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Tesaro's niraparib has an advantage over other PARP inhibitors in that it has been tested successfully in Phase III for ovarian cancer patients with and without BRCA mutations, but AstraZeneca thinks it may have a case for broad labeling without pivotal data in this population.


AstraZeneca PLC thinks there is potential for its poly ADP-ribose polymerase (PARP) inhibitor Lynparza to get FDA approval as a maintenance therapy in ovarian cancer patients broadly, regardless of mutation status. But to do so, it will have to convince regulators to accept a "totality of the evidence" approach.

The company presented impressive data for Lynparza (olaparib) in the SOLO-2 study against placebo as a maintenance treatment in 295 relapsed patients with BRCA mutations on March 14 at the Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, held in National Harbor, Md. This followed a top-line release from the trial in October. (Also see "Lynparza May Still Rival Tesaro's Niraparib In Ovarian Cancer Therapy" - Scrip, 27 Oct, 2016.)

AstraZeneca will be now be discussing the data with FDA in pursuit of expanded labeling beyond fourth-line treatment. Lynparza received accelerated approval from FDA for use after three lines of therapy in germline-BRCA mutated ovarian cancer in December 2014. ( (Also see "AstraZeneca’s Olaparib Clears FDA For Later Therapy Line In Ovarian Cancer" - Pink Sheet, 19 Dec, 2014.)SOLO-2 will serve as the confirmatory trial to convert the drug's status to full approval and also support an indication for maintenance treatment.


While SOLO-2 was done in patients with BRCA mutations, who make up 10%-15% of ovarian cancer patients, Lynparza was tested in a broader population in the Phase II Study 19, an earlier maintenance trial. AstraZeneca believes the drug has prospects for approval in all comers, regardless of mutation status, based on the totality of the data, though it needs to discuss this with regulators, Mika Sovak, executive director and Lynparza global development lead, said in an interview.


This won't be the first time FDA has reviewed Study 19. AstraZeneca initially sought accelerated approval in the US for Lynparza as a maintenance therapy in relapsed ovarian cancer patients with germline BRCA mutations based on Study 19, but agency reviewers had a number of concerns about the data, including toxicities. The agency recommended that the company go back and analyze data in heavily pretreated patients and an evaluation of data from the single-arm, open-label Study 42 paved the way for accelerated approval in December 2014 for the fourth-line BRCA-mutated indication, following a major amendment to a filing. (Also see "Lynparza Approval Shows Benefit/Risk Contrast In Maintenance, Relapse Settings" - Pink Sheet, 5 Jan, 2015.))

Even prior to that, AstraZeneca had made major changes to its development plans of the drug. It initially was developing olaparib for a broad indication but after it became clear that the drug would not show an overall survival benefit in the total population, the company began focusing on those with germline BRCA mutations. (Also see "AstraZeneca Back In The PARP Mix With Olaparib In Ovarian Cancer" - Pink Sheet, 15 Oct, 2013.)

Sovak explained that more is known about the PARP class and suggested that Study 19 may now be viewed in a different light.


SOLO-2 Stands On Its Own


The study tested a new dosing regimen for olaparib (300 mg twice daily) as a maintenance treatment in germline BRCA-mutated platinum-sensitive relapsed ovarian cancer. The current approved dose is 400 mg twice daily and the new regimen promises to reduce the pill burden from 16 to four tablets daily.


The company reported a statistically significant improvement in PFS compared to placebo: 19.1 months vs. 5.5 months, a 70% improvement, per investigator review. It also reported significant improvements on a range of secondary endpoints, including a 50% reduction in time to second progression or death. Safety was in line with prior trial results.


Biomedtracker analyst David Dahan commented that the results were impressive and hold up well in comparison to data for Tesaro Inc.'s competing niraparib, which is under priority review with FDA for a maintenance indication with a June 30 user fee date. Tesaro's niraparib is poised to become the third PARP inhibitor approved, after Lynparza and Clovis Oncology Inc.'s Rubraca (rucaparib), but it could become the first to get an indication regardless of mutation status and for maintenance therapy. (Also see "Tesaro Doubles On Super NOVA Data, Lifts PARP Competitors" - Scrip, 30 Jun, 2016.)


That might be a short-lived advantage, however, if AstraZeneca can leverage its latest data for a broader approval.


Activity in the market suggests investors think AstraZeneca's gain is Tesaro's loss. Tesaro stock was down by 10.59% on March 14 to $153.65.


Cross-trial comparisons suggest Lynparza has similar efficacy as niraparib in gBRCA patients with a better safety profile – for example, lower rates of Grade 3+ thrombocytopenia, neutropenia and anemia, Dahan commented.


"Niraparib, however, has the advantage of having demonstrated efficacy in patients who had tumors with homologous recombination deficiency (HRD) as well as in non-gBRCA patients which may translate to a wider label," he noted.


Although AstraZeneca's Study 19 included platinum-sensitive ovarian cancer patients regardless of BRCA mutation status, the current data in the overall population doesn't seem sufficient for approval in the wider patient subset, Datamonitor Healthcare analyst Zachary McLellan commented.


In a five-year follow-up for Study 19 published last year, median survival in patients treated with Lynparza was longer compared to placebo – by 4.7 months in germline BRCA-mutation-positive patients and 2.0 months in the overall trial population – but the overall survival results were not statistically significant, the analyst observed.


"Additionally, any survival increase in the overall trial population is likely driven by the gBRCAm+ cohort. AstraZeneca announced further analysis into the patients without BRCA mutations who were positive for other homologous recombination deficiencies is ongoing. That data would likely need to be significant and be included in any regulatory submission for Lynparza’s approval beyond BRCAm+ patients," McLellan said.


Niraparib Hits Secondary Goals


Tesaro's filing for niaraparib covers use of the drug as a once-daily maintenance treatment of patients with recurrent platinum-sensitive, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who has a partial or complete response to platinum-based chemotherapy. No FDA advisory committee is needed for the review and Tesaro has advised it expects rapid approval and plans to launch in the first half.


The filing is supported by the Phase III ENGOT-OV16/NOVA study, in which the drug demonstrated a progression-free survival benefit. Positive secondary endpoint data were presented at the SGO meeting on March 13.

In the study, the chemotherapy-free interval was significantly improved for patients who were BRCA-mutation positive as well as those without germline BRCA mutations compared to the placebo control arm (the hazard ratios were 0.26 and 0.50, respectively).


The time to first subsequent treatment was significantly improved for those with and without BRCA mutations. Tesaro also reported a 52% improvement in time to second progression for those with mutations and a 31% improvement in those without mutations, plus a trend toward improved overall survival.


The company had reported in December 2016 that the drug met the primary endpoint of the trial, with significantly increased progression-free survival in patients with (73%) or without (55%) germline BRCA mutations versus control.

Combined with previously released PFS data from the NOVA trial, the evidence reaffirms that niraparib could become the leading PARP inhibitor in treating ovarian cancer, McLellan commented.

"The Tesaro update at SGO showed niraparib treatment significantly improved the chemotherapy-free interval and time to first subsequent treatment over placebo in both germline BRCA-mutated patients and patients without these mutations. This bodes well for niraparib’s regulatory submissions as a maintenance regimen for recurrent platinum-sensitive ovarian cancer patients regardless of mutation status," the analyst said.

Clovis' Rubraca, which was approved in December 2016 for BRCA mutation (germline and/or somatic) associated advanced ovarian cancer after treatment with two or more chemotherapies, is now in Phase III for use as a maintenance treatment in ovarian cancer and data are expected in the middle of this year. (Also see "Clovis Transitions To Commercial Stage On Rubraca Approval" - Scrip, 19 Dec, 2016.)

The study is enrolling patients with and without BRCA mutations, but the primary endpoint is progression-free survival in molecularly defined subgroups.

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