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CHICAGO -- A modest improvement in progression-free survival (PFS) could have a practice-changing impact on management of HER2-negative breast cancer associated with BRCA mutations, specialists said here.

Patients treated with the PARP inhibitor olaparib (Lynparza) had a median PFS of 7.0 months as compared with 4.2 months for patients who received standard chemotherapy. The improvement occurred with a more favorable side-effect profile than seen with chemotherapy and a low rate of toxicity-related discontinuation.

The results earned favorable reviews from breast cancer specialists, who cited the potential for a new therapeutic option for patients with difficult-to-treat breast cancer.

"This is the first phase III study to show an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with a BRCA mutation," Mark Robson, MD, of Memorial Sloan Kettering Cancer Center in New York City, said during a press briefing at the American Society of Clinical Oncology (ASCO) meeting. "It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations and metastatic HER2-negative breast cancer, including, importantly, women with BRCA mutations in triple-negative disease."

The findings were also in addition to the ASCO presentation.

ASCO president Daniel Hayes, MD, called the study outcome a major step forward in the treatment of breast cancer. Precision medicine, which has become mainstream through most of oncology, has figured into treatment of breast cancer for 120 years, he said, beginning with the discovery of the estrogen receptor, followed many years later by identification and elucidation of the role of HER2 in breast cancer.

"For patients whose cancers are negative for those two things, we've had chemotherapy, which is not very precise," said Hayes, a breast cancer specialist at the University of Michigan in Ann Arbor. "This also represents a major step forward in translational medicine. The concept of synthetic lethality, PARP, and DNA repair has been around for about 20 years, but it took some really smart people to finally put 1 and 1 together to get 2 or 3 or 4, and now we have PARP inhibitors."

Despite the enthusiasm, evaluation and interpretation of the results should remain grounded by several issues, Hayes continued. All the patients in the trial had germline BRCA mutations, so the therapy is not ready for use in the general population of patients with breast cancer. Another issue relates to PARP inhibitors' mechanism of action: blocking DNA repair in cancer cells. In normal cells, repair of DNA damage is desirable. The potential consequences of long-term inhibition of DNA repair remain unknown for the most part, he said.

A final consideration relates to the actual data from the trial, which showed that survival curves in the treatment arms eventually came together, reflecting no difference in overall survival.

"We need to understand what the mechanisms of resistance to these drugs are," said Hayes. "Even when the drugs worked, the survival curves ultimately came back together again. This goes back to using the drugs in different ways, perhaps combining them with other therapies. But I do believe this is a really big step forward in breast cancer."

Olaparib is not the first PARP inhibitor studied in breast cancer but is the first "real" PARP inhibitor. The drug iniparib, characterized as a PARP inhibitor, showed promising results in preliminary clinical trials in breast cancer, but ultimately failed the test of a. The explanation for the failure was simple, said Robson: Iniparib was found , even though many investigators at the time thought it did.

Olaparib, the first approved PARP inhibitor, and several other drugs in the class demonstrated efficacy in BRCA-mutant ovarian cancer, providing a rationale evaluating the agents in other tumors associated with DNA-repair defects, which PARP inhibitors target.

Robson reported findings from the randomized which involved 302 patients with metastatic breast cancer and documented BRCA-mutations. The study population had a median age of 44 to 45. About half the patients had hormone receptor-positive disease, and half had triple-negative breast cancer (an aggressive subtype often associated with DNA repair defects). More than 70% of the patients had received prior chemotherapy for metastatic disease, and 28% had received prior platinum therapy in the neoadjuvant, adjuvant, or metastatic setting.

The patients were randomized 2:1 to olaparib or the treating physician's choice of chemotherapy, and treatment continued until disease progression or development of unacceptable toxicity. The trial had a primary endpoint of PFS.

Robson reported that the 2.8-month difference in PFS represented a 42% reduction in the hazard ratio for disease progression or death (HR 0.58, 95% CI 0.49-0.80, P=0.0009). Objective responses occurred almost twice as often with olaparib as with chemotherapy: 59.9% versus 28.8%. The favorable effect of olaparib carried over beyond progression and subsequent treatments, resulting in significant prolongation of time to second progression (HR 0.57, 95% CI 0.40-0.83).

Grade ≥3 adverse events occurred 36.6% and 50.5% of olaparib- and chemotherapy-treated patients, and rates of adverse events leading to discontinuation 4.9% with olaparib and 7.7% with chemotherapy. Evaluations of health-related quality of life consistently favored the olaparib arm across all time points (P=0.0035).

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