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Talazoparib in Patients With Metastatic Castration-Resistant Prostate Cancer and DNA Repair Gene Alterations


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In the phase II TALAPRO-1 trial reported in The Lancet Oncology, Johann S. de Bono, PhD, and colleagues found that monotherapy with the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib produced durable responses in patients with metastatic castration-resistant prostate cancer and DNA damage response (DDR)/homologous recombination repair (HRR) gene alterations.

Johann S. de Bono, PhD

Johann S. de Bono, PhD

Study Details

In the ongoing trial, 127 patients enrolled from sites in 14 countries between October 2017 and March 2020 received talazoparib at 1 mg/d (0.75 mg/d in those with moderate renal impairment) until disease progression or unacceptable toxicity. Patients had received one or two taxane-based chemotherapy regimens for metastatic castration-resistant disease, which had progressed on enzalutamide, abiraterone, or both.

The primary endpoint was confirmed objective response rate on blinded independent central review. Efficacy outcomes were assessed in 104 patients with measurable soft-tissue disease.

Responses

At data cutoff (September 2020), median follow-up was 16.4 months (interquartile range = 11.1–22.1 months). Objective response was observed in 31 (29.8%, 95% confidence interval [CI] = 21.2%–39.6%) of 104 patients, including complete response in 7 (7%). Median duration of response was 12.8 months (95% CI = 6.5 months–not evaluable), with 12 responders having  ongoing response at data cutoff. Response was observed in 26 (46%) of 57 patients with BRCA2 alterations, 2 (50%) of 4 with BRCA1 alterations, 1 (25%) of 4 with PALB2 alterations, and 2 (12%) of 17 with ATM alterations. Stable disease was observed in an additional 37 patients (36%).

Median radiographic progression-free survival was 5.6 months (95% CI = 3.7–8.8 months), including 11.2 months in both patients with BRCA1 or BRCA2 alterations and BRCA2 alterations alone, 5.6 months in those with PALB2 alterations, and 3.5 months in those with ATM alterations.

KEY POINTS

  • Objective response was observed in 30% of patients.
  • Median duration of response was 12.8 months.

Adverse Events

Among 127 patients who received at least one dose of the study drug, grade 3 or 4 adverse events occurred in 48%; the most common were anemia (31%), thrombocytopenia (9%), and neutropenia (8%). Serious adverse events were reported in 34% of patients, with the most common being pulmonary embolism (6%) and anemia (4%).

Adverse events led to discontinuation of treatment in 12%, with causes including hematologic toxicity and vomiting. No treatment-related deaths were observed, and no cases of myelodysplastic syndrome or acute myeloid leukemia were seen.  

The investigators concluded, “Talazoparib showed durable antitumor activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favorable benefit-risk profile supports the study of talazoparib in larger, randomized clinical trials, including in patients with non-BRCA alterations.”

Dr. de Bono, of The Institute of Cancer Research and Royal Marsden Hospital, London, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Pfizer/Medivation. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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