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Lynparza Benefit in Early BRCA-Mutated Breast Cancer Reignites Universal Genetic Testing Discussion

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NEW YORK – The results of the Phase III OlympiA trial, presented during the American Society of Clinical Oncology's virtual annual meeting, has the oncology community asking: Should germline genetic testing for mutations in BRCA1 and BRCA2 be offered to all breast cancer patients?

The trial, from which results?were?published last week in the New England Journal of Medicine, showed that adjuvant treatment with the PARP inhibitor olaparib (Merck/AstraZeneca's Lynparza) significantly delayed cancer progression in germline BRCA1/2-mutated, early-stage, HER2-negative breast cancer patients. Researchers led by Andrew Tutt, head of the division of breast cancer research at the Institute of Cancer Research, randomized 1,836 early-stage, high-risk HER2-negative patients with a germline BRCA1 or BRCA2 mutation to receive either olaparib or a placebo for a period of one year after local treatment and neoadjuvant or adjuvant chemotherapy.

The study showed a clear invasive disease-free survival benefit for patients receiving the PARP inhibitor. After three years of follow-up, 85.9 percent of patients who received adjuvant olaparib and 77.1 percent of those on a placebo were invasive disease-free — meaning they had not experienced local recurrence, distant recurrence, second primary invasive cancer, or death from any cause.

A benefit was also seen specifically in reduction of distant breast cancer recurrence among olaparib-treated patients. Three years out, 87.5 patients in the olaparib group were free of distant disease recurrence versus 80.4 percent in the placebo group. In the PARP inhibitor group 59 patients died, versus 86 in the placebo group.

"Regardless of which way you measure it, whether as the totality of invasive disease-free survival or distant disease-free survival, the results are quite consistent," said Scot Ebbinghaus, Merck's VP and head of late-stage oncology clinical development. Ebbinghaus acknowledged that the most meaningful measure of olaparib's benefit will be overall survival, but those data, while trending in the right direction, won't be mature for a while.

Merck and AstraZeneca will seek approval for olaparib as an adjuvant treatment in early-stage, BRCA1/2-mutated breast cancer patients based on the OlympiA data. "In breast cancer, there's a large body of adjuvant therapy data [showing] a good correlation between disease-free survival and overall survival," he said. "This [invasive disease-free survival] endpoint can lead to a regulatory approval even in the absence of other endpoints being mature."

Olaparib — which has been a joint product of AstraZeneca and Merck's since 2017 when the companies announced a strategic partnership — is already US Food and Drug Administration-approved for a number of cancer indications, including previously treated metastatic breast cancer patients with germline BRCA1/2 mutations. With the metastatic breast cancer indication, the FDA approved Myriad Genetics' BRACAnalysis CDx test to select patients for olaparib.

Ebbinghaus declined to comment on companion diagnostic plans for a potential early-stage olaparib FDA approval. "We'll certainly be partnering with companies that do testing and working with agencies for any additional needs in terms of companion diagnostics," he said. In OlympiA, investigators used Myriad's test to confirm patients' locally determined germline BRCA1/2 mutation status in all regions where the trial was conducted except in China, where BGI Genomics confirmed the results.

Reassessing germline genetic testing guidelines

If the FDA approves olaparib in the adjuvant setting for early-stage BRCA1/2-mutated breast cancer patients, it will most likely trigger a reevaluation of current guidelines on when to test patients for these mutations, which are not only important for informing PARP inhibitor treatment but also for identifying patients' future cancer risks and initiating preventive measures.

In the context of assessing inherited risk of cancer, the National Comprehensive Cancer Network recommends testing for mutations in high-penetrance breast and ovarian cancer susceptibility genes, such as BRCA1/2, based on patients' personal and family cancer history. Specifically, NCCN recommends germline testing for patients with a personal history of breast cancer who have, among other factors, blood relatives with known pathogenic variants in cancer susceptibility genes; a diagnosis under age 45; a diagnosis of?triple-negative breast cancer under age 60; and?Ashkenazi Jewish ancestry.

In its breast cancer treatment guidelines, recent as of April 28, the NCCN states that germline BRCA1/2 mutation testing is clinically indicated for all patients with recurrent or metastatic breast cancer so as to identify candidates for PARP inhibitor therapy. The patients enrolled in OlympiA, however, had early-stage disease and received treatment in the adjuvant, rather than refractory setting, and as such, guidelines would need to be updated to include this patient population.?

The OlympiA results may spur many in the field to push for assessing patients for mutations in high-penetrance cancer risk genes, such as BRCA1/2, earlier in their disease trajectory, though not too long ago a substantial portion of the field seemed not to favor a broad germline testing approach. In December 2020, attendees of the San Antonio Breast Cancer Symposium voted on a key question: Should all patients with breast cancer have germline genetic testing, regardless of age, family history, or eligibility criteria? The results that day — a 60-40 split in favor of a universal, unselected approach to germline testing — reflected a lack of clear consensus in the field.

