OlympiAD’s positive results spell good news for olaparib in breast cancer

June 8, 2017|ObGyn

AT ASCO 2017

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.

Compared with standard single-agent chemotherapy, olaparib (Lynparza) reduced the risk of progression-free survival events by 42% among the 302 patients randomized in OlympiAD, according to results reported in a plenary session at the meeting and simultaneously published (N Engl J Med. 2017 Jun 4. doi: 10.1056/NEJMoa1706450). Overall survival did not differ at the time of the analysis, but mature results await longer follow-up.

“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.

“Frankly, in breast cancer we have been doing precision medicine for about 120 years now, first against the estrogen receptor and second against HER2. For patients whose cancers are negative for those two things, we’ve had chemotherapy, which is not very precise, and this is one area that we really had to work hard on,” he elaborated in the press briefing. “I think it’s almost as much a proof of principle as it is practice changing, and that is, these drugs do work for breast cancer, if we are smart and if we are precise.”

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.