乌鸦传媒視頻

Patients with advanced BRCA-mutated breast cancer receiving a PARP inhibitor plus chemotherapy lived about 2 months longer without disease progression if they stayed on the PARP inhibitor after stopping chemotherapy for reasons other than progression, a randomized trial showed.

Median progression-free survival (PFS) was 14.5 months with veliparib plus chemotherapy and 12.6 months with placebo and chemo. Though modest, the difference did achieve statistical significance (P=0.0016).

Patients assigned to veliparib had the option to continue the PARP inhibitor if they discontinued chemotherapy before disease progression, and more than 40% of the patients in that arm received single-agent veliparib. Investigators credited the continuation of the active drug with the significant difference in PFS, as reported in the .

"The results of this phase III trial show that, when added to carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before disease progression, veliparib resulted in a durable improvement in progression-free survival, with benefit evident at 2 years and 3 years after randomization in patients with advanced HER2-negative breast cancer and a germline BRCA1 or BRCA2 mutation," Veronique Diéras, MD, of the Eugene Marquis Center in Rennes, France, and coauthors concluded.

"These results are noteworthy given the high activity of the carboplatin and paclitaxel control group, in which median progression-free survival was longer than 1 year," they noted. "The high concordance between the investigator-assessed and centrally reviewed progression-free survival results and the nearly identical HRs (hazard ratios) lend further support to these findings and indicate a lack of systematic evaluation bias."

Data for overall survival (OS) remained immature at the primary analysis, but a planned interim analysis showed no difference between the groups, the authors added.

Acknowledging that the absolute difference in PFS left the results open to questions about clinical relevance, the author of an looked beyond the median PFS to the landmark analyses.

"With a median follow-up of nearly 36 months, an estimated 34% and 26% of patients were progression free in the veliparib group and 24 months and 36 months compared with 20% and 11% in the placebo group," stated Melinda Telli, MD, of Stanford University Medical Center in California. "Notably, in a subgroup analysis of patients with triple-negative breast cancer, the median overall survival was 35 months, which represents the best overall survival ever reported for triple-negative breast cancer."

"Although this trial was not designed to specifically evaluate this question, the data certainly challenge the existing dogma of sequential single-agent therapy in this genetically distinct group of patients with advanced breast cancer," Telli added. "The results of this trial force us to consider whether a strategy of platinum-based induction combination chemotherapy followed by PARP inhibitor maintenance, as is standardly used in ovarian cancer, might ultimately lead to superior outcomes for this group of patients [with breast cancer]."

PARP Inhibitors in Breast Cancer

PARP inhibitors have demonstrated efficacy in advanced BRCA-mutated breast cancer, as both olaparib (Lynparza) and talazoparib (Talzenna) have FDA-approved indications. Theoretically, veliparib might offer an advantage over other agents in the class because of its molecular design, Diéras and colleagues noted. The mechanism of action does not involve substantial trapping of PARP protein onto DNA damage repair intermediates. The design may make the drug better suited for use in combination with platinum-based chemotherapy, as PARP trapping is .

The theoretical advantage did not play out in a placebo-controlled of veliparib plus chemotherapy. In that trial, a PFS difference of less than 2 months did not achieve statistical significance, although objective response rate favored veliparib (P=0.027).

Diéras and colleagues reported findings from the , which once again paired veliparib and placebo with chemotherapy in patients with advanced HER2-negative, BRCA-mutated breast cancer. Unlike the phase II trial, BROCADE's design included the wrinkle that allowed patients to receive single-agent veliparib or placebo if they discontinued chemotherapy for any reason prior to disease progression.

Investigators in 36 countries randomized patients 2:1 to veliparib or placebo, each combined with carboplatin-paclitaxel chemotherapy. Eligible patients could have received as many as two prior regimens for metastatic disease. The primary endpoint was PFS.

The intention-to-treat analysis comprised 509 patients with laboratory-confirmed BRCA-mutated breast cancer. About half the patients had triple-negative breast cancer and a similar proportion had hormone receptor-positive tumors. The authors reported that 41% of patients in the veliparib arm and 34% in the placebo arm discontinued chemotherapy before disease progression.

Main Findings

After a median follow-up of about 3 years in each treatment arm, a planned analysis showed a statistically significant difference in PFS in favor of the veliparib arm (HR 0.71, 95% CI 0.57-0.88). A subgroup analysis showed a consistent benefit in favor of veliparib, associated with HRs of 0.66 to 0.80. Landmark analyses showed 2- and 3-year PFS rates of 33.6% and 25.7% with veliparib versus 19.8% and 10.7% with placebo.

The preliminary survival analysis showed a 2-year OS of 61.3% with veliparib and 59.8% with placebo. The absolute difference in favor of veliparib increased at 3 years (46.4% vs 39.3%).

The most common grade ≥3 adverse events were neutropenia (81% with veliparib, 84% with placebo), anemia (42% vs 40%), and thrombocytopenia (40% vs 28%). Serious adverse events occurred in 34% of veliparib-treated patients and 29% of the placebo group. No drug-related deaths occurred in either arm.

Comment