That question under debate at that conference was broad, and didn't specify universal testing for specific genes, which may have inspired many to take an opposing stance. The latest OlympiA data may give many in the field reason to change their minds about broadly testing for BRCA1/2.

Adding to the expanded germline testing discussion during ASCO were data from another PARP inhibitor study — this one a Phase II, single-arm study of talazoparib (Pfizer's Talzenna) in the neoadjuvant setting for BRCA1/2-mutated TNBC patients — which demonstrated close to 50 percent pathological complete response rates and minimal adverse events. These results alongside OlympiA suggest that drugs in the broader PARP inhibitors class may soon be used to treat BRCA1/2-mutated, early-stage breast cancer, making earlier identification of patients with these mutations an imperative.

"This is the first time that there [would be] a treatment available for [these patients]. The obvious next component of that is ensuring that patients know what their BRCA status is," said Merck's Ebbinghaus. "It's going to be increasingly important to be able to identify BRCA mutations in early breast cancer … we hope that the guidelines for testing will evolve similarly to the guidelines for treatment."

Many oncologists agree. "The existing guidelines have specific criteria for who is able to get testing, but I am hopeful that the results of this study will start a dialogue about making genetic testing available to all patients," said Eleonora Teplinsky, a breast and gynecologic oncologist with the Valley Health System. "This study stresses the importance of making genetic counseling and testing accessible and affordable for all patients."

Two years before data from OlympiA were released, the American Society of Breast Surgeons sparked much controversy by recommending genetic testing for all breast cancer patients. "If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history," the ASBrS stated in a 2019 consensus statement.?

"I'm hoping that other guideline organizations, including NCCN, will expand their genetic testing indication, which could lead to insurance coverage," said Sayeh Lavasani, a breast cancer medical oncologist at City of Hope.

Other oncologists acknowledge that expanded testing guidelines in the wake of OlympiA could be beneficial?but have stopped short of evoking the term "universal" due to the low rate of BRCA1/2 mutations — hovering around just 1 percent — among women over age 65 with no known family history of cancer.

"If the rates of mutation are very low in specific subgroups, testing may not be financially or therapeutically beneficial," said Hope Rugo, a breast cancer oncologist at UC San Francisco, though she acknowledged test costs have come down in recent years making broader testing strategies more cost-effective. Moreover, germline genetic testing labs, recognizing that insurers' personal and family history-based coverage criteria are limiting access to a lot of patients, have increasingly pivoted to consumer-facing business models that offer clinical-grade tests for a few hundred dollars.?

Rather than calling for universal genetic testing, Rugo suggested guidelines may be expanded to mirror the eligibility criteria used for OlympiA enrollment — namely, the criteria that patients' diagnoses be HER2-negative and deemed high-risk according to clinical features like node positivity.

"If the goal is to identify patients who are candidates for olaparib adjuvant therapy, and mutation prevalence in a specific patient would be expected to be very low, then perhaps testing should be performed in those patients with high-risk disease who would have met criteria to be enrolled in OlympiA," Rugo said, adding that in an age breakdown of BRCA1/2-positive patients in the OlympiA trial, BRCA1/2 positivity rates were below 2?percent among patients over age 75.

In a discussion following the OlympiA presentation, Nadine Tung, the director of Beth Israel Deaconess Medical Center's cancer risk and prevention program, also acknowledged the low rates of positivity among older breast cancer patients with no family history?but still felt it might be beneficial to expand criteria.

"This debate has been ongoing as to whether all breast cancer patients should have germline BRCA testing, and we kept saying, 'If results of OlympiA are positive, we're going to really need to think about universal testing,'" Tung said, proposing that, if the field does not support universal testing, it may be time to "flip the discussion" and define who should not be tested for germline mutations.

One potential solution to the universal germline genetic testing question, as outlined last year in the Journal of Clinical Oncology, is to universally test breast cancer patients under age 65, and then risk-stratify testing among an older population. This approach has garnered popularity after Susan Domchek, director of the Basser Center for BRCA at the University of Pennsylvania, noted it while presenting the side of the universal germline testing debate at the San Antonio Breast Cancer Symposium in favor of maintaining some eligibility criteria.

Whichever way germline genetic testing guidelines change in the wake of the OlympiA data — if they change at all — the health system is currently doing a poor job of identifying patients with mutations in high-penetrance cancer risk genes. Studies have shown that less than 10 percent of adults with BRCA1/2 mutations in the US have been identified, and less than 20 percent of breast and ovarian cancer patients who should receive testing according to current guidelines are actually receiving it.

"Unfortunately, less than half of patients with breast cancer who qualify for germline genetic testing [by NCCN criteria] are offered testing," Tung said in her discussion. "And underutilization is greatest in minority and underserved populations."

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