS), hypothesizing a 55% 6-mo rPFS rate for cabazitaxel/carboplatin (1-sided α 0.1, 85% power) based on historic data. Secondary endpoints: overall survival (OS), rPFS, objective responses, safety. Results: We enrolled 40 patients across 3 centers in the Department of Defense Prostate Cancer Clinical Trials Consortium from 7/2021-8/2025, including 12 (32%) with NEPC and 28 (68%) with AVPC, with 38 evaluable for efficacy. Median age was 65 yrs, median PSA 2 ng/dl (range 0-807), and 75% with any visceral metastases including 58% with liver and 33% with lung metastases. The % with elevated serum CEA, LDH, or CgA was 88%; 85% had prior ARPI and 70% prior chemo. With a median f/u of 17 mo, CHAMP met its primary endpoint of improving 6-mo rPFS vs. cabazi/carbo with a 6-mo PFS rate of 78% (90% CI 69-100%); median rPFS was 12 mo. See Table for efficacy. We observed 20 G3 (50%) and 7 G4 (18%) toxicities related to treatment on a per patient basis. Two patients are free of disease and off therapy at 30+ mo. Most common overall G3-4 toxicities were anemia (n=15), neutropenia (n=5), sepsis (n=5), thrombocytopenia (n=5), colitis (n=5), febrile neutropenia (n=4), and UTI (n=4), with no treatment-related deaths. Conclusions: Dual PD-1/CTLA4 immune checkpoint blockade with platinum doublet chemotherapy is effective in patients with AVPC/NEPC, resulting in greater efficacy than expected with historic platinum chemotherapy alone, and with acceptable toxicity given disease risk. These results support randomized controlled clinical trials of chemoimmunotherapy in patients with NEPC/AVPC. Clinical trial information: NCT04709276 . Primary Endpoint (n=38) Outcome (95% CI) 6 mo PFS (%) by iRECIST/PCWG3 (1-sided 90% CI) 78% (69-100%) Secondary Endpoints 12 mo rPFS (%, 95% CI) 44% (29-69%) PFS, median by iRECIST/PCWG3, moPFS, median by RECIST/PCWG3, mo 12 (9.6-17)6.8 (4.3-9.2) OS, median, mo12-month OS (%) 12 (9.6-17)46% (30-69%) iRECIST Best Radiographic ResponseORR (CR+PR) %CRPRSDiUPD/iCPD 34%2.6%32%45%13/8%