NEW YORK (GenomeWeb) – Based on a Phase III trial that showed Tesaro's PARP inhibitor niraparib benefitted recurrent ovarian cancer patients regardless of their BRCA mutation status, the drugmaker has decided to pursue market approval of the drug in the overall patient population.
"These landmark results warrant niraparib maintenance therapy to the whole study population, regardless of BRCA mutation status, regardless of HRD [or homologous recombination deficiency] status," said Mansoor Raza Mirza, chief oncologist at Copenhagen University Hospital in Denmark and the primary investigator in the NOVA study, said during a webcast from the European Society of Medical Oncology's annual meeting over the weekend.
Mirza and colleagues simultaneously reported their findings in the New England Journal of Medicine, which showed that median progression-free survival was 21 months in patients with germline BRCA mutations as determined by Myriad's BRACAnalysis CDx; 9.3 months in patients without such mutations, and 12.9 months in patients with homologous repair deficiency as determined by the myChoice HRD next-generation sequencing test. Comparatively, patients receiving placebo had median progression-free survival of 5.5 months when they had germline BRCA mutations, 3.9 months when they didn't have such mutations, and 3.8 months when they were HRD positive.
However, an exploratory analysis in patients who were HRD negative by Myriad's test showed that they also derived clinically meaningful benefit from Tesaro's PARP inhibitor, with median progression-free survival of 6.9 months on niraparib compared to 3.8 months on placebo. The study authors led by Mirza concluded in the NEJM paper that the duration of responses in patients were significantly longer in the niraparib group than in the placebo group "regardless of the presence or absence of [germline] BRCA mutations or HRD status."
Given the unmet need in patients with recurrent ovarian cancer, these data suggest that oncologists are unlikely to use BRACAnalysis or myChoice HRD to determine which patients with platinum-sensitive, recurrent ovarian cancer should receive niraparib. "We are in agreement in our gyne-oncologist community that we cannot just close our eyes on this [data]," Mirza told analysts at ESMO. "I cannot say to these patients that we are not going to give you the treatment."
During the presentation to analysts, Mary Lynn Hedley, Tesaro's president and chief operating officer, agreed. "Dr. Mirza indicated that he would prefer that we submit the application for a broad indication given the clinical meaningfulness of the data that we had seen across the population, and we intend to do that," she said.
Myriad lauded the NOVA trial investigators on a successful study, but maintained that the study was also a success for myChoice HRD, a test that the company has been discussing as a potential companion diagnostic for niraparib, and which it had hoped to launch alongside the drug with the US Food and Drug Administration's approval. The test clearly showed that patients with HRD positive and negative scores had "notable differences" in progression-free survival benefit, Ron Rogers, executive VP of corporate communications, told GenomeWeb.
We still believe that myChoice HRD is likely a useful test. However, the current situation implies a longer timeline to revenue than we had previously hoped.
"Whether the [progression-free survival] benefit in the myChoice HRD negative group is sufficient is entirely in the hands of regulators and we respect their role in this process," he added.
Although the NOVA results had a positive impact on Tesaro's stock price, which had increased by 20 percent to $119.97 during afternoon trading, Myriad's stock price took a hit. At press time, Myriad's stock was trading at $18.73, down 12 percent for the day.
Wells Fargo Securities analyst Tim Evans wrote in a note that the NOVA results suggest that it might take Myriad longer to garner revenues from myChoice HRD, which along with BRACAnalysis CDx and Tumor BRACAnalysis CDx, is a key part of the firm's companion diagnostic portfolio. Myriad has projected its companion diagnostics business will contribute between $122 million and $364 million by 2020, by which time it hopes to bolster its annual revenues to $1.5 billion.
"We still believe that myChoice HRD is likely a useful test," Evans wrote in a note to investors. "However, the current situation implies a longer timeline to revenue than we had previously hoped."
Meanwhile, Piper Jaffray analyst William Quirk had a different take, and wrote that the FDA will restrict niraparib's indication based on BRCA mutation or HRD status. "Our thesis: we believe FDA will weigh the drug's side effects with progression-free survival benefit," Quirk wrote. He predicted that in HRD-negative patients the FDA will likely consider the three-month progression-free survival benefit against the fact that more than 14 percent of patients discontinued niraparib treatment compared to 2 percent of patients on placebo, and that there were significantly higher grade 3/4 toxicities with the PARP inhibitor.
Quirk echoed a point that Myriad's Rogers had highlighted to GenomeWeb, that the FDA did not approve AstraZeneca's PARP inhibitor Lynparza (olaparib) in a maintenance setting despite showing a 3.6 month progression-free survival benefit. The agency approved Lynparza in 2014 with Myriad's BRACAnalysis as a companion diagnostic.
Ovarian cancer patients have limited treatment options, and once they relapse, their outcome is poor. Patients initially receive platinum chemotherapy in combination with a taxane, but after a period of response, they relapse. Patients sensitive to such treatment receive it in six month intervals, but the benefit diminishes with each round.
Platinum-resistant patients receive Avastin, while the 15 percent of ovarian cancer with BRCA1/2 mutations can receive Lynparza after they've progressed on three or more lines of chemotherapy.
Cancer cells can use PARP proteins involved in repairing DNA damage to proliferate. PARP inhibitors, like Lynparza and niraparib, kill cancer cells by blocking these proteins' role in DNA repair. However, studies have shown that these drugs work particularly well in patients with mutations in certain genes, such as BRCA1 and BRCA2, or other biological characteristics that disadvantage a DNA repair process known as homologous recombination.
