Previous results from the phase III OlympiAD trial (NCT02000622) found that the PARP inhibitor olaparib is superior to chemotherapy for patients with BRCA-related advanced breast cancer.
The trial showed a statistically significant and clinically meaningful benefit in progression-free survival for women with HER2-negative metastatic breast cancer and a germline BRCA mutation who received olaparib compared to those who were treated with chemotherapy (median 7.0 months vs. 4.2 months, respectively) (N Engl J Med 2017;377:523-533). Additionally, the patients treated with olaparib were less likely to experience grade 3 or higher adverse events (AEs; 36.6% vs. 50.5%), than chemotherapy patients.
Seeking to further characterize common AEs among these patients, researchers initiated a closer examination of olaparib's tolerability profile. This additional data was presented at the 2017 San Antonio Breast Cancer Symposium and demonstrated that the PARP inhibitor is well-tolerated by patients and fewer side effects occur compared to chemotherapy (Poster SessionP5-21-12).
“We dove a little more deeply into the side effect and tolerability profile of the drug compared to chemotherapy and found that is well-tolerated and grade 3/4 toxicities are quite low,” noted study author Susan M. Domchek, MD, Executive Director of the Basser Center for BRCA at Penn's Abramson Cancer Center, Philadelphia.
This randomized, controlled, open-label trial compared olaparib tablet monotherapy and standard therapy among HER2-negative metastatic breast cancer patients with a germline BRCA mutation who had underwent no more than two previous chemotherapy regimens for metastatic disease.
Eligible patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or single-agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). Of the 302 randomized patients, 205 underwent treatment with olaparib while 97 received standard therapy.
The primary endpoint was progression-free survival; key secondary endpoints included safety and tolerability. The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 was utilized to grade adverse events.
“If necessary, AEs could be managed by supportive treatment in accordance with local treatment practice guidelines, dose interruption for a maximum of 4 weeks, dose reduction to 250 mg bid initially, then a further reduction to 200 mg bid if needed. No further dose reduction was allowed, and the dose was not to be re-escalated to initial dose,” according to investigators.
Poster Session P5-21-12
These new findings build upon the initial results of the OlympiAD trial, which found that the response rate for the olaparib group was 59.9 percent compared to 28.8 percent in the chemotherapy group, and confirm the tolerability and safety of this PARP inhibitor.
This analysis found that patients who received olaparib were 15 percent less likely to experience serious side effects, such as significant nausea, vomiting, and diarrhea, compared to those who received chemotherapy (36.6% vs. 50.5%, respectively).
Ten patients (4.9%) in the olaparib group discontinued treatment due to an adverse event compared to seven (7.7%) patients in the chemotherapy arm.
While nausea, vomiting, and anemia were more frequent in the olaparib arm, no grade ≥3 events of nausea and vomiting during the treatment period, according to Domchek.
Dose modifications for nausea and vomiting were infrequent. Initial onset of nausea and vomiting typically occurred within the first month of treatment. Investigators reported that the majority of nausea and vomiting cases resolved within 5 weeks and 2 days, respectively. Anti-emetics or anti-nauseants were used in 29.8 percent of olaparib patients compared to 34.0 percent among those receiving chemotherapy.
“There is low-grade nausea in many patients, but for the most part it goes away after a few months,” noted Domchek. “It is important that we can tell patients that, not only can we can manage this side effect, but that it will improve with time.”
Anemia among patients in the olaparib cohort rarely led to discontinuation of treatment. Initial onset of anemia usually occurred in the first 3 months after starting olaparib and was resolved in 75.6 percent of patients.
“Our analysis sought to confirm that anemia did not worsen the longer patients were on olaparib,” Domchek told Oncology Times. “We found that the risk of developing anemia remained fairly constant throughout exposure to the drug.”
Researchers concluded that olaparib monotherapy was generally well-tolerated in this patient population and the “safety profile of the tablet formulation in OlympiAD was consistent with that previously observed in monotherapy studies.”
“These results show that not only is the PARP inhibitor more effective than standard chemotherapy—which we saw earlier [in 2017]—but that patients also tolerate it better, which speaks to their quality of life during treatment,” Domchek emphasized, in a statement. “These patients have particularly aggressive cancers that are difficult to treat. If we can provide a treatment option that gives them a chance to fight their disease and avoid serious side effects so they can continue living their lives, it's another boon to olaparib's advantages over standard chemotherapy.”
This additional analysis adds to the significance of the OlympiAD findings, which led to the expanded FDA approval of olaparib to include the treatment of patients with metastatic disease and a germline BRCA mutation.
With this approval, olaparib is the first PARP inhibitor approved to treat breast cancer; additionally, it is the first time any drug has been approved to treat certain patients with metastatic breast cancer who have a BRCA mutation, according to the FDA. The treatment eligibility of patients is determined based on the FDA-approved genetic test, BRACAnalysis CDx.
“Olaparib is an exciting new option for BRCA1/2 mutation carriers with metastatic breast cancer,” Domchek noted. “When compared to chemotherapy, olaparib was associated with improvements in response rate, time to tumor progression, and quality of life.
“This is the first trial to demonstrate that a PARP inhibitor is better than chemotherapy in any disease,” she concluded. “As 50 percent of individuals in this study had triple-negative breast cancer, this is particularly good news for the subset of patients with BRCA mutation associated triple-negative [disease].”
Catlin Nalley is associate editor.