A phase 1b study of novel immunogenic cell death inducer PT-112 plus PD-L1 inhibitor avelumab in metastatic castrate-resistant prostate cancer (mCRPC) patients.
Authors: Alan Haruo Bryce, Roxana Stefania Dronca, Brian Addis Costello, Ana Aparicio, Sumit Kumar Subudhi, Joseph F. O'Donnell, Jose Jimeno, Christina Yeaeun Yim, Tyler David Ames, Matthew Price, Daniel D. Karp
Journal: Journal of Clinical Oncology (2021)

e17025 Background: PT-112 is a novel pyrophosphate-platinum conjugate that induces immunogenic cell death, reaches highest concentrations in bone (osteotropism), and synergizes with immune checkpoint inhibitors (ICIs) in preclinical models. Phase I studies in solid tumors, as monotherapy and in combination with PD-L1 inhibitor avelumab (“PAVE”), as well as in multiple myeloma as monotherapy have demonstrated that PT-112 is well-tolerated and active. We present updated safety and exploratory efficacy findings in a mCRPC sub-population treated with PAVE, including a cohort of patients at a lower-frequency dosing schedule. Methods: A total of 32 mCRPC patients (pts) received 800 mg of avelumab on days 1 and 15 of a 28-day cycle, of whom 18 received PT-112 on days 1, 8 and 15 at 200mg/m 2 (n = 17) or 150 mg/m 2 (n = 1); a separate cohort of 14 received PT-112 on days 1 and 15 at 300 mg/m 2 (n = 13) or 200mg/m 2 (n = 1). Results: Median age was 68 (range 47-87) and number of prior lines of therapy (Tx) was 7 (2-12), including prior platinum-containing therapy in 11 (34%) and ICI Tx in 9 pts (28%). Baseline grade 2 anemia was seen in 7 (22%) pts. The most common treatment-related adverse events (TRAEs) were anemia (47%) and thrombocytopenia (41%); 23 pts (72%) had ≥1 grade 3-4 TRAE, with no cases of bleeding, sepsis, or grade 5 TRAEs. Antitumor effects included 8 (25%) pts with a PSA reduction of ≥50% (PSA 50 ); 5 (16%) were maintained through ≥1 follow-up. Of ten pts with RECIST-measurable disease, 3 had tumor volume reductions, one with a confirmed partial response (PR). Twenty-four (75%) pts experienced a reduction in serum alkaline phosphatase (ALP) (median reduction 15%), and improvement in patient-reported pain and quality of life was observed. For the 13 pts given 300 mg/m 2 PT-112 bi-weekly, 7 (54%) had prior platinum-containing Tx and 4 (31%) had baseline grade 2 anemia. The most common TRAEs were anemia (69%) and thrombocytopenia (54%), with 11 (85%) pts having ≥1 grade 3-4 TRAE. Four pts (31%) had PSA 50 reductions; 3 (23%) were maintained through ≥1 follow-up. Conclusions: PAVE is safe and generally well tolerated in mCRPC patients at the doses and schedules tested, providing meaningful antitumor effects in heavily pre-treated patients, including tumor volume, PSA and ALP reductions. Reductions in ALP may be indicative of anti-cancer activity at bone sites of disease. Although the sample sizes are small, the frequency of confirmed PSA 50 responses and of grade 3-4 TRAEs was slightly higher in the group receiving biweekly 300 mg/m 2 PT-112, and higher rates of TRAEs may be explained by higher baseline anemia and/or prior platinum Tx. Further clinical investigation of the combination of PT-112 plus ICIs in a less heavily pre-treated mCRPC population is warranted. A phase 2 study of PT-112 monotherapy in mCRPC is ongoing. Clinical trial information: NCT03409458.