Talazoparib Associated with Antitumor Activity in Patients with DNA Damage Repair Mutations

The first interim analysis of a phase 2 trial has found that monotherapy with talazoparib demonstrated encouraging antitumor activity in patients with DNA damage repair (DDR) mutations and docetaxel pretreated metastatic castration-resistant prostate cancer (mCRPC).

Phase 2 and 3 studies with poly ADP ribose polymerase (PARP) inhibitors have demonstrated antitumor activity in patients with mCRPC with DDR mutations and who were previously treated with novel hormonal therapy. It is well known that talazoparib is a potent inhibitor and trapper of PARP, according to the study authors.

TALAPRO-1 planned to enroll approximately 100 patients with measurable soft tissue disease, progressive mCRPC, and DDR mutations likely sensitive to PARP inhibitors, including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C.

Enrollment was planned for patients who received up to 2 chemotherapy regimens, at least 1 of which being taxane-based, and who progressed on at least 1 novel hormonal therapy, such as enzalutamide or abiraterone acetate.

Patients were to receive oral talazoparib 1 mg per day, with the dose adjusted to 0.75 mg per day in case of moderate renal impairment. Patients are treated until radiographic progression, unacceptable toxicity, or consent withdrawal.

The study primary endpoint was objective response rate (ORR) according to blinded independent review. Secondary endpoints are time to overall response, duration of response, prostate-specific antigen (PSA) decrease to less than 50%, circulating tumor cell (CTC) count conversion to 0 and <5 per 7.5 mL of blood, time to PSA progression, radiographic progression-free survival (rPFS), overall survival, safety, patient-reported outcomes, and pharmacokinetics.

A planned interim analysis of safety and efficacy was performed after 20 patients with BRCA1/2 were on treatment for less than or at 8 weeks.

Eighty-one patients received talazoparib and 43 patients enrolled by February 12, 2019, were evaluable for the primary endpoint, of those 20 with BRAC1/2, 2 with PALB2, 14 with ATM, and 7 with other mutations.

All included patients received prior docetaxel treatment and 49% prior cabazitaxel.

The ORR was 25.6%, 50% in patients with BRCA1/2 mutations, and 7.1% in patients with ATM. Overall median rPFS was 5.6 months, whereas rPFS in patients with BRCA1/2 mutations was 8.2 months, and 3.5 months in patients with ATM mutations.

The most common treatment-emergent adverse events were anemia, nausea, asthenia, decreased appetite, constipation, and decreased platelet count.

The authors concluded that treatment with talazoparib shows encouraging antitumor activity in patients with docetaxel-pretreated mCRPC, especially in those with BRCA1/2 mutations.

Reference

• Talazoparib Shows Encouraging Antitumor Activity in Docetaxel Pretreated MCRPC [news release]. Published February 20, 2020. https://www.esmo.org/oncology-news/talazoparib-shows-encouraging-antitumour-activity-in-docetaxel-pretreated-mcrpc. Accessed February 21, 2020.