Veliparib-Chemo Combo a New Option for
BRCA-Mutated Breast Cancer?

M. Alexander Otto, MMS, PA

September 17, 2020

Adding the investigational poly (ADP-ribose) polymerase (PARP) inhibitor veliparib (AbbVie) to carboplatin-paclitaxel (CarboTaxol) for BRCA-mutated, HER2-negative advanced breast cancer extended progression free survival 1.9 months beyond CarboTaxol alone in a phase 3 trial from the company.

Median investigator-assessed progression-free survival (PFS), the primary endpoint, was 14.5 months with veliparib vs 12.6 months with placebo (HR 0.71, 95% CI, 0.57 - 0.88, P = .0016); all patients received CarboTaxol. Subgroup analyses showed similar benefits in triple-negative and hormone receptor-positive subjects.

The study was published online August 27 in Lancet Oncology.

The median overall survival was 33.5 months in the veliparib group vs 28.2 months in the control arm (HR 0.95, 95% CI 0.73 - 1.23, P = .67). This result was not statistically significant, but was not mature at the time of reporting.

Even so, "these data suggest that veliparib, in combination with carboplatin and paclitaxel, should be considered as a new treatment option for patients with BRCA-associated advanced breast cancer who are candidates for chemotherapy," write the investigators, led by oncologist Veronique Dieras, MD, a breast cancer specialist at the Centre Eugene Marquis in Rennes, France, and an AbbVie advisor.

Challenging the Monotherapy Dogma

In an accompanying editorial, oncologist Melinda Telli, MD, an associate professor of medicine and director of the Stanford Cancer Institute Breast Cancer Program, Stanford, California, and also an AbbVie advisor and researcher, noted that the design was distinct from previous PARP inhibitor investigations because it tested veliparib in combination with a highly active platinum-based doublet, instead of as monotherapy against non-platinum options as in earlier trials.

"Although one can question the clinical relevance of a 1.9 month difference in median progression-free survival," the PFS curves "are quite distinct from [previous] PARP inhibitor monotherapy studies in that [they] begin to separate late and there is a long tail on the curves. An estimated 34% and 26% of patients were progression free in the veliparib group at 24 months and 36 months compared with 20% and 11% in the placebo group," Telli writes.

"Notably, in [the] 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," she says.

"The data certainly challenge the existing dogma of sequential single-agent therapy in this genetically distinct group of patients with advanced breast cancer," writes Telli. The results of the trial, dubbed BROCADE3, "represent an important step forward in this field and provide a strong rationale for future comparative studies of this approach versus PARP inhibitor monotherapy," she concludes in her commentary.

Benefits Emerge after Transition to Monotherapy

BROCADE3 subjects had HER2-negative, inoperable, locally advanced or metastatic breast cancer with germline BRCA1 or BRCA2 mutations; 337 were randomized to CarboTaxol plus veliparib at 120 mg orally twice daily for 7 days of each 21-day cycle, and 172 to the doublet plus placebo. 

They had approximately 11 cycles of chemotherapy, median follow-up was about 36 months, and about 80% were treated in the first-line metastatic setting.

As allowed in the trial, 38% continued blinded monotherapy at an escalated dose of 300-400 mg twice daily when chemotherapy was discontinued before progression, and 44% of placebo patients crossed over to veliparib after disease progression.

The results "suggest that the overall progression-free survival benefit…is derived both from the inclusion of veliparib with carboplatin-paclitaxel and from the continuation of veliparib monotherapy when chemotherapy is discontinued…The potential for veliparib to maintain responses after a fixed duration of veliparib, carboplatin, and paclitaxel warrants further investigation, because this strategy would represent a major shift in the treatment of metastatic breast cancer," the investigators write.

A Double Whammy Against Cross-resistance

The most common grade 3 or worse adverse events were neutropenia (81% in the veliparib group vs 84% in the control group), anemia (42% with veliparib vs 40%), and thrombocytopenia (40% veliparib vs 28%).

"Although hematological toxicities" — a major concern with the combined approach — "were frequent in both treatment groups, the [incidence] of clinically important sequelae, including grade 3 or worse infections associated with neutropenia and grade 3 or worse hemorrhages associated with thrombocytopenia, were relatively infrequent," the researchers write.

Overall, adverse events led to discontinuation in 16% of veliparib subjects and 11% in the control arm. There were no veliparib-related deaths.

Among patients who transitioned to blinded monotherapy at the higher dose, the only grade 3 or worse adverse event that occurred more frequently with veliparib more than placebo was nausea (5% veliparib vs 2% control) and seizure (2% veliparib vs none). "The clinical significance of the difference in seizure frequency between treatment groups is unclear," the study team says.

There have been concerns about cross-resistance with platinum-based chemotherapy and PARP inhibitors, in part because they both target tumor DNA. But the investigators offered a counterpoint: combining the two might "allow patients to benefit from both agents before developing cross-resistance."

Competitor Studies Unfair?

The team noted that patients with hormone receptor-positive, BRCA-mutated breast cancer who are no longer candidates for endocrine therapy might benefit from the combination. In their subgroup analysis of those subjects, median PFS was 13 months and overall survival 32.4 months in the veliparib group.

As for the two PARP inhibitor monotherapies already on the US market for BRCA-mutated breast cancer, the approach has yet to be tested head-to-head against highly-active platinum-based regimens. "As such," the investigators note, "whether or not PARP inhibitor monotherapy is superior to single-agent platinum chemotherapy remains an unanswered question."

On that topic, editorialist Telli writes: "One can speculate about whether PARP inhibitor monotherapy would have been approved had [previous] studies included platinum chemotherapy in the comparator group."

Ninety-nine percent of the subjects in the study were women, 87.9% were White, and 86% lived outside the United States.

The study was funded and conducted by AbbVie, veliparib's maker. Dieras is an advisor for the company; other investigators reported advisory and other ties to AbbVie, including honoraria and institutional research funding. Several were AbbVie employees with stock interests. Telli has served in an advisory role for AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro; and has received research funding to her institution from AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro.

Lancet Oncol. Published online August 27, 2020. Abstract, Editorial

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