Extended Follow-Up Shows Continued Olaparib Benefit in BRCA+ MBC

Mark E. Robson, MD

Olaparib (Lynparza) continued to show a numerical overall survival (OS) benefit with a favorable hazard ratio for OS versus chemotherapy in patients with BRCA-positive, HER2-negative metastatic breast cancer, according to an extended, exploratory follow-up analysis of the phase III OlympiAD trial.¹

Data from the follow-up, which were presented in a poster at the 2019 San Antonio Breast Cancer Symposium (SABCS), showed a median OS in the overall study population of 19.3 months with the PARP inhibitor olaparib versus 17.1 months with chemotherapy (HR, 0.84; 95% CI, 0.63-1.12). The 4-year OS rates were 18.9% versus 14.2% respectively.

“We continue to see benefit from olaparib compared to chemotherapy, particularly in the first-line setting,” lead study author Mark E. Robson, MD, chief of Breast Medicine Service, Memorial Sloan Kettering Cancer Center, said in an interview with OncLive at SABCS.

Patients receiving olaparib in the second- or third-line settings had a median OS of 18.8 months versus 17.2 months for those receiving chemotherapy (HR, 1.00; 95% CI, 0.72-1.40), with 4-year OS rates of 17.1% versus 14.8%, respectively. In hormone receptor—positive patients, the median OS was 21.8 months with olaparib compared with 21.3 months in the control group (HR, 0.79; 95% CI, 0.53-1.19), with 4-year OS rates of 23.1% versus 17.4%, respectively.

The median OS was 17.2 months versus 13.3 months with olaparib versus chemotherapy, respectively, in patients who received prior platinum-based chemotherapy (HR, 0.74; 95% CI, 0.45-1.25). The 4-year OS rates in the subgroup were 16.8% versus “not calculable.” Among patients with no prior platinum-based chemotherapy, the 4-year OS rate was 20.4% versus 16.3% with olaparib versus chemotherapy, respectively, and the median OS was 20.3 months versus 19.6 months, respectively (HR, 0.86; 95% CI, 0.62-1.21).

In the triple-negative breast cancer (TNBC) population, the median OS was 17.4 months versus 14.9 months in favor of the PARP inhibitor (HR, 0.87; 95% CI, 0.59-1.29). The 4-year OS rates in patients with TNBC were 15.4% versus 11.9%, respectively.

In comparison to these rates from the extended analysis, the median OS at the final prespecified OS analysis was 19.3 months with olaparib versus 17.1 months with chemotherapy (HR, 0.90; 95% CI, 0.66-1.23).²

The OlympiAD trial included 302 patients with HER2-negative metastatic breast cancer who harbored germline BRCA1 or BRCA2 mutations. The study was conducted in 19 countries across Europe, Asia, North America, and South America. Patients were allowed to have received up to 2 prior lines of chemotherapy in the metastatic setting. In the study, patients were randomly assigned in a 2:1 ratio to 21-day cycles of 300-mg twice daily oral olaparib (n = 205) or physician’s choice of standard chemotherapy (n= 97; capecitabine, vinorelbine, or eribulin). The primary endpoint of the trial was progression-free survival (PFS) per a blinded independent review.

In March 2018, the trial protocol for OlympiAD was amended to allow further exploratory follow-up analyses of OS and serious adverse events (SAEs) beyond the final OS analysis deadline established in the initial study protocol. The OS cutoff date for the final OS analysis was September 25, 2017, and the cutoff for the exploratory analysis was March 3, 2019.

The median follow-up for the exploratory analyses was 18.9 months versus 15.5 months in the olaparib versus chemotherapy arms, respectively. The median time on study treatment was 8.3 months versus 3.5 months, respectively. In the olaparib arm, 8.8% of patients received treatment for ≥3 years compared with no patients in the control arm.

The median patient age was around 45 and about one-third of patients were non-white (mainly Asian). In both arms, there was a nearly even split between patients who were hormone-receptor positive or triple negative. Across the overall study population, 71% had received prior chemotherapy in the metastatic setting, and 28% had received prior platinum-based therapy in the neoadjuvant, adjuvant, or metastatic setting. Patients who received prior platinum regimens had to have completed the therapy within 12 months of starting the OlympiAD trial.

Fourteen patients remained on olaparib and no patients remained on chemotherapy at the data cutoff for the exploratory analysis and the authors wrote in their poster that, “The baseline characteristics of the small number of patients continuing to receive olaparib were generally consistent with those of the overall population, albeit with a greater proportion having better performance status at baseline and who had not received prior chemotherapy for metastatic disease.”

Subsequent anticancer therapies received by the 288 patients who discontinued the trial included PARP inhibitors (2% in olaparib arm versus 11.3% in chemotherapy arm), platinum chemotherapy (42.4% vs 48.5%, respectively), other cytotoxic chemotherapy (65.4% vs 73.2%), hormone therapy (19.5% vs 25.8%), and targeted treatments/biologics (18% vs 21.6%).

Regarding the SAE component of the exploratory follow-up, there were no new SAEs related to olaparib that emerged between the initial OS data cutoff date and the March 3, 2019, cutoff. The SAE rate with olaparib was 16.6% at the initial cutoff and 17.6% at the extended cutoff. Rates for all SAEs remained low with longer follow-up, and the incidence of specific SAEs remained consistent with longer follow-up.

“We do not see any new toxicities emerging, and in particular, do not see AML/MDS in the olaparib arm,” Robson said.

The FDA approved olaparib in January 2018 for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. Additionally, HR-positive patients should have prior endocrine therapy or not be considered appropriate for such treatment. The approval was based on PFS data from the OlympiAD trial showing that olaparib reduced the risk of disease progression or death by 42% and improved the median PFS by 2.8 months versus standard chemotherapy.

Moving forward, Robson said the next steps with PARP inhibitors in ovarian cancer include exploring the agents in “early-stage disease (OLYMPIA, NEOTALA trials), in patients without germline BRCA mutations but with other alterations, and in combinations.”

References

1. Robson M, Im S-A, Senkus E, et al. OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract PD4-03.
2. Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019;30(4):558-566. doi: 10.1093/annonc/mdz012.

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Among patient subgroups, the numerical benefit was greatest for olaparib in patients receiving the PARP inhibitor as frontline treatment for metastatic disease (median OS, 22.6 vs 14.7 months; HR, 0.54; 95% CI, 0.32-0.92). The 4-year OS rates for these patients were 24.6% versus 12.8%, respectively.