OlympiAD: Olaparib extends PFS in BRCA-mutated metastatic breast cancer
The oral PARP inhibitor olaparib significantly improved progression-free survival (PFS) in women with BRCA-positive, HER2-negative breast cancer compared with standard chemotherapy in the phase III OlympiAD* trial, ushering in a new era of hope in BRCA-mutated breast cancer.
The study met its primary endpoint of progression-free survival (PFS), assessed by blinded independent central review. At a median follow-up of 14 months, PFS was 2.8 months longer and the risk of disease progression or death was 42 percent lower with olaparib than with chemotherapy. The objective response rate (ORR) was twice higher with olaparib at 59.9 percent vs 28.8 percent with chemotherapy. [ASCO 2017, abstract LBA4; N Engl J Med 2017;doi:10.1056/NEJMoa1706450]
“Olympiad is the first phase III study in patients with metastatic breast cancer to show benefit for a PARP inhibitor over an active comparator,”said lead investigator Dr Mark Robson, director of the Clinical Genetics Service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, US. “It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations.”
The OLYMPIAD trial included 302 patients from 19 countries across Europe, Asia, North America, and South America with HER2-negative metastatic breast cancer who harboured germline BRCA1 or BRCA2 mutations and had received up to two prior lines of chemotherapy in the metastatic setting. The median age of the patients was 44 years, one-third of them were Asians. Forty-nine percent were HR-positive, 51 percent were triple-negative.
Patients were randomized in a 2:1 ratio to receive olaparib 300 mg tablets (slightly lower dose than the approved dose of 400 mg)
twice daily (n=205) or physician’s choice of standard single-agent chemotherapy (capecitabine, vinorelbine, or eribulin in 21-day cycles; n= 97). Secondary endpoints included overall survival (OS), time to second progression or death, ORR, and effect on health-related quality of life (QoL). The median duration of follow-up was 14.5 months with olaparib and 14.1 months with standard chemotherapy.
The PFS analysis occurred after 163 events in the olaparib cohort and 71 events in the chemotherapy cohort. The median PFS was significantly longer with olaparib (7 months vs 4.2 months with chemotherapy, HR, 0.58; p<0.001).The OS data are not yet mature, but an interim analysis showed a median OS of 19.3 months with olaparib vs 19.6 months with chemotherapy.
The median time to second progression or death was 13.2 months with olaparib and 9.3 months with chemotherapy (HR 0.57; p = 0.0033).
Olaparib was generally well-tolerated, with less than 5 percent of the cohort discontinuing treatment due to toxicity (7.7 percent with chemotherapy). The most common adverse events reported with olaparib were nausea, anaemia, and fatigue of low grade (1 or 2). There were fewer grade 3 and 4 toxicities and there was an improvement in overall QoL in the olaparib cohort.
“The results are practice-changing,” said discussant Dr Allison Kurian from the Stanford University School of Medicine in Stanford, California, US. “Finally, we have a positive phase III trial. This is the end of the beginning for PARP inhibitor in breast cancer.”
Olaparib is US-FDA approved for the treatment of BRCA-positive advanced ovarian cancer following ≥3 prior lines of chemotherapy. The BRACAnalysis CDx® used in OylmpiAD is also FDA-approved as a companion test to identify BRCA1/2 mutations and inform patient management relevant to olaparib and another PARP inhibitor, niraparib.