New Standard for BRCA-Mutated Breast Cancer?

CHICAGO — A new option for women with BRCA-mutated breast cancer has emerged. The poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib (Lynparza, Astra Zeneca) significantly improved progression-free survival in women with human epidermal growth factor 2 (HER2)–negative metastatic breast cancer with a germline BRCA mutation, when compared with standard therapy.  

The drug is already approved for use in BRCA-mutated ovarian cancer and is now likely to also have BRCA-mutated breast cancer added to its indications. Because of their underlying defect in DNA repair, cancer cells with BRCA mutations are particularly vulnerable to treatments that target PARP.

At a median follow-up of 14 months, progression-free survival was 2.8 months longer and the risk for disease progression or death was 42% lower with olaparib monotherapy than with chemotherapy.

The findings were presented here during the plenary session at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting and simultaneously published in the New England Journal of Medicine.

“This is the first phase 3 randomized trial in breast cancer that shows PARP inhibitors are superior to chemotherapy for HER2-negative metastatic breast cancer patients who have a BRCA mutation,” said lead study author, Mark E. Robson, MD, clinic director of the Clinical Genetics Service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

 “This study is proof of the principle that breast cancers with defects in a specific DNA damage repair pathway are sensitive to a targeted therapy designed to exploit that defect,” said Dr Robson.

Olaparib was also generally well tolerated, with less than 5% of the cohort discontinuing treatment because of toxicity, and these findings support its use as an effective treatment option in patients with breast cancer, he explained.

Promising in Breast Cancer

The OlympiAD trial is a phase 3 randomized trial that compared the efficacy and safety of olaparib with those of single-agent chemotherapy (physician’s choice) in women with  HER2-negative metastatic breast cancer and a germline BRCA mutation.

Olaparib was approved by the US Food and Drug Administration in 2014 for the treatment of advanced ovarian cancer with BRCA mutations.

“There are 3 PARP inhibitors that have been approved for ovarian cancer, but this is the first randomized study in breast cancer,” commented Amy Tiersten, MD, a professor of medicine at Mt. Sinai School of Medicine in New York City, who was approached by Medscape Medical News for an independent comment. “There are no survival data yet, but it is promising.”

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Of particular importance is that olaparib is a potential treatment for triple-negative breast cancers. “About 80% of BRCA1 breast cancers are triple negative, and for years we have been searching for targeted therapies for this patient subgroup,” said Dr Tiersten.

“Prior to the report from this trial, there really wasn’t a particular targeted therapy for triple-negative breast cancer,” she noted. “But now there is, at least in a BRCA-associated triple-negative breast cancer.”

Improved Time to Progression

In the OlympiAD trial, Dr Robson and his colleagues randomly assigned 302 patients to receive olaparib 300 mg twice daily (n = 205) or standard therapy (n = 92), which consisted of 21-day cycles of capecitabine (2500 mg/m2 orally on days 1 to 14) or vinorelbine (30 mg/m2 intravenously on days 1 and 8) or eribulin (1.4 mg/m2 intravenously on days 1 and 8).

At the time of the primary analysis, 94 patients (45.9%) in the olaparib group and 46 patients (47.4%) in the chemotherapy group had died, with a median time to death of 19.3 months vs 19.6 months.

Overall survival did not significantly differ between the two groups (hazard ratio for death, 0.90; P = .57).

At 77% data maturity, progression-free survival duration was significantly longer in the olaparib cohort than in patients receiving chemotherapy: 7.0 vs 4.2 months (hazard ratio, 0.58; P = .0009).

The objective response rate also favored olaparib, at 59.9% vs 28.8%.

“Another interesting point which I haven’t seen in other trials is that they looked at the second time to progression,” said Dr Tiersten. “Patients who had progressed on study and then went on to subsequent therapies had a longer time to progression on their next therapy as well, if they had been randomized to olaparib.”

“This is very important because there was some concern that the cancer may return in a more resistant form and it did not,” she noted.

The median time from randomization to a second progression event or death after a  first progression was 13.2 months for patients in the olaparib cohort compared with 9.3 months for those receiving standard chemotherapy (hazard ratio,  0.57; P = .003).

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Patients who received olaparib also experienced fewer adverse events. The rate of grade 3 or higher events was 36.6% in the olaparib group vs 50.5% for those receiving chemotherapy (ie, the standard-therapy group).

Anemia, nausea, vomiting, fatigue, headache, and cough were more common in patients receiving olaparib, while neutropenia, palmar–plantar  erythrodysesthesia,  and an increase in  liver function enzymes  were  more common in those receiving chemotherapy.

The rate of treatment discontinuation due to toxicity was 4.9% for olaparib and 7.7% for chemotherapy.

New Standard of Treatment?

Overall, these results are “very exciting as we now have something other than chemotherapy to offer these patients,” said Dr Tiersten.

These results show that olaparib should be the standard of care over standard chemotherapy.
Dr Amy Tiersten

“There are many other ongoing PARP inhibitors clinical trials, but at least in patients who fit the criteria of this trial, these results show that olaparib should be the standard of care over standard chemotherapy, in patients who have had up to two lines of prior therapy,” she added. “Olaparib has better efficacy, fewer side effects, and better quality of life. Thus, this is what I would use in this setting.”

Susan Domchek, MD, executive director of the Basser Research Center for BRCA at the University of Pennsylvania’s Abramson Cancer Center, Philadelphia, who led some of the seminal studies that contributed to the development of OlympiAD, reiterated that olaparib should be a new standard therapy for germline BRCA1/2 mutation–associated metastatic breast cancer.

“The combination of improved progression-free survival, improved response rates, and less toxicity is terrific news for our patients,” she told Medscape Medical News.

In this study, olaparib was given in the first through third lines of therapy, and she emphasized that further work is needed to assess the optimal timing of this treatment.

“There are no direct comparison of different PARP inhibitors at this time,” Dr Domchek noted. “Olaparib is the first PARP inhibitor to be shown to be superior to chemotherapy in any disease.”

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Concerns and Questions

However,  ASCO President Daniel F. Hayes, MD, pointed out that while these data represent “a major step forward in translational medicine,” as well as one for breast cancer in general, more investigation is needed.

Olaparib has fewer side effects and is more effective, but there are no survival data yet, he noted.

“We also don’t know about long-term toxicity,” he said, noting that olaparib inhibits DNA repair in cancer cells, but it is unknown how this may affect healthy cells.

Secondary leukemias have been reported, primarily in the ovarian cancer setting. “We have to be cognizant of that,” Dr Hayes said. “It’s not common but is still a concern, especially in a curative setting.”

More study is also needed on how best to use olaparib, he explained. “Instead of comparing it to chemotherapy, what about adding it to chemotherapy or combining it with other agents?”

Finally, another question is the timing. “Instead of waiting until the patients are far down the road, what if we moved it further up, or even into the adjuvant setting?” he said. “There will be trials reporting on that in the next year or two, or that will be conducted.”

This study was funded by AstraZeneca. Dr Robson and Dr Domchek have disclosed relationships with industry, including AstraZeneca; several coauthors have also made similar disclosures.

American Society of Clinical Oncology (ASCO) 2017 Annual Meeting. Presented June 4, 2017. Abstract LBA4.

N Engl J Med. Published online June 4, 2017.

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