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PARP Inhibitor Shows Benefit in BRCA-Mutated Breast Cancer Subpopulation at ASCO

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CHICAGO (GenomeWeb)– A subpopulation of metastatic breast cancer patients with germline mutations in BRCA1 and BRCA2 genes had a 42 percent lower chance of progression with AstraZeneca's PARP inhibitor Lynparza (olaparib) compared to chemotherapy, a study has shown.

The randomized study presented at the American Society of Clinical Oncology's annual meeting is the first to show a PARP inhibitor extends progression-free survival in advanced breast cancer patients. It also is a sign of the expanding utility of BRCA testing in precision medicine.

The Phase III study randomized 300 patients with hormone receptor-positive or triple-negative metastatic breast cancer to treatment with Lynparza or chemotherapy (capecitabine, vinorelbine, or eribulin). The study participants were all HER2 negative, had previously been treated with chemotherapy for metastatic breast cancer, and had to have inherited deleterious or likely deleterious BRCA mutations as determined by Myriad Genetics' BRACAnalysis CDx.

In the study, median progression-free survival was seven months for Lynparza-treated patients, compared to 4.2 months in those receiving chemotherapy. Lynparza shrank tumors in 60 percent of patients, versus 29 percent of those on chemotherapy. Mark Robson from Memorial Sloan Kettering Cancer Center, who led the study, reported at the meeting that Lynparza reduced the chance of progression in women with BRCA-mutated advanced breast cancer by 42 percent.

Currently there are three PARP inhibitors, including Lynparza, available on the market, but for the treatment of advanced ovarian cancer. Although some small studies previously suggested that advanced, BRCA-mutated breast cancer patients respond to PARP inhibitors, this is the first study to demonstrate a drug in this class benefits this patient population against standard chemos. “Finally, a Phase III study that is positive in breast cancer,” said Allison Kurian from Stanford University, who reviewed the study data at the annual meeting.

In a preplanned analysis, 46 percent of patients had died, and there was no significant difference in overall survival between the two arms. However, final overall survival analysis will be conducted when 60 percent of the study participants have died. Kurian noted that in most of the studies of PARP inhibitors in ovarian cancer, these drugs haven't shown an overall survival benefit.

Several experts highlighted the fact that half the patients enrolled in the study were triple-negative breast cancer patients, who tend to be younger and have poor prognosis, and limited treatment options. “It is our opinion that olaparib should be an effective treatment option for women with BRCA mutations and metastatic, HER2-negative breast cancer, including, importantly, women with triple-negative BRCA[-mutated] disease,” Robson said.

The study, published in the New England Journal of Medicine, was not powered to identify subgroups that might have a robust benefit from Lynparza, but when researchers just considered ER- and PR-positive breast cancer patients, the hazard ratio wasn't statistically significant. This led Kurian to wonder if the benefit with Lynparza seen in the study was being driven by triple-negative breast cancer patients. “We do need further study of subgroups to understand who really benefits from this therapy,” Kurian said. 

Patients on Lynparza had fewer serious adverse events, and fewer patients on this arm dropped out of the study due to therapy-related complications, compared to those receiving chemo. The patients themselves also reported better quality of life on Lynparza than on chemotherapy.

“This is really a major step forward for us,” said ASCO President Daniel Hayes. Oncologists have been practicing precision medicine in estrogen receptor-positive and HER2-positive breast cancers for more than a century, he noted, “But for cancers that are missing those two [features], we've had chemotherapy, which is not very precise.”

While this study provides proof of the principle that breast cancers with defects in DNA damage repair pathways are sensitive to drugs that target those weaknesses, it is also practice-changing, several experts said. “These drugs do work in breast cancer if we're smart and if we're precise, and that's a great step forward,” Hayes said.

Based on this data, AstraZeneca announced several months ago that it was working with health regulators to garner approval for Lynparza in this setting. In conjunction with the ASCO presentation, Myriad Genetics said it plans to submit a supplementary premarket approval application for BRACAnalysis CDx as a test that can identify HER2-negative metastatic breast cancer patients who respond to Lynparza.

Several years ago, the US Food and Drug Administration approved Lynparza for patients with germline BRCA-mutated advanced ovarian cancer, who have received three or more prior lines of chemotherapy. At that time, the FDA also approved BRACAnalysis CDx to identify patients with germline mutations who are most likely to respond to the drug. 

