Medivation Acquires BioMarin's PARP Inhibitor Talazoparib

David Hung, MD

Medivation has announced that it will purchase the PARP inhibitor talazoparib (BMN-673) from BioMarin Pharmaceutical for $410 million, with additional milestone and royalty payments of up to $160 million. Once the agreement closes, Medivation will become responsible for all global research, development, regulatory, and commercialization costs.

“Acquiring all worldwide rights to talazoparib provides Medivation with a transformational opportunity to diversify and expand our proprietary portfolio and global oncology franchise,” David Hung, MD, president and chief executive officer of Medivation, said in a statement. “Talazoparib's potential to act alone or augment the effects of a wide array of tumor DNA-damaging oncology therapies and its high potency and level of activity in various cancers make talazoparib a great strategic fit for Medivation's oncology portfolio, building on existing strengths as well as potentially allowing Medivation to expand into new oncology indications.”

Talazoparib is a highly potent inhibitor of PARP 1/2 that selectively targets tumor cells with BRCA1, BRCA2, or PTEN gene mutations. The agent is being explored across a variety of solid tumors, and is furthest along in development as a treatment for patients with breast cancer. In this setting, a number of clinical trials are currently recruiting participants.

The open-label phase III EMBRACA study is assessing talazoparib in patients with locally advanced and/or metastatic breast cancer germline BRCA mutations. In this study, patients will be randomized in a 2:1 ratio to talazoparib at 1.0 mg daily for 21 continuous days or physicians' choice of chemotherapy. The primary endpoint of the study is progression-free survival (PFS).

The initial target enrollment for the study was 430 participants by the end of 2015; however, since the initiation of the study new data has become available, suggesting a lower than anticipated PFS with chemotherapy. Given this new finding, data from less than 430 patients may sufficiently satisfy the statistical requirements for the primary endpoint. Although an initial goal of late 2015 was set, BioMarin believes that enrollment in EMBRACA will complete in the first half of 2016 (NCT01945775).

Initial data from a phase I/II trial for patients with breast cancer were presented at the 2013 European Cancer Congress for the potent PARP inhibitor.¹ In this study, 14 patients with germline BRCA-mutated breast cancer were treated with 1 mg/day of talazoparib.

The objective response rate (ORR) with talazoparib by RECIST criteria was 50%, which included 1 complete response. Additionally, 36% of patients had stable disease, for a clinical benefit rate (CBR) of 86%. When including patients who received talazoparib in a dose escalation cohort (N = 18), the ORR by RECIST was 44% with a CBR of 72%.

The primary dose-limiting toxicity seen with talazoparib in this study was thrombocytopenia. Hematologic adverse events grade >1 included anemia (25%), thrombocytopenia (20%), and neutropenia (12.5%). Fatigue, nausea, and alopecia were observed in 26% to 29% of patients.

In July 2015, BioMarin announced that the phase II ABRAZO trial exploring talazoparib in patients with deleterious germline BRCA1/2 mutations and locally advanced and/or metastatic breast cancer had met an initial efficacy assessment. In this study, patients were assigned to 1 of 2 cohorts (35 patients each) based on their prior exposure to chemotherapy.

At the initial analysis, treatment with talazoparib effectively shrank tumors in at least 5 patients per cohort, per RECIST criteria. In fact, the agent met this criterion before each cohort was capable of fully enrolling. With the completion of this milestone, the study was expanded from 70 to 140 participants. Completion of enrollment is anticipated in the first quarter of 2016 (NCT02034916).

In addition to the ABRAZO study, a second phase II study is assessing talazoparib in patients advanced cancer who harbor a variety of genetic characteristics. The study will assess the efficacy of talazoparib in those with somatic alterations in BRCA1/2, mutations/deletions in PTEN or PTEN loss, mutations/deletions in other BRCA pathway genes (ATM, PALB2, NBS1, Fanconi Anemia genes), and those with germline mutation in BRCA1/2 who do not have breast or ovarian cancer. This study plans to enroll 180 patients, with a primary endpoint of clinical benefit rate (CBR; NCT02286687).

“PARP inhibitors are an exciting class of oncology therapeutics that have been associated with promising activity across multiple tumor types, including breast and prostate cancer,” said Hung. “These latter two disease indications are areas in which Medivation has proven expertise and development capabilities and in the case of prostate cancer, an established and successful commercial presence.”

Medivation's only FDA-approved agent is enzalutamide (Xtandi), a potent androgen receptor (AR) inhibitor for men with prostate cancer. Early research has suggested that PARP1 could be a regulator of AR function, with a potential role for combination strategies in men who become resistant to AR inhibition.

In the phase II TOPARP study, single-agent PARP inhibition showed an ORR of 87.5% in patients with resistant prostate cancer who harbored a somatic or germline defect in DNA repair genes. Across the full study, the ORR was 32.7%. In this experiment, 96% of patients were resistant to prior AR-targeted therapy.²

In an investigator-sponsored trial, enzalutamide is being explored with the PARP inhibitor niraparib for patients with metastatic castration-resistant prostate cancer. The study hopes to enroll 24 patients with a goal of discovering a maximum-tolerated dose (NCT02500901). Although not yet initiated or announced, a similar study combining enzalutamide with talazoparib seems likely.

“We believe that Medivation is an outstanding company to drive the future development of talazoparib and ensure it reaches its full therapeutic potential,” Hank Fuchs, MD, chief medical officer at BioMarin, said in a statement. “Medivation's expertise and track record in oncology clinical development and commercialization has been well demonstrated by the Company's success to date. Placing talazoparib in their capable hands allows us to optimize our portfolio and focus our resources on established areas of expertise—developing novel products to treat rare and ultra-rare genetic diseases.”

Early combination studies have been initiated for talazoparib, primarily looking at the PARP inhibitor with chemotherapy. In an NCI sponsored phase I study, talazoparib is being combined with carboplatin and paclitaxel for patients with unresectable or metastatic solid tumors (NCT02317874).

A second study is looking at talazoparib plus irinotecan with or without temozolomide in children with refractory or recurrent solid tumors (NCT02392793). Both trials are focused on determining a maximum-tolerated dose for future investigations, along with efficacy and safety.

References

1. Ramanathan R, Wainberg Z, Mina L, et al. PARP inhibition with BMN 673 in ovarian and breast cancer patients with deleterious mutations of BRCA1 and BRCA2. Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract LBA29.
2. Mateo J, Sandhu S, Miranda S, et al. Phase II trial of the PARP inhibitor olaparib in sporadic and unselected metastatic castration resistant prostate cancer (mCRPC). Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract CT322.