AstraZeneca Back In The PARP Mix With Olaparib In Ovarian Cancer

Olaparib is off the shelf and into a Phase III trial against ovarian cancer in platinum-sensitive BRCA-positive patients, adding to the list of late-stage PARP inhibitors vying for first-in-class status.

AstraZeneca PLC has launched twin Phase III trials of its once-shelved PARP inhibitor olaparib as maintenance monotherapy in women with BRCA-positive ovarian cancer, following a reassessment of olaparib’s potential based on genomic analysis.

Olaparib was once a widely anticipated drug for ovarian cancer, but in December 2011 AstraZeneca announced it was dropping it after a review of Phase II data showed the gain in progression-free survival was not likely to translate into an overall survival benefit.

Ultimately, however, an efficacy signal in the BRCA-positive subgroup led to an internal review of the development program and subsequently to its revival (Also see "Pharma Adapts Ovarian Cancer Drugs Amid Genomics Revolution" - Pink Sheet, 1 Jul, 2012.). The retrospective analysis showed a median progression-free survival of 11.2 months with olaparib compared to 4.3 months for placebo in BRCA-positive patients (Also see "AstraZeneca Oncology Focused On Combinations, But Differentiation Will Be Key" - Pink Sheet, 17 Jun, 2013.).

At the end of 2011 AstraZeneca announced it was taking an impairment charge of $381.5 million in its fourth-quarter results because of the olaparib failure and the likely failure of a Phase III antidepressant (Also see "AstraZeneca Takes Impairment Charge After Olaparib, TC-5214 Setbacks" - Pink Sheet, 20 Dec, 2011.).

But, concurrent with the announcement that olaparib was back in the clinic, the company announced a pre-tax impairment charge of $285 million would be reversed and the asset restored to the balance sheet in the third quarter of 2013. In addition, the reversal would be excluded from core earnings per share.

The Study of Olaparib in Ovarian cancer (SOLO) program is enrolling about 600 women in the U.S. and Europe. The primary endpoint for both trials is progression-free survival, with overall survival as a secondary endpoint. Both groups will receive daily olaparib 300 mg orally or placebo.

SOLO 1, being conducted in the U.S. with the National Cancer Institute-funded Gynecologic Oncology Group, aims to enroll 344 women with high-risk BRCA-positive ovarian cancer who had a partial or complete response after first-line platinum-based chemotherapy.

SOLO 2, being conducted in collaboration with the European Network of Gynaecological Oncology Trial Groups, aims to enroll 264 women with platinum-sensitive BRCA-positive relapsed ovarian cancer who have completed at least two lines of platinum-based chemotherapy.

A Drug Class Revived By Genomics

Poly ADP-ribose polymerase inhibitors interrupt signaling enzymes involved in the repair of damaged DNA, providing a secondary assault on quickly multiplying cancer cells with DNA already damaged by chemotherapy, a process sometimes called synthetic lethality. When PARPs first went into development, the hope was that chemo plus a PARP inhibitor would be a lethal one-two punch, but the results were disappointing.

Then efforts like AstraZeneca’s led to the notion that mutated BRCA genes, which also are associated with DNA repair vulnerabilities, might also leave cancer cells susceptible to PARP attack, particularly cells of platinum-sensitive cancers.

In concert with the AstraZeneca announcement, Myriad Genetics Inc. announced that it had expanded a collaboration with the firm for its BRACAnalysis diagnostic test. Myriad supplied BRACAnalysis to support the Phase II olaparib trial and will now supply it to the Phase III program as a companion diagnostic. Myriad plans to build out a new laboratory within its Salt Lake City facility to meet FDA requirements for companion diagnostic devices, the company said. In August, FDA approved Myriad’s Investigational Device Exemption for BRACAnalysis, enabling its use in clinical trials as a companion diagnostic.

Following a June Supreme Court ruling on gene patents Myriad has mounted a strategy to defend against lawsuits and patent expirations (Also see "Myriad Wields Proprietary Database To Protect Testing Market" - Medtech Insight, 30 Aug, 2013.).

AstraZeneca’s agreement with Myriad is non-exclusive, and the testing company has PARP collaborations with other companies working in the field, including Tesaro Inc. and BioMarin Pharmaceutical Inc., the two companies with PARP inhibitors likely to compete with olaparib.

Three Phase III PARPS

Tesaro Inc., in Waltham, Mass., has what appears to be the most advanced candidate in the field. The Phase III NOVA trial, testing its candidate niraparib as maintenance therapy in high-risk serious platinum-sensitive, relapsed ovarian cancer, launched July 23 with a target enrollment of 360 women in two cohorts. Patients will be placed in one of two arms based on their BRCA mutation status, then randomized from there to drug or placebo, giving the drug an equal chance of success in BRCA+ and BRCA- populations. The primary endpoint is progression-free survival with overall survival as a secondary endpoint (Also see "Tesaro’s Niraparib Takes PARP Inhibitor Lead In Ovarian Cancer" - Pink Sheet, 27 Aug, 2013.).

Both olaparib and niraparib have shown strong efficacy in multiple subgroups of ovarian cancer patients, particularly in the platinum-sensitive population, Leerink Swann analyst Howard Liang observed in a June 7 note to stockholders during the 2013 meeting of the American Society for Clinical Oncology. Overall, he said, niraparib has a 40% overall response rate in BRCA mutated patients compared with 33% for olaparib.

BioMarin has said its candidate, BMN-673, would start Phase III in the third quarter. The candidate’s efficacy “appears comparable” for the platinum sensitive BRCA-mutated patients, with a 50% response rate (10/20), Liang said. But in her note from ASCO, Deutsche Bank analyst Robyn Karnauskas opined that data from BMN-673 “suggests it is likely not more effective vs. Tesaro’s niraparib.”