CHICAGO – The oral PARP inhibitor olaparib likely offers a new treatment option for patients with BRCA-related HER2-negative metastatic breast cancer, according to results of the randomized phase III OlympiAD trial reported at the annual meeting of the American Society of Clinical Oncology.
Inhibitors of PARP, or poly(ADP-ribose) polymerase, exploit defective DNA repair due to BRCA mutations, lead author Mark E. Robson, MD, clinic director of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, noted in a press briefing.
“PARP inhibitors have already been approved for the treatment of ovarian cancer in patients with mutations of BRCA1 or BRCA2, and recently in other circumstances. And there have been a couple of small studies that have suggested that breast cancer in BRCA mutation carriers could also be responsive to PARP inhibitors,” he said.
Dr. Mark E. Robson
“This is the first phase III study that’s shown an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with BRCA mutations,” Dr. Robson commented. “It was generally well tolerated, with less than 5% of patients discontinuing treatment for toxicity, and a lower rate of grade 3 or worse side effects.”
“It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations who have metastatic HER2-negative breast cancer, including importantly women with BRCA mutations in triple-negative disease,” he concluded.
Findings going forward
Although the trial was positive, the absolute difference in progression-free survival was just 2.8 months, and the curves converged over time, raising questions about potentially more efficacious PARP inhibitors or strategies for getting greater benefit out of olaparib.
“There are three PARP inhibitors in the developmental stage in breast cancer, and there are noncomparative trials and no really good ways to make a decision about which one is better,” Dr. Robson commented.
Several strategies are being explored for enhancing the benefit of these drugs, he continued. “One is combining it with a conventional chemotherapy agent, which is hard to do because of overlapping bone marrow toxicity, so it’s tough to get full doses of chemotherapy and full doses of PARP inhibitor in. Another is to combine it with other targeted agents that interact with components of the DNA damage repair pathway … and there are certainly combination therapy trials that are underway. And then third is … a combination of olaparib with an immuno-oncology agent.”
Additionally, some studies are evaluating expansion of PARP inhibitors to populations such as patients with triple-negative breast cancer who do not have an identifiable BRCA mutation, on the assumption that they have similar, somatic DNA defects that might be susceptible to this class of agents, according to Dr. Robson.
“The studies have been small and at least the initial ones have not been particularly encouraging,” he said. “But as mentioned, combination approaches now are being evaluated as a way to potentially ‘soup up’ the effect in a broader group of patients.”
Expert perspective
The OlympiAD trial represents a “major step forward in breast cancer” in terms of both translational medicine and precision medicine, according to ASCO President Daniel F. Hayes, MD, FACP, FASCO.
Dr. Daniel F. Hayes
Trials moving olaparib into earlier metastatic settings and possibly even the adjuvant setting will likely be conducted in the next year or 2, speculated Dr. Hayes, who is also clinical director of the breast oncology program and Stuart B. Padnos Professor in Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Potential issues of long-term toxicity, such as secondary leukemias, will need to be kept in mind, especially if olaparib is moved to the curative treatment setting, he cautioned. And a better understanding of resistance (as suggested by the converging progression-free survival curves) and how to overcome it will be key. “That goes back to using it in different ways, clever ways, perhaps combining it with other sorts of therapies,” he said.
Study details
OlympiAD, which was funded by AstraZeneca, enrolled patients with HER2-negative metastatic breast cancer and a centrally confirmed germline (inherited) BRCA mutation who had received anthracyclines and taxanes, and up to two lines of chemotherapy for metastases.
They were randomized 2:1 to open-label treatment with either olaparib (300 mg., twice daily) or single-agent chemotherapy of the treating physician’s choice among three options (capecitabine, eribulin, or vinorelbine). A tablet formulation and dose of olaparib were used that differ from the currently approved capsule formulation and dose to reduce pill burden, Dr. Robson noted.
The patients were about equally split between BRCA1 and BRCA2 mutations, and between hormone receptor–positive disease and triple-negative disease, he reported. The majority (71%) had received chemotherapy for metastases, and a sizable minority (28%) had received prior platinum in the (neo)adjuvant or metastatic setting.
With a median follow-up of about 14.5 months, median progression-free survival assessed by central radiologic review was 7.0 months with olaparib and 4.2 months with chemotherapy (hazard ratio, 0.58; P = .0009).
The median time to investigator-reported second progression or death was also longer with olaparib (13.2 vs. 9.3 months; HR, 0.57; P = .0033).
Median overall survival was about 19-20 months in each group and not significantly different in an interim analysis.
The olaparib group had lower rates of grade 3 or worse adverse events (36.6% vs. 50.5%) and treatment discontinuation because of adverse events (4.9% vs. 7.7%).
The main adverse event of any grade with olaparib was nausea, which was usually mild; only about a quarter of affected patients required antiemetics, according to Dr. Robson. Patients also commonly experienced anemia, requiring transfusion in some cases, and fatigue.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; rand receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro.