With breakthrough therapy designation (BTD) for rucaparib as a monotherapy in advanced ovarian cancer (OC), Clovis Oncology Inc. joins a limited few in the sector with more than one BTD win, having earlier achieved the same status for rociletinib, an epidermal growth factor receptor inhibitor for non-small-cell lung cancer.

The BTD stamp for rucaparib also marks the first time a poly ADP-ribose polymerase (PARP) inhibitor rang the bell, London-based Astrazeneca plc having failed to win the designation for olaparib (Lynparza), though the compound was cleared via the accelerated pathway in December for advanced OC in patients with defective BRCA genes.

Regulatory officials "always maintain the right to take [BTD] away, too," Boulder, Colo.-based Clovis' CEO Patrick Mahaffy told BioWorld Today, but even if Astrazeneca's confirmatory study is successful, rucaparib still boasts a broader population of OC patients who might benefit. "That alone, I think, eliminates the risk," he said. "The breakthrough [status] is more about the fact that they recognized the opportunity to improve on what's out there today."

Clovis' therapy, an inhibitor of PARP1 and PARP2, is indicated for women who have received at least two lines of prior platinum-containing therapy, with BRCA-mutated tumors, inclusive of both germ-line BRCA and somatic BRCA mutations. "It's not part of the breakthrough designation, but in the trial we're actually evaluating rucaparib in a patient population described as being 'BRCA-like,' with tumors that have behavioral characteristics that are similar, most notably in that they have deficiencies in DNA repair," Mahaffy said. "People have talked about [going after the BRCA-like population] before, and any number of efforts have been made to retrospectively fit a group of patients into a definition, but that has all of the issues associated with a retrospective analysis. We're doing it [prospectively]."

The regulatory progress with rucaparib arranges another piece on the PARP chessboard, as Waltham, Mass.-based player Tesaro Inc. is possibly lining up to make a bid for BTD for niraparib in OC this year, if interim data from the QUADRA study in recurrent disease prove strong, though the company has not said explicitly that it will shoot for the status. Phase III data from Tesaro's second-line maintenance study called NOVA against ovarian tumors are expected in the second half of the year, and there's another phase III experiment, known as BRAVO, in BRCA-positive breast cancer.

Leerink Partners LLC analyst Howard Liang noted that Astrazeneca's Lynparza was cleared for marketing for an indication – advanced OC patients with germline BRCA mutations who have been treated with three or more prior lines of chemotherapy – that "overlaps [with] but is not identical to the population for which rucaparib has received the BTD." Astrazeneca has the SOLO-2 confirmatory study ongoing for Lynparza and due to report data this year. Liang agreed with CEO Mahaffy that positive results are "unlikely to lead the FDA to rescind rucaparib's BTD status or [to] affect its potential filing for accelerated approval," which is expected in the middle of next year, pending positive data from the ARIEL2 trial, Liang wrote in a research report. Clovis' new drug application filing would cover fourth-line or greater ovarian cancer patients with either BRCA mutations or the 60-gene "BRCA-ness" signature identified in 2010. "While the BTD only covers the former, the benefit from frequent FDA dialogues is likely to apply to both indications," in Liang's view.

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J.P. Morgan analyst Cory Kasimov called Clovis "one of our favorite names" among companies of its size, "as we believe the company is well positioned with two promising, wholly owned, late-stage oncology compounds, now both with BTD, and a third asset, lucitanib, enrolling phase II trials." An oral, dual-selective inhibitor of the fibroblast growth factor receptor and the vascular endothelial growth factor receptor, lucitanib came to Clovis via the 2013 buyout of Ethical Oncology Science SpA, of Milano, Italy. In a research report, Kasimov reiterated his "overweight" rating on shares of Clovis. (See BioWorld Today, Nov. 21, 2013.)

"We developed an algorithm that's being applied by our partners at Foundation Medicine [that looks] across the genome of the tumor for definition of a cutoff, if you will, what defines BRCA-like compared to biomarker negative," Mahaffy said. "Importantly with our assay, we can also identify approximately a third of women who probably won't get much benefit" from rucaparib, he said.

At the start of this month, Astrazeneca said it was expanding its companion diagnostic collaboration with Salt Lake City-based Myriad Genetics Inc. to use the latter's BRACAnalysis CDx test to prospectively identify which patients with metastatic pancreatic cancer may respond to treatment with Lynparza. When the compound won FDA clearance for ovarian cancer, the FDA also cleared the test for identifying the appropriate patients – the first time U.S. regulators cleared a complex laboratory developed test (LDT) under the premarket approval application process, and the first-ever approval of an LDT companion diagnostic.

PARP inhibitors, even those in nascent research, have stirred excitement. In November 2013, the Merck Serono arm of Darmstadt, Germany-based Merck KGaA paid an undisclosed up-front payment and pledged as much as €170 million (then US$228 million) more in development and commercial milestones for ex-China rights to Beigene Co. Ltd.'s preclinical Beigene-290, under investigation for cancers "that no other people are pursuing today," CEO John Oyler of Beijing-based Beigene said at the time. (See BioWorld Today, Nov. 14, 2013.)

In ovarian cancer, Cortellis Clinical Trials Intelligence lists 49 trials with PARP inhibitors, 13 of which are recruiting with seven yet to start doing so. Of those recruiting, three are phase III and one is phase II; the rest are earlier stage.

Clovis' stock (NASDAQ:CLVS) closed Tuesday at $74.10, up $5.46.