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In Ongoing Phase II Trial, Clovis Still Refining 'BRCAness' Signature for PARP Inhibitor Rucaparib


NEW YORK (GenomeWeb) – Clovis Oncology said last week it is continuing to refine its "BRCAness" signature with the help of Foundation Medicine's next-generation sequencing platform, after interim data from a Phase II study showed that 40 percent of patients with this signature responded to Clovis' investigational PARP inhibitor rucaparib.

The drugmaker is working with Foundation Medicine to develop an NGS-based companion diagnostic for rucaparib as a treatment for high-grade serous ovarian cancer patients. In the Phase II ARIEL2 trial, the partners are working on locking down a DNA repair signature that will identify best responders to the drug. Once Clovis and Foundation settle on this signature, they will apply it in a Phase III trial to stratify patients and determine the safety and efficacy of rucaparib in the ovarian cancer subpopulation.

At a symposium on molecular targets for cancer drugs hosted in Barcelona last week by multiple oncology organizations, Elizabeth Swisher of the University of Washington's School of Medicine presented interim data from ARIEL2. The prospective study is planning to enroll 180 patients with high-grade ovarian cancer who have received one or more platinum-based regimens. All patients in the single-arm trial will receive rucaparib until they experience disease progression.

In patients with somatic and germline BRCA mutations, the rate of overall response to rucaparib – defined as a reduction in tumor burden – was 70 percent, Swisher reporter at the meeting. Only 40 percent of those with the "BRCAness" signature experienced tumor shrinkage. Among those without either BRCA mutations or the DNA repair signature, the overall response rate was 8 percent.

A spokesperson for Clovis noted that the study is ongoing and the signature will be further refined before moving on to Phase III trials. "The signature is yet to be optimized using ARIEL2 data and we may be able to identify even more accurately who does and doesn't respond to rucaparib," the company spokesperson told GenomeWeb.

"What we do know is that the response seen with rucaparib treatment in women with a BRCAness signature is a very positive finding given that this is a patient population with limited treatment options … that was previously thought not to respond to PARP inhibitor therapy," the spokesperson added.

So far, based on the interim analysis, researchers reported that approximately 67 percent of the patients treated in the Phase II trial have either a BRCAness signature or a BRCA mutation. The study to date also shows the drug is well tolerated by patients, as none of the study participants have discontinued the trial due to rucaparib-related adverse events.

Clovis is among a number of drug developers advancing PARP inhibitors, and all of them are using companion diagnostic strategies to identify best responders to their drugs. Most are working with Myriad Genetics, using either its germline BRCA test, or a combination of the germline test and a new tumor diagnostic, while others are using a NGS-based homologous recombination deficiency (HRD) test currently under development.

Studies to date have convincingly shown that PARP inhibitors aren't efficacious in all breast and ovarian cancer patients, necessitating the use of companion diagnostics.

PARP proteins are involved in repairing DNA breaks in cells, which may incur damage millions of times in a day. However, when a person has mutations in genes involved in DNA repair (i.e. BRCA1 and BRCA2), this can cause this corrective mechanism to malfunction, which in turn can lead to cancer. Since cancer patients who carry mutations in DNA repair genes already have an impaired ability to fix the damage, researchers want to further disable their cellular repair pathways by giving PARP inhibitors. By doing so, they hope that patients' rapidly multiplying cancer cells will be inundated with faulty DNA and die.

There are genes other than BRCA1/2 that are important in DNA repair, and as such drugmakers like Clovis want to develop a NGS-based test that can identify more patients who have molecular characteristics similar to those with BRCA mutations and who can potentially respond well to PARP inhibition. Defining the signature for identifying patients with "BRCAness" characteristics has been challenging for drugmakers.

Before embarking on molecular testing strategies, researchers tried to track which patients responded well to DNA-damaging platinum-based drugs as a general guide for identifying potential best responders to PARP inhibitors. "This is better than nothing, but not ideal," the Clovis spokesperson said in an email. "Indeed all patients in ARIEL2 were platinum-sensitive and yet the biomarker-negative subset had minimal responses to rucaparib, showing that you will never have a great PARP inhibitor responder signature if you only use a platinum outcome to inform the signature."

Foundation Medicine didn't respond to questions for this article. However, the Clovis spokesperson told GenomeWeb that the company is continuing conversations with the US Food and Drug Administration about the Phase III ARIEL3 program for rucaparib. The pivotal Phase III trial, according to Clovis, is currently recruiting participants with the goal of ultimately including 540 platinum-sensitive, high-grade, ovarian cancer patients. Study participants will be randomized to receive rucaparib or a placebo.

Researchers will first enroll patients who have BRCA mutations; then a larger group with the BRCAness" signature with or without BRCA mutations; and then all comers. For the time being, the only information Clovis is willing to divulge is that it is planning to make simultaneous regulatory submissions for the drug and the companion diagnostic – a strategy that the agency considers optimal. Clovis has previously said it expects to file an NDA for rucaparib by 2017.

In the meantime, if AstraZeneca's clinical program for its PARP inhibitor olaparib manages to convince the FDA of the drug's safety and benefit, it may be the first drug in the class to reach the market. AstraZeneca had a tough time before the Oncologic Drugs Advisory Committee over the summer, receiving an 11-to-2 vote against the accelerated approval of olaparib as a treatment for plantinum-sensitive, relapsed ovarian cancer patients with germline BRCA mutations.

In the BRCA-mutated patient subpopulation, progression-free survival was 7.1 months longer in the olaparib-treated group compared to those on placebo, but there wasn't a statistically significant improvement in overall survival. Since the advisory committee review, AstraZeneca has submitted additional data to the FDA and has said that it expects to hear from the agency about olaparib's NDA by Jan. 3, 2015.

In the ARIEL2 interim analysis, Clovis reported overall response rate, but the data to date suggest that rucaparib may improve progression-free and even overall survival of patients with a "BRCAness" signature or BRCA mutations over a comparator drug. "Objective response is a crude measure of drug efficacy in solid tumors that effectively measures only apoptosis (i.e. [tumor] shrinkage)," the Clovis spokesperson explained. "It's a useful surrogate in single-arm trials for efficacy."

Ultimately, what matters is whether the drug is stopping disease progression and the patient feels better. "So, even if [the] overall response rate is 40 percent, it's likely that many more patients are deriving real benefit that can eventually be measured as [a] progression-free survival (or even [an] overall survival) advantage over a comparator," the spokesperson said. "But this requires randomized trials with control arms, as is underway with ARIEL3."