In NOVA, 553 patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer were randomized to receive niraparib or placebo. But recognizing that ovarian cancer patients are a genetically heterogeneous population, Mirza and colleagues stratified patients based on their germline BRCA status using Myriad's BRACAnalysis CDx. For patients without germline BRCA mutations, researchers used Myriad's myChoice HRD test to determined their homologous recombination deficiency status.
In patients with germline BRCA mutations, median progression-free survival was 21 months for patients on niraparib compared to 5.5 months on placebo. Half of the 138 patients receiving niraparib had not progressed at 18 months. "This is extraordinary. We haven't seen such [Kaplan-Meier] curves for 30 years, since we had cisplatin introduced in ovarian cancer," Mirza told analysts. "We saw some difference with taxol, some difference with Avastin, but we haven't seen these curves before."
Patients in the overall non-germline BRCA mutation cohort also saw "extraordinary improvement" in outcomes on niraparib, Mirza highlighted, with median progression-free survival of 9.3 months compared to 3.9 months on placebo. In this subset, 30 percent were on niraparib without progression at 18 months.
Drilling further into this subset of patients without germline BRCA mutations, patients who were HRD positive by Myriad's test had a median progression-free survival of 12.9 months on niraparib compared to 3.8 months on placebo. More than a third of the patients on niraparib hadn't progressed at 18 months.
In the HRD-positive group, there was a group of patients who had somatic BRCA mutations, and they derived benefit from niraparib comparable to patients with germline BRCA mutations, with median progression-free survival of 20.9 months on niraparib compared to 11 months on placebo. In the HRD-positive group with wild-type BRCA status, median progression-free survival was 9.3 months on niraparib compared to 3.7 months on placebo.
Mirza's group conducted exploratory analysis in HRD-negative patients to make sure that the benefit seen in cohort without germline BRCA mutations wasn't due entirely to patients who had homologous recombination deficiency. In the HRD-negative population, patients on niraparib experienced median progression-free survival of 6.9 months compared to 3.8 months on placebo, with nearly 20 percent of 92 patients on treatment for 18 months without their disease advancing.
Going back to the clinic, I will have a very hard time, because all my patients would like to have this drug.
Mirza told analysts that he would still test his ovarian cancer patients for BRCA mutation status in order to characterize the hereditary breast and ovarian cancer risk among their family members. "If they are BRCA positive, we have to have the counseling for the families. It won't matter for the patient regarding the treatment to do the BRCA test, but for the families we need it," he explained.
However, he did not believe the HRD test separated responders to niraparib from non-responders. "The HRD test — I'm sorry, I live in Denmark, and it's the taxpayer who pays," he said. "I'm not going to use the HRD test as it is now. We have to have a better test."
When pushed by analysts as to whether there was any indication in the NOVA trial as to the utility of the HRD test to predict response and if there were any confounding factors in the HRD-negative population, Hedley noted that a range of interaction tests provided confidence that patients in that subpopulation were actually deriving benefit from niraparib.
The hazard ratio in the HRD-negative subpopulation was .58, which Mirza highlighted as clinically meaningful, particularly since oncologists are used to seeing hazard ratios of .68 in studies involving Avastin. While some patients in the HRD-negative population did not respond to niraparib, Mirza reminded analysts that one-fifth of patients derived long-term benefit without progression.
"I think the challenge [is that] … the test doesn't define which patient will benefit and which one won't," Hedley said. "So, when [doctors] treat with chemotherapy or Avastin or anything, you know the majority of patients won't respond. You have to look at it from the perspective of a treating oncologist treating patients with recurrent ovarian cancer who are going to die."
"Going back to the clinic, I will have a very hard time, because all my patients would like to have this drug," Mirza told analysts.
Patients on the drug experienced more grade 3/4 thrombocytopenia, anemia, neutropenia, fatigue, and hypertension compared to those on placebo. The toxicities were easily managed, Mirza said, and did not impact patients' quality of life.
The study has not yielded mature overall survival data yet, since less than 20 percent of patients on either treatment arm had died at data cutoff. Mirza noted, though, that there is no reason to believe from the results so far that the progression-free survival advantage will not extend to overall survival.
At the time of data cutoff, 47 patients with germline BRCA mutations were still on niraparib and had not progressed compared to 4 patients on placebo. In patients without germline BRCA mutations, 46 patients were on niraparib without progression and 12 patients were on placebo.
Hedley indicated that Tesaro would launch expanded access programs for niraparib in the US and Europe after submitting a new drug application with the FDA and a marketing authorization application with the European Medicines Agency in the fourth quarter. Tesaro has already had pre-NDA discussions with the FDA and the agency has granted niraparib fast-track designation.
The pre-NDA meeting with the FDA has given Tesaro some confidence about submitting the NDA for a broad population, Hedley said.
Tesaro is using Myriad's HRD test in the PRIMA study, which is investigating niraparib as maintenance treatment for HRD-positive advanced ovarian cancer patients after front-line platinum treatment. Hedley noted that in PRIMA Tesaro could use the HRD test to look first at how well niraparib benefits HRD-positive patients and if those results are positive then explore the drugs' benefit in the broader population as was done in NOVA.
Myriad's Rogers highlighted that the company has 22 ongoing studies where developers of PARP inhibitors are using its BRCA and HRD tests to study whether the drugs work best in a specific patient population. "[Myriad] will continue to strive for diagnostics that can improve patient care and optimize healthcare spend," Rogers said.