AbbVie’s phase 2 PARP study misses survival endpoints; hopes rest on bigger phase 3

AbbVie will be looking to a larger phase 3 trial to see whether its PARP inhibitor can boost survival further.

AbbVie missed its survival targets in a new midstage trial of its PARP breast cancer candidate veliparib in combo with chemo, but the company is still hopeful its med can win out in an ongoing, larger late-stage study.

Its med, a poly(ADP-ribose) polymerase (PARP) inhibitor which is designed to stop cancer cells being able to repair, was being tested among patients who had locally recurrent or metastatic breast cancer with BRCA1 or BRCA2 mutations.

The primary endpoint of this 290-patient phase 2 “Brocade” study was progression-free survival (PFS), with overall survival (OS) and objective response rates being secondary endpoints.

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It failed however to hit statistical significance in either PFS an OS, missing its primary endpoint and a secondary, with improvement in PFS in the veliparib arm being 14.1 months versus 12.3 months, while the trend to improved OS also failed to hit statistical significance (28.3 months versus 25.9 months).

In its remaining secondary endpoint, overall response rate (ORR) for the veliparib arm was 77.8%, compared with 61.3% for the placebo arm.

There was some better news on the safety front, as the company saw “no significant increase in toxicity” with the addition of veliparib in the treatment arms, with the most common grade 3 or higher adverse events being neutropenia, which was seen in just over half of patients on placebo and veliparib.

In the study, 97 were randomized to veliparib plus carboplatin and paclitaxel, 99 to placebo plus carboplatin and paclitaxel, and 94 to veliparib plus chemo med temozolomide.

Today’s read-out is from the findings from the carboplatin and paclitaxel with veliparib or placebo arms.

More than half of the patients in these arms of the trial had hormone receptor–positive breast cancer, about 40% had triple-negative breast cancer, and a few had HER2-positive breast cancer. Disease characteristics were balanced between the two arms, AbbVie said in a statement.

So, what happened to its survival rates? Dr Vince Giranda, project director at AbbVie Oncology Development, told FierceBiotech: “[This study] had approximately 90 patients per arm, but was limited in its ability to detect improvements in PFS at the p < 0.05 level of significance. Because we saw positive trends in PFS and OS with no increased side effects, it warrants additional investigation in a larger phase 3 study.”

This late-stage test will be “better powered” to find those as yet elusive statistically significant increases in PFS and OS, the Big Pharma said. Dr Giranda explained that the phase 3 “will be sized to detect significant differences in clinically relevant endpoints.”

I asked when a read-out of these data should be available: “We do not have specific timing yet, but are hopeful that this study provides more definitive answers on whether veliparib could become a part of routine clinical care.”

Dr Giranda added: “There hasn’t been a lot of progress in the treatment of BRCA positive breast cancer; and treatment options have been limited for this patient population, which tends to skew younger. There is a great need for new research in BRCA1 and BRCA2 mutation cancers right now, and PARP inhibitors, like veliparib, are helping to fill that gap.”

PARP inhibitors had until the summer been something of a neglected class of cancer therapy, with AstraZeneca’s ovarian cancer med Lynparza (olaparib), the only PARP inhibitor already on the market, having an FDA nod for BRCA-positive patients, which makes up about 10% to 15% of the ovarian cancer population.

It will likely soon have much more competition, however, with a number of PARPs in the pipeline, including talazoparib, a late-stage drug Pfizer acquired in its $14 billion deal for Medivation, as well as Tesaro’s niraparib and Clovis’ rucaparib.

I asked Dr Giranda whether he believed AbbVie’s PARP could compete in what could soon be a competitive market, as all three drugs could also be approved ahead of its offering: “We are taking a targeted approach to potentially increase the efficacy of platinum chemotherapy; and this focus is distinct from other late-stage clinical PARP inhibitors.”

The pharma was down by more than 3% this morning on the news.

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