Full Arvinas, Pfizer data confirm potential and limits of ‘Protac' drug in breast cancer

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2 days ago

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An experimental breast cancer drug from Arvinas and partner Pfizer modestly slowed disease progression in people whose tumors had changes to a specific gene, but did not provide a clear benefit to others who lacked that mutation.
Full study results set to be presented Saturday at the American Society of Clinical Oncology's annual meeting provide a clearer picture of the drug's potential — and its limitations — than were available in March, when the companies shared an overview of trial outcomes.
While the findings suggest the drug, an oral pill called vepdegestrant, may be a new option for a subset of breast cancer patients, they likely mean its use will remain narrow, should it win an approval.
In their Phase 3 trial, Arvinas and Pfizer tested vepdegestrant against the injectable drug fulvestrant in 624 people who had the most common type of advanced breast cancer — tumors positive for estrogen receptors but negative for a protein called HER2. Trial participants had been treated before with hormone therapy and another type of drug known as a CDK4/6 inhibitor. Two-hundred and seventy participants had mutations in the ESR1 gene, which is known to help tumors develop resistance to treatment.
The detailed data unveiled Saturday show vepdegestrant extended progression-free survival in people with ESR1 mutations by a median of five months, compared to 2.1 months for those on fulvestrant.
Among study participants overall, however, median progression-free survival was similar: 3.8 months on vepdegestrant versus 3.6 months on fulvestrant. PFS measures the time from a treatment response to when either disease progression or death.
Speaking in a briefing with reporters ahead of ASCO, Jane Lowe Meisel, co-director of breast medical oncology at the Winship Cancer Institute of Emory University School of Medicine, described vepdegestrant as an 'exciting option.'
Yet she noted in a statement how 'on average, patients did not have prolonged responses on either agent, highlighting the need for combination therapies and continued development in this space.'
Fulvestrant, the drug Arvinas and Pfizer tested vepdegestrant against, is a common treatment for advanced breast cancers that are hormone receptor positive and HER2 negative. The drug, which has been on the market for over two decades, blocks growth signaling to tumors through those hormone receptors. But the therapy has drawbacks, such as monthly intramuscular injections and a range of side effects.
Vepdegestrant works differently. The oral drug is what's known as a proteolysis-targeting chimera, or PROTAC. It is designed to break down estrogen receptors, thereby cutting off the signals that promote tumor growth. To date, vepdegestrant is the first PROTAC to advance through Phase 3 testing, and the first of its type to tested in people with advanced breast cancer.
Study researchers also measured overall survival but data on that score remain 'immature.' Essentially, too few people have died in the trial to draw conclusions about the statistical differences between the vepdegestrant and fulvestrant groups.
Side effects for both treatments were common. Just over one-fifth of participants taking vepdegestrant experienced side effects that were rated severe or life-threatening, compared to 17.6% on fulvestrant. More participants on vepdegestrant — 2.9% — stopped treatment due to side effects at 2.9%, compared to 0.7% among those on fulvestrant.
While vepdegestrant held no apparent benefit among the overall population, the drug could still hold promise for breast cancer patients with the ESR1 mutation.
Such a role would be valuable as treating ESR1-mutated breast cancer remains challenging. Research led by Memorial Sloan Kettering Cancer Center researchers a decade ago found ESR1 mutations change the shape of the estrogen receptor in such a way that keeps pushing the cancer to grow, even in the absence of an estrogen signal. ESR1 mutations are estimated occur in approximately 40% to 50% of patients who undergo first-line therapy for metastatic breast cancer.
Testing for the mutation is now done regularly, but typically occurs only after cancer has progressed or returned. It's become more prevalent since the approval of Orserdu, which is cleared for use in people with ER-positive, HER2-negative breast cancer that is positive for ESR1 mutations.
Pfizer and Arvinas in March said they will share data from their study with health regulators in support of potential drug approval applications. But since then, the companies have scaled back their development of vepdegestrant, removing plans for two other Phase 3 trials. Arvinas also cut one-third of its staff.
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