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.

Publication/Presentation Date

9-4-2025

Abstract

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/m

ISSN

1573-0646

Disciplines

Medicine and Health Sciences

PubMedID

40906325

Department(s)

Department of Medicine, Hematology-Medical Oncology Division

Document Type

Article

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