Background: PT-112, the first pyrophosphate conjugate in Phase I/II clinical development, induces robust immunogenic cell death and is osteotropic, prompting study in mCRPC during Phase I. We report safety and efficacy findings in the mCRPC sub-population given PT-112 monotherapy (NCT02266745) or in combination with avelumab (“PAVE”) (NCT03409458, ongoing). Methods: Patients (pts) received PT-112 days 1, 8, 15 of a 28d cycle; pts on the PAVE combination also received 800 mg avelumab days 1 and 15; all enrolled during dose escalation or at PT-112 doses previously deemed safe. Pts on therapy (Tx) for ≥2 cycles or who stopped Tx due to progressive disease or treatment-related adverse events (TRAEs) were evaluated for exploratory efficacy. Results: 10 pts on PT-112 (200-420 mg/m²) and 18 pts on PAVE (150-200 mg/m² PT-112) were evaluable for safety. The most common PT-112 TRAEs were thrombocytopenia (70%, grade (Gr) ≤3) and fatigue (40%, Gr ≤2) with mono-Tx; nausea (50%, Gr ≤2) and fatigue (39%, Gr ≤2) with PAVE. Mono-Tx pts had 6.5 median prior lines of Tx; 2/7 pts with measurable disease (MD) had reductions in target lesions; prostate specific antigen (PSA) declined in 3/10 pts, 1 with ≥50% reduction; and serum alkaline phosphatase (ALP) reductions were seen in 9/10 pts. PAVE pts had 5.5 median prior lines of Tx; radiographic reductions were seen in 2/9 pts with MD; PSA declined in 6/14 pts, 3 with ≥50% decrease, with 1 responder progression free 11.3 months (microsatellite stable). An additional response is ongoing at 4 mos, with 93% PSA decrease and 48% reduction in target lesions (PIK3CBmut & PTEN loss). 13/14 pts with bone metastases had ALP reductions. Pain improvement, opioid cessation and improved performance status were noted in both cohorts. Conclusions: PT-112 was well-tolerated with evidence of efficacy in mCRPC as mono-Tx and in combination with avelumab in heavily pre-treated pts. Bone pain improvement and nearly universal observation of ALP reduction suggest marked therapeutic activity of PT-112 in bone metastases. Serologic / RECIST responses and prolonged disease control in multiple pts substantiate further development of PT-112 in mCRPC. Clinical trial information: NCT02266745, NCT03409458