Can a PARP Inhibitor-Chemotherapy Combination Improve Advanced Breast Cancer Outcomes?

The addition of the PARP inhibitor veliparib (AbbVie) to carboplatin (Paraplatin) and paclitaxel (Taxol) offered significant improvement over the latter two agents alone in patients with HER2-negative advanced breast cancer and a germline BRCA mutation, according to the results of a randomized, phase III trial. The trial was presented at the European Society for Medical Oncology (ESMO) 2019 Congress held September 27-October 1 in Barcelona, Spain.

“Early studies of PARP inhibitors in combination with platinum chemotherapy have been challenging due to exacerbation of myelosuppression, and this may be the result of PARP trapping activity,” said Véronique Diéras, MD, of the Institut Curie in Rennes, France, who presented the new study’s results at ESMO. “Veliparib potently inhibits PARP with minimal PARP trapping [trapping of the PARP enzymes at sites of damaged DNA], and this feature may allow... for better use in combination with platinum chemotherapy.” 

The BROCADE3 trial included a total of 509 patients with advanced, HER2-negative breast cancer; all patients had a germline BRCA1or BRCA2mutation, as it is understood that these cancers have increased sensitivity to both platinum agents and to PARP inhibitors. Patients were randomized to receive either veliparib plus carboplatin and paclitaxel (337 assigned patients, 334 treated) or placebo plus carboplatin and paclitaxel (172 assigned, 170 treated). If both carboplatin and paclitaxel were discontinued prior to disease progression, patients then received blinded veliparib or placebo.

Patient characteristics were well-balanced between the two groups. The median age in the veliparib group was 47 years and 45 years in the placebo group. Just under 90% in both groups were white.

The study met its primary endpoint regarding progression-free survival (PFS). The median PFS with veliparib was 14.5 months, compared with 12.6 months with placebo, for a hazard ratio (HR) of 0.705 (95% CI, 0.566-0.877; P= 0.002). At 24 months, 34% of veliparib patients were progression-free compared with 20% of placebo patients. At 36 months, these rates were 26% and 11%, respectively. A PFS analysis by independent central review found similar results, with a median PFS of 19.3 months with veliparib and 13.5 months without it for an HR of 0.695 (95% CI, 0.537-0.899; P= 0.005).

An interim analysis of overall survival showed some separation, though this did not reach significance. The median OS was 33.5 months with veliparib and 28.2 months with placebo, for an HR of 0.945 (95% CI, 0.729-1.225; P= 0.666).

Response rates were similar, at 75.8% with veliparib and 74.1% with placebo. The clinical benefit rate at 24 weeks (complete response or partial response or stable disease) was 90.7% with veliparib and 93.2% with placebo. Responses appeared more durable with veliparib, with a median duration of response of 14.7 months compared with 11.0 months without the PARP inhibitor.

A total of 115 patients in the veliparib group (34%) experienced a serious adverse event (AE), compared with 29% of the placebo group. AEs leading to dose interruption of the study drug occurred in 90% of veliparib patients and in 86% of placebo patients. Neutropenia, thrombocytopenia, and anemia were among the most common AEs. Diéras said that the addition of veliparib did not substantially alter the toxicity profile of the chemotherapy combination.

“This is the first phase III trial to evaluate a PARP inhibitor with highly-active platinum chemotherapy in patients with advanced breast cancer harboring a germline BRCAmutation,” Diéras said. “The addition of veliparib to carboplatin and paclitaxel provided a statistically significant and clinically meaningful benefit in patients with HER2-negative advanced breast cancer with a germline BRCAmutation.” She said these results suggest eligible patients should be offered PARP inhibition along with chemotherapy.

Sherene Loi, MBBS, PhD, of the Peter MacCallum Cancer Centre in Australia, also discussed the study for ESMO. She noted that the PFS curves are similar to those seen with a similar PARP inhibitor-chemotherapy combination in ovarian cancer, where they separate following the cessation of chemotherapy.

“In my opinion, it’s hard to know if the effect observed is due to upfront veliparib-chemotherapy combination, and/or the continuation phase of monotherapy,” she said. “I think it’s important to await further for mature OS data and patient-reported outcomes.”