In the phase III OlympiAD study, tumors shrank in about 60% of women with BRCA mutation–associated metastatic breast cancer who received the PARP inhibitor olaparib compared with 29% who received chemotherapy; the median time to disease progression was 7 months compared with 4.2 months, respectively. These findings are the first to demonstrate that a PARP inhibitor can improve progression-free survival in metastatic, hereditary breast cancer.

After years of failures and delays for inhibitors of the DNA repair enzyme PARP in the treatment of breast cancer, one has finally proven its worth in a phase III trial of women with metastatic disease who inherited a BRCA mutation and whose tumors progressed despite prior treatment.

On June 4, clinicians reported at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, that patients who received the anti-PARP agent olaparib (Lynparza; AstraZeneca) had a 42% reduced chance of tumor progression compared with those given standard chemotherapy. The median progression-free survival was 7 months for those on olaparib versus 4.2 months for patients taking capecitabine, vinorelbine, or eribulin. The findings were published concurrently in The New England Journal of Medicine.

“This represents a remarkable move forward for patients with limited treatment options,” said BJ Rimel, MD, a gynecologic oncologist at Cedars-Sinai Medical Center in Los Angeles, CA, who was not involved in the study but has consulted for AstraZeneca.

The objective response rate was 29% with chemotherapy, but 60% with olaparib—a level that's “exceptional in this population,” Rimel said. Severe side effects were less common for those taking the PARP inhibitor, occurring in 37% of olaparib recipients compared with 50% of those treated with chemotherapy. The most common side effects with olaparib were nausea, anemia, and fatigue.

Overall survival data are not yet available, but that didn't dampen the enthusiasm of Karen Gelmon, MD, a medical oncologist at the BC Cancer Agency in Vancouver, Canada, who has studied olaparib in other trials. “Although they'd like an improvement in overall survival, what [patients] really want is an effective nontoxic drug that is going to keep them stable for as long as possible,” she said—and the PARP inhibitor seems to do that better than anything else available for hereditary, metastatic breast cancer.

The multinational OlympiAD study, led by Mark Robson, MD, from Memorial Sloan Kettering Cancer Center in New York, NY, included 302 patients with previously treated metastatic breast cancer who harbored germline mutations in BRCA1 and/or BRCA2—alterations that reduce the cell's ability to repair damaged DNA, making tumors particularly vulnerable to PARP inhibition. Half of the participants had triple-negative breast cancer (TNBC) and the other half had HER2-negative, hormone receptor–positive disease; all were randomized 2:1 to either olaparib or physician's choice chemotherapy.

Olaparib earned FDA approval in late 2014 for the treatment of hereditary BRCA-mutated advanced ovarian cancer. On the strength of the OlympiAD results, AstraZeneca said it plans to file a supplementary marketing application before the end of the year to add hereditary BRCA1- and BRCA2-associated metastatic breast cancer to the drug's label.

If approved, it would be the culmination of a long and bumpy road for PARP inhibitors for the treatment of breast cancer. In early 2011, Sanofi-Aventis reported that iniparib failed to prolong survival in a phase III trial in metastatic TNBC. (Iniparib was the most advanced putative PARP inhibitor at the time, although researchers subsequently showed that it didn't actually block PARP at clinically relevant doses.)

Around the same time, AstraZeneca announced that it would put off phase III development of olaparib for breast cancer, choosing instead to focus on ovarian cancer as the drug's lead indication. Other companies—including Pfizer and Clovis, the makers of rucaparib (Rubraca)—soon followed by putting breast cancer studies on the back burner, while other PARP inhibitors failed to show efficacy in late-stage breast cancer trials.

AbbVie, for example, provided data at the ASCO meeting showing that the addition of its anti-PARP agent veliparib to a regimen of carboplatin and paclitaxel had no noticeable impact on response rates in a phase III trial of patients with TNBC; and Tesaro said recently that it doesn't expect to get registration-eligible data for niraparib (Zejula) in patients with advanced breast cancer with inherited BRCA mutations after a large number of participants pulled out of the chemotherapy control arm of the company's phase III study.

Looking ahead, talazoparib (Pfizer) remains in phase III testing for this same population, while olaparib is also being evaluated in late-stage trials involving other types of breast cancer, including high-risk, nonmetastatic BRCA-associated breast tumors as well as TNBC that lacks a BRCA alteration.

Daniel Hayes, MD, a breast cancer specialist at the University of Michigan–Ann Arbor and the president of ASCO, is hopeful that olaparib or another PARP-targeted agent will ultimately find a niche beyond treating metastatic BRCA-mutated disease. “This is really just our first step to move forward with this class of drugs,” he said. –Elie Dolgin

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.