PARP Inhibitors Usher in a New Era for BRCA+ Breast Cancer Treatment

The availability of PARP inhibitors for the treatment of patients with BRCA-mutant metastatic breast cancer has the potential to usher in a new era for targeted therapies. Studies are currently ongoing in the adjuvant setting, as well as in combination with other agents, Debu Tripathy, MD, said in a presentation 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&#8210;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%).

“There were differences in toxicity,” Tripathy said. “Anemia might be more frequent with talazoparib and neutropenia, although it is not seen as frequently as in the chemotherapy groups. I will point out that fatigue is a common event, although it might be a little more common with talazoparib.”

Ongoing PARP Inhibitor Studies

Combinations are a logical next step for the PARP inhibitors, with early findings already available for veliparib plus carboplatin and paclitaxel from the phase II BROCADE-2 trial.³ The median PFS was 14.1 months (95% CI, 11.5-16.2) for the veliparib arm and 12.3 months (95% CI, 9.3-14.5) for the placebo group (HR, 0.789; 95% CI, 0.536-1.162; P = .231). The ORR was 77.8% for veliparib versus 61.3% in the placebo group.

The phase III BROCADE-3 study is currently assessing the efficacy and tolerability of carboplatin and paclitaxel with veliparib or placebo for patients with HER2-negative BRCA-associated advanced breast cancer. The study has fully accrued with a primary completion date of May 31, 2018 (NCT02163694).

Several other single-agent trials are also underway. The phase III BRAVO trial is looking at niraparib for HER2-negative, BRCA-mutant advanced breast cancer, with results expected in May (NCT01905592). Additionally, the phase III OlympiA trial is comparing adjuvant olaparib with placebo as a treatment for patients with HER2-negative, germline BRCA-mutant breast cancer. The primary endpoint of the study is invasive disease-free survival, with a primary completion date in March 2020. Study enrollment in the trial is expected to end in April 2018, Tripathy said.

Outside of these studies, PARP inhibitors are being explored with a variety of partners, he noted. “Trials are ongoing in the adjuvant setting, in biomarker-specified BRCA-wild type and in combinations with radiation therapy, immunotherapy, signal transduction inhibitors, such as PI3K/mTOR, Wee1 kinase inhibitors, and CDK 4/6 inhibitors,” he said.

The phase II SWOG 1416 study is exploring other potential markers that could predict response to PARP inhibitors. This trial includes an arm of patients with germline BRCA mutations along with other arms to assess other DNA-repair—associated markers, such as high levels of homologous repair deficiency or mutations in homologous repair genes (NCT02595905). The estimated primary completion date for this study is in October 2021.

References

• Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. 2017;377:523-33. N Engl J Med. doi: 10.1056/NEJMoa1706450.
• Litton JK, Rugo HS, Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07.
• Han HS, Diéras V, Robson M, et al. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: a randomized, phase 2 study. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S2-05.