Hint of Survival Benefit With Olaparib in HER2-Negative/BRCA-Positive Metastatic Breast Cancer

Mark E. Robson, MD

Women with HER2-negative metastatic breast cancer associated with a germline BRCA mutation may have a slight survival advantage with a poly (ADP-ribose) polymerase (PARP) inhibitor instead of chemotherapy, according to updated results of the phase III randomized OlympiAD trial.

Though not statistically powered to evaluate overall survival, the trial yielded a 26% reduction in the survival hazard for patients treated with olaparib (Lynparza) versus chemotherapy (HR 0.735; P = .045). A 2-month difference in median overall survival (OS) in favor of the olaparib arm did not achieve statistical significance.

A subgroup analysis showed almost a 50% reduction in the hazard among women who received olaparib as initial therapy for metastatic disease, Mark E. Robson, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, reported at the American Association for Cancer Research meeting in Chicago, Illinois.

“We observed a numerical difference in overall survival in favor of olaparib over physician’s choice of chemotherapy,” said Robson. “The difference was consistent across all subgroups. The results suggest the possibility of a greater benefit among patients who have not received prior chemotherapy for metastatic breast cancer. The safety profile of olaparib was consistent with the primary analysis, indicating no relevant cumulative toxicity with extended exposure.”

The findings came from a prespecified survival analysis of the OlympiAD trial (NCT02000622) involving patients with metastatic HER2-negative breast cancer and germline BRCA mutations. Eligible patients had received no more than 2 prior chemotherapy regimens for metastatic disease, and prior anthracycline and taxane treatment in the neoadjuvant or adjuvant setting was allowed.

Investigators randomized 302 patients 2:1 to olaparib or to the treating physician’s choice of chemotherapy. Treatment continued until disease progression or development of unacceptable toxicity.

The trial had a primary endpoint of progression-free survival (PFS), and the primary data analysis showed a statistically significant 2.8-month difference in PFS in favor of olaparib (7.0 vs 4.2 months) representing a 42% reduction in the hazard for disease progression or death (P <0.001).

The trial design included a prespecified analysis of OS after a cumulative total of 190 deaths in the 2 arms of the trial. An interim survival analysis after 140 deaths showed a 35% reduct4ion in the survival hazard in favor of olaparib (P = .018). At that analysis, the olaparib group had a median OS of 19.3 versus 19.6 months with chemotherapy (HR 0.90; 95% CI, 0.63-1.29).

The final survival analysis occurred after a median follow-up of 18.9 months in the olaparib arm and 15.5 months in the chemotherapy arm. Median OS remained at 19.3 months with olaparib but had declined to 17.1 months with chemotherapy, a difference associated with a hazard ratio of 0.90 (95% CI, 0.66-1.23; P = .513).

Robson said a higher proportion of patients in the olaparib arm were alive at 6 months (93.1% vs 85.8%) and 12 months (54.1% vs 48.0%).

The survival analysis across prespecified subgroups yielded one notable difference. Patients who had received no prior chemotherapy in the metastatic setting had a median OS of 22.6 months with olaparib versus 14.7 months with chemotherapy. The difference translated into a 49% reduction in the hazard ratio in favor of olaparib (95% CI, 0.29-0.90; P = .02). In contrast, patients in second- or third-line treatment for metastatic breast cancer had a median OS of 18.8 months with olaparib and 17.2 months with chemotherapy.

Patients with no prior platinum therapy in the metastatic setting had a median OS of 20.3 months with olaparib and 19.6 months with chemotherapy. That compared with median values of 17.3 and 13.3 months with olaparib and chemotherapy, respectively, in the subgroup with prior exposure to platinum-containing chemotherapy, this was not a statistically significant difference.

Among patients with hormone receptor-positive (estrogen or progesterone) breast cancer had a median overall survival of 21.8 months with olaparib and 21.3 months with chemotherapy. The subgroup of patients with triple-negative breast cancer had median OS of 17.4 and 14.9 months with olaparib and chemotherapy, respectively. Neither difference achieved statistical significance.

Robson reported that olaparib-treated patients had a median treatment duration of 230 days and a median relative dose intensity of 99.4%.

The final analysis showed that the 2 treatment arms had a similar incidence of adverse events (AEs; 97.6% vs 95.6%) and drug-related AEs (86.8% vs 81.3%). Grade ≥3 AEs occurred more often with chemotherapy (49.5% vs 38.0%), as did AEs leading to discontinuation (7.7% vs 4.9%). Nausea, vomiting, anemia, and fatigue occurred more often with olaparib, whereas neutropenia, liver-enzyme elevation, alopecia, and hand-foot syndrome occurred more often with chemotherapy.

Robson ME, Im S-A, Senkus E, et al. OlympiAD final overall survival: olaparib versus chemotherapy treatment of physician’s choice (TPC) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Presented at: American Association for Cancer Research Annual Meeting, April 14-18, 2018, Chicago, IL. Abstract CT038. http://www.abstractsonline.com/pp8/#!/4562/presentation/11138.

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