PARP Inhibitors Arrive for BRCA+ Breast Cancer

Silas Inman @silasinman
Published: Saturday, Mar 10, 2018

Debu Tripathy, MD
Debu Tripathy, MD
The PARP inhibitors have finally become available for patients with BRCA-mutant metastatic breast cancer, ushering in a potential new era for targeted therapies with studies currently ongoing in the adjuvant setting and exploring combinations, according to a presentation by Debu Tripathy, MD, at the 2018 Miami Breast Cancer Conference®.

There are currently 5 PARP inhibitors being explored for patients with breast cancer, with each demonstrating different levels of activity against PARP. The agent with the highest level of “PARP trapping,” Tripathy said, is talazoparib, followed by niraparib, rucaparib, olaparib, and veliparib.

“We know now that the PARP inhibitors exist on a spectrum of biological properties. Those with the highest so-called PARP trapping activity sequester the PARP enzyme and make it unavailable to the DNA repair machinery,” said Tripathy, professor and chair, Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center. “Not only does this correlate with higher potency but more toxicity when combined with cytotoxic chemotherapy.”

Phase III Findings for PARP Inhibition

Of the explored PARP inhibitors, the first to gain approval was olaparib (Lynparza), which was FDA-approved in January 2018 for patients with HER2-negative, germline BRCA1/2-mutant metastatic breast cancer following prior chemotherapy. This indication was based on findings from the phase III OlympiAD trial, which randomized 302 patients with HER2-negative, germline BRCA1/2-mutated metastatic breast cancer to receive 300-mg olaparib tablets twice daily (n = 205) or chemotherapy treatment of physician's choice (n = 97).

In the study,1 median PFS was 7.0 months in the olaparib arm versus 4.2 months with standard chemotherapy (HR, 0.58; 95% CI, 0.43-0.80; P = .0009). The objective response rate (ORR) was 59.9% with olaparib versus 28.8% with chemotherapy. Median overall survival (OS) was not improved between the 2 arms; however, Tripathy noted that the data were still immature. The median OS was 19.3 months with olaparib and 19.6 months for chemotherapy (HR, 0.90; 95% CI, 0.63-1.29; P = .5665).

There was a more pronounced benefit for the PARP inhibitor in patients with triple-negative breast cancer. In those with hormone receptor (HR)-negative, HER2-negative disease, there was a 57% reduction in the risk of progression or death with olaparib versus chemotherapy (HR, 0.43; 95% CI, 0.29-0.63). In patients with HER2-negative, HR-positive breast cancer, the reduction in progression or death was 18% with olaparib, which was not statistically significant (HR, 0.82; 95% CI, 0.55-1.26).

Adding to this approval, findings from the phase III EMBRACA trial exploring talazoparib were presented at the 2017 San Antonio Breast Cancer Symposium.2 In this study, patients were randomized to oral talazoparib at 1 mg daily (n = 287) or physician’s choice of therapy (n = 144). All patients in the trial had BRCA-mutant advanced breast cancer.

At a median follow-up of 11.2 months, the median PFS was 8.6 months (95% CI, 7.2-9.3) with talazoparib compared with 5.6 months (95% CI, 4.2-6.7) with physician’s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71; P <.0001). The 1-year PFS rate was 37% with talazoparib versus 20% with chemotherapy. In patients with central nervous system metastasis, the median PFS was 5.7 months with talazoparib versus 1.6 months for chemotherapy (HR, 0.32; 95% CI, 0.15-0.68; P = .0016). The ORR was 62.6% versus 27.2%, respectively.

At the interim analysis, the OS was 22.3 months with talazoparib versus 19.5 months for chemotherapy, which showed a hint of improvement, Tripathy said (HR, 0.76; 95% CI, 0.54-1.06; P = .105). The OS rates at 24 months were 45% and 37%, for talazoparib and chemotherapy, respectively. The 36-month OS rates were 34% and 0%, respectively.

“Randomized trials of olaparib and talazoparib show longer PFS with PARP inhibition compared to single-agent chemotherapy in BRCA-mutation‒associated metastatic breast cancer,” said Tripathy. “There’s a hint of greater activity in HR-negative and non-platinum exposed. There's no difference yet apparent in survival but the data are not mature.”

With both agents showing similar efficacy, the adverse events (AEs) become a differentiating factor between the 2 PARP inhibitors. With olaparib, the most common AEs were nausea (58%), anemia (40%), vomiting (30%), fatigue (29%), neutropenia (27%), diarrhea (21%), and headache (20%). For talazoparib, the most common AEs were anemia (53%), fatigue (50%), nausea (49%), neutropenia (35%), headache (33%), alopecia (25%), vomiting (25%), diarrhea (22%), and constipation (22%).




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