New PARP inhibitor shows improved PFS in advanced breast cancer

By Naveed Saleh, MD, MS, for MDLinx
Published November 2, 2018

Key Takeaways

Talazoparib yielded longer progression-free survival when compared with standard chemotherapy in patients with advanced breast cancer and BRCA1/2 germline mutations, according to a recent article published in the New England Journal of Medicine.

“The poly(adenosine diphosphate–ribose) [PARP] inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2,” wrote the authors, led by Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston.

Cancer cells with BRCA1/2 mutations lack repair mechanisms for double-stranded DNA breaks—they rely on the repair pathway for single-stranded breaks, which is regulated by PARP. PARP inhibitors kill BRCA1/2 cancer cells due to the buildup of DNA damage.

Along with catalytic inhibition, PARP inhibitors result in PARP trapping at sites of DNA damage.  Preclinical models have suggested that PARP trapping may further enhance cancer-cell death in addition to catalytic inhibition.

Talazoparib is a powerful PARP inhibitor, with high PARP inhibition and PARP-trapping potential; the drug’s PARP-trapping potential is 100-fold greater than other PARP inhibitors now being studied.

In this randomized, open-label phase 3 trial, researchers compared the safety and efficacy of talazoparib with the specialist’s choice of standard single-agent chemotherapy for the treatment of locally advanced or metastatic breast cancer in patients with BRCA1/2 mutations.

The researchers randomized 431 patients in a 2:1 ratio to receive either talazoparib (1 mg once daily) (N=287) or standard single-agent therapy of the specialist’s choosing (ie, capecitabine [44%], eribulin [40%], gemcitabine [10%], or vinorelbine [7%]) (N=144).

The primary endpoint was radiologic progression-free survival. Secondary endpoints included overall survival, the objective response rate, the clinical benefit rate at 24 weeks, and the duration of response. The team identified the clinical benefit rate at 24 weeks as the rate of complete response, partial response, or stable disease at 24-plus weeks.

Results showed that median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs 5.6 months; HR for disease progression or death: 0.54; 95% CI: 0.41 to 0.71; P < 0.001).

The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs 27.2%; OR: 5.0; 95% CI: 2.9 to 8.8; P < 0.001). All other secondary endpoints favored talazoparib vs standard therapy, as well.

The most common adverse events included anemia, fatigue, and nausea in patients administered talazoparib, and nausea, fatigue, and neutropenia in patients administered standard therapy. Grade 3 or 4 hematologic adverse events were experienced by 55% of patients in the talazoparib group, and 38% in the standard-therapy group.

Grade 3 nonhematologic adverse events occurred in 32% of talazoparib patients and 38% of standard-therapy patients; the majority of nonhematologic adverse events in talazoparib group were grade 1.

In total, 5.9% of talazoparib patients discontinued treatment secondary to adverse events vs 8.7% of those receiving standard chemotherapy.

“Patient-reported outcomes favored talazoparib,” wrote the authors. “Significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status–quality-of-life and breast symptoms scales were observed.”

The authors conceded that one limitation of the current study was the open-label design, which was necessary due to the mix of oral and intravenous treatment options in the standard-therapy group. Nevertheless, 18 patients in the standard-therapy group withdrew before taking the first dose, whereas only one patient withdrew before the first dose in the talazoparib group.

“Among patients with advanced breast cancer and a germline BRCA1/2 mutation,” concluded the authors, “single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib.”

This study was funded by Pfizer.

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