BARCELONA – Adding veliparib to chemotherapy improved progression-free survival and provided a more durable benefit than did chemotherapy alone for HER2-negative advanced germline BRCA-associated breast cancer in the randomized, placebo-controlled, phase 3 BROCADE3 study.
Dr. Veronique C. Dieras
Investigator-assessed median progression-free survival (PFS), the primary study endpoint, was 14.5 vs. 12.6 months in 337 patients randomized to receive the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib along with carboplatin/paclitaxel (CP) and 172 who received placebo and CP (hazard ratio, 0.71), Veronique C. Diéras, MD, reported at the European Society for Medical Oncology Congress.
“The benefit looks durable; more patients in the veliparib arm were still progression free at 2 years (34% vs. 20%), and at 3 years (26% vs. 11%),” said Dr. Diéras of Institut Curie, Paris, and Centre Eugene Marquis, Rennes, France.
The PFS benefit was confirmed by independent central review, and was apparent in all subgroups analyzed, except perhaps in patients with prior brain metastases, who comprised a very small group, she noted.
Among the secondary study endpoints were median overall survival (33.5 vs. 28.2 months at an interim analysis; HR, 0.95), clinical benefit rate (90.7% and 93.2% at 24 weeks), and objective response rate (75.8% and 74.1%).
“This is very important to note,” she said, referring to the high percentage of patients who benefited from CP alone. “But, again, if we look at the duration of response, in the veliparib arm the median duration of response was 14.7 months, whereas it was 11 months in the placebo arm.”
Participants in the double-blind trial were adults with a median age of 47 years who were randomized 2:1 to CP with veliparib or placebo for the treatment of germline BRCA1- or BRCA2-mutated metastatic breast cancer and had received no more than two prior lines of cytotoxic therapy; 48% were estrogen receptor– and/or progesterone receptor–negative, 8% had prior platinum therapy, 4% had a history of central nervous system metastases, and 19% had prior chemotherapy for metastatic disease.
They received placebo or veliparib at an oral dose of 120 mg twice daily on days −2 to 5 with carboplatin (area under the curve 6 on day 1) and weekly paclitaxel (80 mg/m2 on days 1, 8, and 15) in 21-day cycles until disease progression, and as allowed per study protocol, 44% crossed over from the placebo to veliparib group, Dr. Diéras said.
Common adverse events in the veliparib and placebo groups, respectively, included neutropenia (in 89% and 91% of patients), thrombocytopenia (81% and 71%), anemia (80% and 70%), and nausea (73% and 64%), she said, adding that the most common grade 3 adverse events were anemia (42% and 40%), neutropenia (81% and 84%), and thrombocytopenia (40% and 28%).
However, less than 10% of patients discontinued the study drug because of adverse events, she noted.
“In fact, the addition of veliparib to cytotoxic chemotherapy didn’t impair the administration of cytotoxic chemotherapy,” she said, adding that the mean number of CP cycles was 11 in both arms.
Select adverse events of special interest in the veliparib and placebo groups, respectively, included infection within 14 days of neutropenia (any grade, 37% and 36%; grade 3+, 5.4% and 1.8%), hemorrhage within 14 days of thrombocytopenia (any grade, 10% and 7%; grade 3+, 0.3% and 0%), and myelodysplastic syndromes (0.3% in both groups, with 0 grade 3+ events), she said.
“We know that germline BRCA-mutated breast cancers have increased sensitivity to platinum agents. Moreover, according to the concept of synthetic lethality, we do know also that these mutated tumors are very good candidates for PARP inhibition, so there is a strong rationale to combine a PARP inhibitor with cytotoxic chemotherapy with platinum,” she said.
Early studies of such combinations have been challenging because of exacerbation of myelosuppression, which may be the result of “the PARP trapping activity of some compounds,” but veliparib potently inhibits PARP with minimal PARP trapping, and thus may be better tolerated in combination with CP, she explained.
“In fact, in a phase 2 randomized trial – BROCADE2 – we did observe numerical increases in PFS and overall survival with [veliparib+CP],” she said.
In BROCADE3, the addition to veliparib to CP provided “a statistically significant and clinically meaningful benefit in patients with HER-negative advanced breast cancer and a germline BRCA mutation” without substantially altering the toxicity profile of C/P, she said.
“Considering these results, in my opinion, patients harboring BRCA mutations with advanced breast cancer [who are] candidates for chemotherapy should be offered this treatment option,” she concluded.
Invited discussant Sherene Loi, MBBS, PhD, head of the Translational Breast Cancer Genomics and Therapeutics Laboratory at Peter MacCallum Cancer Center, Victoria, Australia, said the investigators should be commended for conducting this phase 3 trial, and agreed that the approach is “reasonable to consider in a patient who does need chemotherapy.”
Dr. Sherene Loi
However, Dr. Loi said, it remains unclear if the PFS benefit seen in BROCADE3 is “due to the combination upfront and/or the monotherapy,” and suggested waiting for additional data before considering veliparib + CP as the new standard of care for germline BRCA1- and BRCA2-mutated advanced breast cancer.
“Current ESMO guidelines advise that single-agent chemotherapy be given sequentially in the absence of visceral crisis, therefore I think it’s important to await further for mature OS data and patient-reported outcomes,” she said, adding that it is also important to wait for the correlative analyses to “try to understand the rate of BRCA reversions and other resistance mechanisms in plasma.”
BROCADE3 was funded by AbbVie. Dr. Diéras reported advisory/consultancy roles for several pharmaceutical companies including AbbVie. Dr. Loi reported relationships with numerous pharmaceutical companies.
SOURCE: Diéras V et al. ESMO 2019, Abstract LBA9.