In March, the FDA approved Zejula (niraparib) for the maintenance treatment in recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer following response to platinum-based chemotherapy. Despite Myriad's BRACAnalysis CDx being used in the study that led to Zejula's approval, and which showed that patients with BRCA mutations had a greater magnitude of benefit from the drug than patients without such mutations, the agency did not require BRCA testing as a condition for prescribing the drug in this setting. However, the agency did approve Myriad's test as a complementary diagnostic.

Myriad believes that the latest study showing that in BRCA-mutated, HER2-negative breast cancer patients had a nearly three-month median progression-free survival advantage over chemotherapy treated patients will not only help grow acceptance of precision oncology strategies, but also expand access to BRCA testing.

“This is yet further evidence of the fact that there is power in using these companion diagnostic tools to identify patients that are maximally going to benefit from drugs,” said Johnathan Lancaster, chief medical officer of Myriad Genetic Laboratories. “It's also raising awareness in the community of the importance of genetic testing because we've only ever thought of BRCA genetic testing in the context of hereditary risk.”

Of the 60,000 HER2-negative metastatic breast cancer patients in the US, two thirds currently don't meet BRCA testing guidelines that require a strong family or personal history of the disease. However, if the FDA approves Lynparza in this indication, Myriad estimated that it will triple the number of patients with metastatic breast cancer who are eligible for BRCA testing.

Beyond BRCA testing, AstraZeneca is exploring using Myriad's new myChoice HRD Plus test to identify best responders to Lynparza. The original myChoice HRD test detects whether patients have somatic mutations in BRCA1 and BRCA2 genes and other "genomic scars" by measuring heterozygosity loss, telomeric allelic imbalance, and large-scale state transitions. MyChoice HRD Plus also gauges mutations in 102 genes. 

AstraZeneca has also said it was working with Foundation Medicine to develop a companion test for Lynparza that will detect alterations in a panel of genes associated with homologous recombination repair (HRR) pathways involved in fixing DNA double-stranded breaks. An AstraZeneca spokesperson said the firm is “committed to identifying all patients who may benefit from Lynparza. The underlying science supports the investigation of [the drug] as a treatment for breast cancers harboring other molecular defects associated with DNA-repair defects.” 

Though the study presented at the ASCO annual meeting is small, AstraZeneca is conducting additional Phase III studies investigating Lynparza in breast cancer. Robson noted that researchers are looking at combining Lynparza with chemo, other targeted agents, and immunotherapy. There are also efforts to study the drug in combination with other agents in earlier metastatic and adjuvant settings.

A spokesperson for AstraZeneca highlighted that there is a Phase III breast cancer trial recruiting patients with early stage, BRCA1/2 mutated disease, called OlympiA, that is exploring Lynparza as an adjuvant treatment in HER2-negative breast cancer. The drugmaker is also investigating Lynparza in combination with durvalumab in advanced breast cancer patients.

“The sad news [is] that those two [progression-free survival] curves still come together,” Hayes said about the trial presented at the annual meeting. “We need to understand what the mechanism to resistance to these drugs are. Even when they work, the curves still ultimately came back together again.”

It will be important to monitor cancer patients receiving PARP inhibitors for long-term toxicities, he cautioned, since the DNA repair mechanism is part of normal cellular replication process, and inhibiting this process via PARP inhibitors had resulted in some ovarian cancer patients developing leukemias. Kurian added that future studies should look at how patients with germline mutations in non-BRCA1/2 genes, such as ATM or other DNA-repair genes, respond to Lynparza.

The present study doesn't consider Lynparza's response in BRCA1/2 mutation-negative patients, but the Southwest Oncology Group is doing a trial investigating Lynparza in triple-negative breast cancer patients who are BRCA1/2 wildtype, in which researchers will conduct biomarker analysis to try to identify a best responder subpopulation. Meanwhile, within the ASCO-sponsored TAPUR trial there will be an arm enrolling patients with germline or somatic BRCA1/2 mutations in order to further explore Lynparza in unapproved indications.

“This study is like so many we've seen over the years in oncology, where you first study the drug in a far advanced treatment population and it seems to have a modest effect,” said ASCO Chief Medical Officer Richard Schlisky. But over time “we learn to use it better, differently, in combination and in earlier stage disease, and the results are much more impactful.” 

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