Olaparib superior to chemo in BRCA-related breast cancer

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While previous studies have suggested olaparib could benefit patients with advanced breast cancers, according to a study presented at American Society of Clinical Oncology Annual Meeting, olaparib improves profession-free survival better than standard chemotherapy.

Six years ago an international team of physician scientists known as BRCA-TAC led a charge to advance clinical testing of the PARP inhibitor olaparib in cancer patients with known inherited mutations in BRCA1 and BRCA2. Now, during the plenary session of the American Society of Clinical Oncology Annual Meeting (abstract LBA4), that push came full circle with the presentation of results of the phase III OlympiAD trial demonstrating for the first time that olaparib is superior to chemotherapy in patients with BRCA-related advanced breast cancer.

"Although previous studies suggested olaparib could benefit patients with advanced breast cancers, we are now reporting that olaparib improves profession-free survival better than standard chemotherapy," said study co-author Dr Susan Domchek, executive director of the Basser Research Centre for BRCA at the University of Pennsylvania's Abramson Cancer Centre, who led some of the seminal studies that contributed to the development of OlympiAD. "Based on our previous work, leaders in BRCA research have been advocating for this trial for many years, urging pharmaceutical companies to focus on efforts that are now generating new therapies for our patients."

The new findings were presented on behalf of the international consortium by Dr Mark E Robson, clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Centre.

PARP – poly (ADP-ribose) polymerase – is an enzyme used by healthy cells to repair themselves. However, cancer cells also use PARP to repair DNA damage, thus extending their growth and possible lethality. Olaparib selectively binds to and inhibits PARP, preventing it from repairing DNA damage in cancer cells, particularly those cancer cells which have lost BRCA1 or BRCA2 function. This may help control the tumor or shrink it.

In 2011, Domchek organised the BRCA-TAC group which called on industry partners to recognise the value in extending trials of PARP inhibitors to BRCA patients. "Patients and clinical investigators eagerly awaited phase III studies to obtain regulatory approval for PARP inhibitors in BRCA-related malignancy. To date, these trials have not materialized, and a pathway to approval is not clear," the group wrote back then, adding that to proceed would require "commitment and collaboration from academics, pharmaceutical companies, and the regulatory agencies." Although proportionally small – only about 5% of breast cancer patients may have BRCA1/2 mutations – BRCA-TAC noted that these patient populations had a high likelihood of benefitting from olaparib, and BRCA mutation carriers "still constitute a significant absolute number of patients worldwide who could benefit from these agents."

An earlier study led by Domchek and colleagues resulted in the first FDA approval of olaparib in 2014 for patients with pretreated BRCA1/2 associated ovarian cancer. That study, a phase II trial showed olaparib produced an overall tumor response rate of 26 percent in patients with advanced cancers associated with BRCA1 and BRCA2 mutations who had not previously responded to standard therapies. For many of the patients in these trials, olaparib was at least their third cancer therapy, illustrating the difficulty of treating cancers associated with these genetic mutations.

"The action spurred by the BRCA-TAC group is proof of what can happen with we put our patients first, and advocate on their behalf for the development of better treatment options," Domchek said. "Working together as partners, we have the opportunity and obligation to be involved in the development of trials that explore new and promising avenues for investigation."

Background: Olaparib is an oral PARP inhibitor with anti-tumor activity in HER2-negative mBC with a gBRCAm (NCT00494234). OlympiAD (NCT02000622) was a randomized, open-label, phase III study that assessed efficacy and safety of olaparib vs standard single agent chemotherapy treatment of physician’s choice (TPC) in pts with HER2-negative mBC and a gBRCAm.
Methods: Pts aged ≥18 y with HER2-negative mBC (hormone receptor positive or triple negative [TN]) and a gBRCAm, who had received ≤2 chemotherapy lines for mBC, were randomized (2:1) to olaparib tablets (300 mg po bid) or TPC (21-day cycles of either capecitabine [2500 mg/m2 po days 1–14], vinorelbine [30 mg/m2 IV days 1 and 8] or eribulin [1.4 mg/m2IV days 1 and 8]). Treatment was continued until objective disease progression (RECIST v1.1) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR).
Results: 302 pts were randomized (median age 44 y; 50% TN; 71% prior chemotherapy for mBC; 28% prior platinum) of whom 205 received olaparib and 91 received TPC (6 TPC pts were not treated). At 77% data maturity, PFS by BICR was significantly longer in pts treated with olaparib vs TPC (HR 0.58; 95% CI 0.43, 0.80; P=0.0009; 7.0 vs 4.2 months, respectively). Time to second progression (investigator-assessed) was also longer in the olaparib arm (HR 0.57; 95% CI 0.40, 0.83). Objective response rate was 59.9 and 28.8% in olaparib and TPC arms, respectively. Grade ≥3 adverse events (AE) occurred in 36.6 and 50.5% of olaparib and TPC pts, with AEs leading to discontinuation in 4.9 and 7.7% of pts, respectively. Mean change from baseline in global health-related quality of life (HRQoL, EORTC-QLQ-C30) across all timepoints favored olaparib (difference vs TPC 7.5; 95% CI 2.48, 12.44; P=0.0035).
Conclusions: Olaparib tablet monotherapy provided a statistically significant and clinically meaningful PFS benefit to HER2-negative mBC pts with a gBRCAm, compared to standard TPC. The safety profile of olaparib was consistent with prior studies. The efficacy benefit was seen beyond the first progression and HRQoL also improved.

Mark E Robson, Seock-Ah Im, Elżbieta Senkus, Binghe Xu, Susan M Domchek, Norikazu Masuda, Suzette Delaloge, Wei Li, Nadine M Tung, Anne Armstrong, Wenting Wu, Carsten Dietrich Goessl, Sarah Runswick, Pier Franco Conte

University of Pennsylvania School of Medicine material 2017 ASCO abstract

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