Again, a PARP Inhibitor Has Potential in BRCA+ Breast Cancer

Pam Harrison

December 11, 2017

SAN ANTONIO ― Talazoparib, a poly adenosine diphosphate ribose polymerase (PARP) inhibitor currently in development by Pfizer, has been shown to extend progression-free survival (PFS) compared with standard chemotherapy in women with metastatic breast cancer with a germline BRCA mutation, and the drug is generally well tolerated, an international, open-label, phase 3 study indicates.

This is the second time in the past 12 months that a PARP inhibitor has been reported to have efficacy in this setting.

Olaparib (Lynparza, AstraZeneca) was similarly reported to improve PFS in the same patient group earlier this year. By inhibiting the PARP enzyme, both talazoparib and olaparib prevent DNA from repairing damage, causing tumor cell death.

"We are very pleased that the phase 3 EMBRACA trial - the largest randomized clinical trial conducted in this group of patients with hereditary breast cancer - met its primary efficacy endpoint of progression-free survival," Jennifer Litton, MD, associate professor in the Department of Breast Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, said in a statement.

Dr Jennifer Litton

"And in EMBRACA, talazoparib demonstrated superior clinical benefit in all subsets of patients regardless of receptor subtype, number of prior lines of chemotherapy, BRCA mutation type, or central nervous system metastasis," she added.

The study was reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017.

A total of 431 patients were randomly allocated to receive either talazoparib 1 mg once daily or the physician's choice of treatment (PCT). Chemotherapy could include capecitabine, eribulin, gemcitabine, or vinorelbine.

The median age of the group was 46 years, and 54% of the group had hormone receptor–positive disease. Slightly more patients, at 55%, had BRCA2-positive breast cancer than BRCA1-positive breast cancer, and slightly more than a third had not received prior chemotherapy for advanced breast cancer.

At a median follow-up of 11.2 months, median PFS was 8.6 months for women in the PARP inhibitor arm, which was 46% longer than the median PFS for patients receiving PCT, at 5.6 months (P < .0001).

Overall survival (OS) at interim analysis was 22.3 months for the talazoparib arm compared with 19.5 months for the PCT arm, which was not statistically significant. However, the result is expected to mature over time. EMBRACA is sufficiently powered to reveal a difference in OS over time, Dr Litton noted.

Secondary endpoints all favored the PARP inhibitor over standard chemotherapy.

 

Talazoparib Chemotherapy
Complete response 5.5% 0%
Partial response 57.1% 27.2%
Clinical benefit at week 24 68.6% 36.1%
Duration of response 5.4 months 3.1 months (P = .0005)

 

Asked by Medscape Medical News to comment on the study, session moderator Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, Texas, felt that EMBRACA should be seen as a "first step" in addressing DNA repair as a target for treatment.

"Several other PARP inhibitors have shown positive results, so I think the concept has been shown to work in some of these patients," Dr Osborne said.

"Now the trick is to find out who is going to respond best to PARP inhibitors and to identify the mechanism of resistance, because in some cases, tumor cells are able to repair the BRCA mutation, and if there is no longer any mutation, the drug is no longer going to work," he added.

"So now we are trying to refine who we should treat, because some patients get greater benefit from this treatment than others, and we need to identify who these patients are," Dr Osborne said.

Adverse Events

Grade 3 and 4 anemia was the most common hematologic toxicity seen in association with PARP inhibitor treatment, occurring in 55% of patients in the talazoparib arm compared to 38% in the PCT arm.

However, Dr Litton stressed that only two of the patients being treated with talazoparib had to discontinue treatment because of anemia and that, overall, the drug was well tolerated. Fatigue, nausea, and headache were the most common nonhematologic adverse events.

Importantly, the patients who were treated with talazoparib also demonstrated an improvement in global health status, as measured by the EORTC QLQ-30 questonnaire. Scores on the EORTC QLQ-30 increased by a mean of 3 points from baseline among the patients in the talazoparib arm, compared to a 5.4-point decline for patients who received PCT.

"Time to a clinically meaningful deterioration that persisted was a median of 24.3 months in the talazoparib arm compared with 6.4 months in the PCT arm," Dr Litton observed (P < .001).

"And overall, once-daily oral talazoparib was well tolerated in comparison to chemotherapy," she added.

Asked by Medscape Medical News if a 3-month prolongation in PFS is clinically meaningful, Dr Litton acknowledged that it was moderate but that the separation in PFS curves between the PARP inhibitor arm and the PCT arm was real - the curves separated early and remained that way - "so you get a quick response and continued improvement," she noted.

With only 51% of projected events occurring at the time of the current analysis, "the overall survival curves are also separating, and they do not come back together either, which I think is very interesting and important," Dr Litton said.

"Most importantly," Dr Litton added, "with talazoparib, patients can take a pill once a day and they're done, which is much more attractive than having to take multiple pills every day or sitting in a chemotherapy chair," she suggested.

The study was funded by Pfizer. Dr Litton has received research funding from EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline and serves on advisory boards for Pfizer and AstraZeneca. Dr Osborne has financial ties to multiple pharmaceutical companies, including AstraZeneca, Genentech, and Gilead Sciences.

San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS6-07, presented December 8, 2016.

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