A phase Ib/II study of intermittent talazoparib plus temozolomide in patients with metastatic castration-resistant prostate cancer (mCRPC) and no mutations in DNA damage repair (DDR).

Abstract

e17036 Background: Poly (ADP-ribose) polymerase (PARP) inhibition exhibits an enhanced cytotoxic effect in cancers with DDR alterations, but as monotherapy has little activity for those without DDR defects. A variety of combinatorial methods utilizing PARP inhibitors are under investigation to determine if a multimodal approach could benefit patients without DDR alterations. Supported by pre-clinical models, we hypothesized that the PARP inhibitor talazoparib in combination with the chemotherapy temozolomide could induce DNA damage leading to cell death and tumor response. Methods: This is a single arm Phase 1b/2 study of escalating doses of intermittent talazoparib (Day (D) 1-6) plus temozolomide (D2-8) in 28D cycles in patients with mCRPC without DDR mutations. Patients must have failed at least one androgen receptor signaling inhibitor and may have received chemotherapy in the hormone sensitive setting. Response is determined by a composite endpoint of overall response per RECIST v1.1, PSA50% decline, and CTC conversion from >1 to 0. Pharmacokinetic samples were collected, and the mTPI-2 method was used in escalation. Results: 13 patients were enrolled across 4 dose levels in escalation. The most common adverse events were anemia (any grade (Gr) 31%, Gr3 23%), thrombocytopenia (any Gr 54%, Gr3+ 30.7%), fatigue (Gr≤2, 62%), and nausea (Gr1 46%). There was one patient with a DLT (Gr3 neutropenic fever, Gr4 thrombocytopenia). The identified RP2D was talazoparib 1 mg (D1-6) and temozolomide 75mg/m2 (D2-8). 4 (30.8%) patients met the efficacy endpoint (3 CTC responses, 1 PR, 0 PSA50% decline). While there were no PSA50 responses, 2 (15.4%) patients had a PSA30% decline. Median duration on trial was 20 weeks with 4 (30.8%) patients on trial for ≥6mos, 2 of whom also met the efficacy endpoint. Conclusions: Hematologic toxicity was dose limiting in this combination strategy using intermittent dosing of talazoparib and temozolomide in patients with mCRPC without DDR alterations. A reduction in CTCs to 0 was identified at several dose levels, and PSA30% declines were seen in 2 patients. With identification of the RP2D, enrollment in the Phase 2 study is currently underway. Clinical trial information: NCT04019327 .