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Pfizer PARP Inhibitor Delays Progression Over Chemotherapy in BRCA-Mutated Advanced Breast Cancer

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SAN ANTONIO – Advanced breast cancer patients with BRCA1/2 mutations receiving Pfizer’s PARP inhibitor talazoparib lived, on average, three months longer without their disease progressing, compared to those receiving chemotherapy chosen by their doctors, according to data presented at the San Antonio Breast Cancer Symposium on Friday.

Researchers led by MD Anderson Cancer Center’s Jennifer Litton presented a Phase III, randomized study, called EMBRACA, involving more than 400 patients with HER2-negative, BRCA-mutation positive advanced or metastatic breast cancer. They reported at SABCS that treatment with talazoparib resulted in a median progression-free survival of 8.6 months compared to 5.6 months for those receiving their physician’s choice of treatment with capecitabine, eribulin, gemcitabine, or vinorelbine.

Litton highlighted that EMBRACA is the largest randomized trial to date evaluating a PARP inhibitor in advanced breast cancer patients and was powered to detect a difference in overall survival between the treatment arms. Interim median overall survival with 51 percent projected events was 22.3 months in the talazoparib arm versus 19.5 months in the chemotherapy arm. This was not a statistically significant finding, though further follow-up is needed before final overall survival data will be available.

In the trial, more patients on talazoparib saw their tumors shrink, experienced a clinical benefit, and had a longer duration of response compared to chemotherapy-treated patients. According to patient-reported quality life measures, there was a significant delay in deterioration of health on talazoparib compared to physician-chosen chemotherapy.

Litton noted that talazoparib was well tolerated in the study, with patients experiencing minimal hematologic toxicities and there were few adverse events resulting in treatment discontinuation. More than half the patients randomized to talazoparib experienced anemia, which she noted was a toxicity that has been seen across the PARP inhibitor class of drugs. There were similar rates of alopecia in both treatment arms, though for most talazoparib-treated patients, this was a grade 1 toxicity. Deaths due to adverse events occurred in 2 percent and 3 percent of patients in the talazoparib and comparator arms.

In the study, patients’ BRCA status was centrally confirmed by Myriad Genetics, which inked a companion diagnostic partnership with Medivation to use its BRACAnalysis CDx for the development of talazoparib.

Last year, Pfizer acquired Medivation in a deal valued at $14 billion. At the time, Pfizer highlighted the fact that among Medivation’s various valuable assets, talazoparib was a potent PARP inhibitor that could be efficacious in a number of different cancers. In addition to advanced breast cancer, the drug has shown single-agent activity in prostate, ovarian, and small-cell lung cancer.

There is currently no commercially available PARP inhibitor for breast cancer, though a number of agents are under development. The US Food and Drug Administration has approved three PARP inhibitors to date ㅡ AstraZeneca’s Lynparza (olaparib), Clovis Oncology’s Rubraca (rucaparib), and Tesaro’s Zejula (niraparib) ㅡ but all for ovarian cancer.

The agency approved Myriad’s BRCA test as a companion diagnostic for Lynparza when used as a maintenance therapy for platinum-sensitive ovarian cancer; and as a complementary diagnostic for Zejula, when used as a maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Earlier this year, Myriad said it would work with Clovis to advance BRACAnalysis CDx for identifying best responders to its third-line advanced ovarian cancer drug Rubraca as part of a post-marketing commitment for the drug.

Rubraca was initially approved with Foundation Medicine's next-generation sequencing test FoundationFocus CDxBRCA, which gauges somatic mutations, while BRACAnalysis CDx is a germline test. Germline BRCA testing is performed to assess risk of breast and ovarian cancer in affected and unaffected women, while somatic testing is done to inform treatment decisions in cancer patients. Patients who find out they harbor BRCA mutations only after they get cancer through somatic testing may also have germline mutations, which has broader implications for their own and their family members’ cancer risk.

“We’re going to have to look at what we do for patients we find somatic mutations in as we increase our use of next-generation sequencing in the tumor and how we communicate that to our patients, especially when we find something that suggests a germline [mutation] though they may not have had those results,” Litton said.

In reviewing the data from the EMBRACA trial, Kent Osborne from Baylor College of Medicine, noted that while a doctor might look at the outcomes and consider them to be a good advance in the treatment of advanced breast cancer, patients might not be so impressed by a three-month progression-free survival advantage. According to the American Cancer Society, 22 percent of stage IV breast cancer patients are alive five years after diagnosis.

“Patients may look at it and say, ‘Gee, a few more responses and a three-month prolongation in the average of my time to progression, that’s not a very big advantage,’” he said, wondering what the next steps were in terms of combination treatment and efforts to battle resistance.

In another Phase III study presented earlier this year involving 300 hormone receptor-positive or triple-negative metastatic breast cancer patients who had germline BRCA mutations, researchers compared Lynparza against chemotherapy (capecitabine, vinorelbine, or eribulin). They found that median progression-free survival was seven months for Lynparza-treated patients, compared to 4.2 months in those receiving chemotherapy, and the PARP inhibitor shrank tumors in 60 percent of patients, versus 29 percent of those on chemotherapy.

Beyond the progression-free survival data, Litton said that the EMBRCA results are promising in that 12 patients on talazoparib had a complete response versus none on the comparator arm, and several patients on the PARP inhibitor had a duration of response that was 33 months, much higher than what was seen in chemo-treated patients.

She added that her group will work on identifying the characteristics of these “extraordinary responders,” study the mechanisms of resistance, and explore the use of combination drugs to stave off resistance and extend duration of response.

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