Phase II study of talazoparib in advanced cancers with BRCA1/2, DNA repair, and PTEN alterations

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Cancer cells with BRCA1/2 deficiencies exhibit sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors.
• DNA Damage Repair (DDR) pathways are crucial in maintaining genomic stability and are often dysregulated in cancer.

Purpose of the Study:

• To evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with various DNA-Damage Repair (DDR) alterations.
• To assess the clinical benefit rate (CBR) of talazoparib across different molecularly defined cohorts.

Main Methods:

• Phase II clinical trial enrolling 79 patients with DDR alterations into four cohorts: somatic BRCA1/2, other homologous recombination repair (HRR) pathway alterations, PTEN alterations, and germline BRCA1/2 alterations.
• Primary endpoint: Clinical Benefit Rate (CBR) defined as complete response, partial response, or stable disease for ≥24 weeks.
• Patients had received a median of 4 prior lines of therapy.

Main Results:

• Overall CBR for cohorts 1-4 were 32.5%, 19.7%, 9.4%, and 30.6%, respectively.
• Talazoparib demonstrated a clinical benefit in patients with somatic BRCA1/2 and germline BRCA1/2 alterations.
• PTEN mutations were associated with reduced survival and a trend towards shorter time to progression, with limited clinical benefit observed in this cohort.

Conclusions:

• Talazoparib is effective in a select group of DNA-Damage Repair (DDR)-altered patients, particularly those with BRCA1/2 mutations.
• Patients with PTEN mutations or loss derived limited clinical benefit from talazoparib treatment.
• Further investigation is warranted to determine if PTEN status is prognostic or predictive of response to PARP inhibitors.