A phase 1b/2 study of intermittent talazoparib plus temozolomide in patients with metastatic castration-resistant prostate cancer and no mutations in DNA damage response genes.

As monotherapy, PARP inhibitors have little cytotoxic effect in tumors without homologous recombinant repair (HRR) alterations. Supported by preclinical models, we hypothesized that the PARP inhibitor talazoparib in combination with temozolomide chemotherapy could induce DNA damage leading to cell death and tumor response in patients with metastatic castration-resistant prostate cancer (mCRPC) without HRR alterations. In this phase 1b/2 trial (NCT04019327; registration date July 11, 2019), patients with progressive mCRPC without HRR mutations who failed at least one androgen receptor signaling inhibitor were enrolled in escalating doses of intermittent talazoparib plus temozolomide to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) in Phase 1b. Phase 2 used a composite endpoint of overall response per RECIST v1.1, 50% decline in prostate-specific antigen (PSA), and/or circulating tumor cells (CTC) conversion from ≥ 1 cell/7.5 mL to 0. Sixteen patients were enrolled across 4 dose levels. The most common adverse events were thrombocytopenia, neutropenia, anemia, fatigue, and nausea. In phase 1b, one patient receiving talazoparib 1 mg and temozolomide 75 mg/m² had a dose-limiting toxicity (grade 3 neutropenic fever, grade 4 thrombocytopenia). The RP2D was talazoparib 1 mg once daily (QD) (D1-6) and temozolomide 75 mg/m² QD (D2-8) in 28D cycles. The phase 2 portion was terminated early. Across dose levels, three (18.8%) patients met the efficacy endpoint. Hematologic toxicity was dose-limiting in this combination strategy using intermittent dosing of talazoparib and temozolomide in patients with mCRPC without HRR alterations. The risk/benefit profile did not support further evaluation.