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AbbVie Pursues Phase III Veliparib Study in BRCA Mutated Breast Cancer After Phase II Survival Trend

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SAN ANTONIO (GenomeWeb) – In a randomized Phase II study, advanced breast cancer patients with BRCA mutations receiving AbbVie's PARP inhibitor veliparib in combination with platinum-based chemotherapy had better progression-free survival and overall survival compared to those receiving just chemo, but these improvements were not statistically significant.

In the Phase II trial funded by AbbVie, researchers led by Moffitt Cancer Center's Hyo Sook Han enrolled nearly 300 locally recurrent or metastatic breast cancer patients with BRCA1/2 mutations as determined by Myriad Genetics' BRACAnalysis test. Patients were randomized to receive veliparib plus carboplatin and paclitaxel, just the carboplatin/paclitaxel regimen, or veliparib and temozolomide.

Focusing on the first two arms, Sook Han reported at the San Antonio Breast Cancer Symposium yesterday that patients on the veliparib plus carboplatin/paclitaxel had median progression-free survival of 14.1 months compared to 12.3 months on the chemo only arm, while median overall survival was 28.3 months versus 25.9 months in the respective arms. Overall response rate was 77.8 percent in the veliparib arm compared to 61.3 percent in the comparator.

Although progression-free and overall survival endpoints didn't reach statistical significance, they trended in favor of the veliparib arm, giving AbbVie reason to continue to investigate the drug in a Phase III trial, called BROCADE3.

"The Phase II trial was a signal generation trial, and the positive trends … observed were sufficient to warrant start of the ongoing Phase III trial," Vince Giranda, project director at AbbVie Oncology Development, told GenomeWeb in an email. He added that the signals observed in the Phase II study helped AbbVie figure out the cohort size for the Phase III trial.

In BROCADE3, AbbVie plans to enroll 500 advanced breast cancer patients with BRCA mutations, also determined by the BRACAnalysis CDx, and randomize them to receive the same regimens as in the Phase II trial: veliparib plus carboplatin/paclitaxel or just carboplatin/paclitaxel.

AbbVie has generated a lot of data to support its decision to pursue further investigation of the drug. Early-stage clinical trials have shown that veliparib by itself has activity in BRCA-mutated breast cancer, and is also efficacious in combination with paclitaxel and carboplatin. In the I-SPY2 trial, veliparib and carboplatin added to standard neoadjuvant treatment increased pathologic complete responses in triple-negative breast cancer patients.

Still, some attendees at the meeting questioned the drug firm's rationale to continue studying the drug in Phase III trials given the drug failed to meet its primary endpoint in Phase II. While the addition of veliparib didn't significantly increase toxicity, some pointed out that the drug would cost significantly more than the standard chemo regimen it was compared to.

New York-based oncologist Steven Vogl suggested moreover that a three-arm study like the one AbbVie performed allows the drug company more leeway to analyze the data so its drug is presented in the best light. "You can do all sorts of manipulations. You can do subgroups, [saying,] 'Well, we'll do BRCA1 and not BRCA2, or we'll do BRCA1 and the Jewish [people with] BRCA1 [mutations,]" he said. "There are an infinite number of ways you can play around with the data."

According to Sook Han, however, the third arm of the Phase II study, which included veliparib in combination with temozolomide, did not improve progression-free survival over the carboplatin/paclitaxel arm. But "because the Phase II randomized trial gave us an answer we were looking for," she said AbbVie was able to exclude that arm from the Phase III study design.

In the Phase II study, Sook Han said researchers conducted subgroup analysis, but didn't note significant difference in progression-free survival between patients with BRCA1 and BRCA2 mutations, or in different breast cancer subtypes.

Studies have shown that patients with BRCA mutations or with homologous recombination deficiencies respond particularly well to PARP inhibitors. As the scientific understanding of these response mechanisms have grown, AbbVie has expanded its diagnostic toolbox, hoping to identify various patient subsets who might benefit from its drug.

AbbVie inked a companion diagnostics deal with Myriad in 2010 to use its BRACAnalysis CDx to determine germline BRCA mutations in patients enrolled in veliparib studies. The firm expanded that partnership in 2014 to use Myriad's Tumor BRACAnalysis CDx in an effort to also identify patients with somatic mutations who might benefit from veliparib. Then, earlier this year, the drugmaker said it would use Myriad's myChoice HRD next-generation sequencing test in non-small cell lung cancer studies involving veliparib.

A number of Myriad's drug partners are using its somatic and germline BRCA tests, as well as its myChoice HRD assay in an effort to understand the genomic profiles of all potential responders to their PARP inhibitors.

AstraZeneca, for example, received accelerated approval from the US Food and Drug Administration in 2014 for its PARP inhibitor Lynparza (olaparib) alongside BRACAnalysis CDx for advanced ovarian cancer patients who had received three or more lines of chemotherapy. However, AstraZeneca recently agreed to use Myriad's new myChoice HRD Plus test in an exploratory study involving its PARP inhibitor Lynparza (olaparib).

The original myChoice HRD test detects whether patients have somatic mutations in BRCA1 and BRCA2 genes and other "genomic scars" by measuring heterozygosity loss, telomeric allelic imbalance, and large-scale state transitions. The newly launched MyChoice HRD Plus also gauges mutations in 102 genes.

Myriad recently began submitting a rolling pre-market approval application with the FDA for its myChoice HRD test as a companion diagnostic for Tesaro’s ovarian cancer PARP inhibitor niraparib. Data from a Phase III trial showed that recurrent ovarian cancer patients benefitted from niraparib regardless of BRCA mutation status or HRD test status, but patients in BRCA mutations and those who are HRD positive derived a greater magnitude of benefit compared to patients without these markers. Tesaro has said it is pursuing approval of the drug in the overall population, but the FDA will determine the label of the drug.

However, AbbVie is focusing primarily on patients with BRCA mutations in Phase II and Phase III trials of veliparib in advanced breast cancer. "Both Phase II and III trials have used Myriad as the central lab to determine BRCA status," Giranda said. "Only those patients with BRCA-deficient tumors are enrolled in these studies."

He added that "in research where a novel agent (e.g. veliparib) is combined with an active agent (e.g. carboplatin), a randomized, blinded, and placebo-controlled trial is one of the best methods by which to determine if addition of the novel agent provides a benefit."

Virginia Kaklamani from the University of Texas Health Science Center in San Antonio also seemed to defend the need to explore veliparib in Phase III studies. She noted that the response rate advantage seen in the Phase II veliparib arm may be important to patients looking for quality of life improvements.

"A few years ago we never used to do randomized Phase II clinical trials. We used to do Phase I trials that were dose finding, Phase II trials that were just giving us a hint of efficacy, and then large Phase III trials that were definitive trials, " Kaklamani reminded. "Now, we've moved to those randomized Phase II trials, but that should not deter us from pursuing a potentially interesting medication."