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AstraZeneca and Daiichi Sankyo’s TROP2-directed antibody-drug conjugate failed a key survival endpoint in a late-phase breast cancer study, potentially throwing a wrench into its ongoing FDA review. Datopotamab deruxtecan, which is also called Dato-DXd, did not reach statistical significance in the overall survival portion of a Phase 3 trial’s dual primary endpoint, according to a Monday release. In the TROPION-Breast01 study, Dato-DXd was tested against investigator’s choice of chemotherapy in more than 700 subjects with previously treated unresectable or metastatic HR-positive, HER2-low or negative breast cancer. Jefferies analysts have said Dato-DXd has the potential to reach $9.4 billion in global peak sales, with $1.2 billion coming from breast cancer. The treatment is currently under FDA review with a PDUFA date of Jan. 29, 2025. Last year, the company said Dato-DXd met the progression-free survival (PFS) part of the dual primary endpoint. The median PFS was 6.9 months for Dato-DXd versus 4.9 months for chemotherapy. AstraZeneca said Monday that the OS data disappointment was likely influenced by participants’ use of ADCs for breast cancer that were approved throughout the course of the trial, including the company’s own Enhertu. When the drugmaker announced PFS data, it said OS data were not mature yet but were trending in favor of Dato-DXd. The OS setback “complicates” regulatory talks for approval in breast cancer, the Jefferies analysts said Monday. Nevertheless, AstraZeneca’s head of oncology R&D Susan Galbraith said it plans to “continue discussions” with regulatory bodies and “apply insights” from the data to its broader Dato-DXd breast cancer development program. The candidate is being tested in other breast cancer patients, such as ones with triple-negative or HR-low, HER2-negative breast cancer alone, and in combination with immunotherapy in other Phase 3 trials. In patients recruited in the TROPION-Breast01 study, OS is a key measure. Dato-DXd’s potential market competitor, Gilead’s ADC Trodelvy, achieved a 14.4-month OS compared with 11.2 months for chemotherapy in its Phase 3 trial with a similar population to TROPION-Breast01. Trodelvy, which also targets TROP2, won an FDA label expansion for HR-positive, HER2-negative breast cancer in February last year. Elsewhere, Dato-DXd is under review for previously treated advanced nonsquamous non-small cell lung cancer. In May, it also failed to hit its OS goal in the 600-participant TROPION-Lung01 test in locally advanced or metastatic NSCLC despite achieving the PFS endpoint.

Dive Brief:An experimental medicine from AstraZeneca and Daiichi Sankyo failed to help people with a common form of breast cancer live longer than those who received standard chemotherapy in a Phase 3 trial, the companies said Monday, raising more questions about the therapys approval prospects.AstraZeneca and Daiichi previously said that the treatment, a so-called antibody-drug conjugate called datopotamab deruxtecan, met one of its study goals by meaningfully delaying tumor progression in certain people with advanced, HER2-negative breast cancer. The partners filed for approval based on that finding, and the Food and Drug Administration is expected to issue a decision by early 2025. That result hasnt translated to a survival benefit, though, which is a stronger measure of a cancer drugs worth. In a statement, AstraZeneca said subsequent treatments study participants received after their disease progressed were likely to have affected survival results. But the finding likely complicates regulatory discussions, wrote Jefferies analyst Peter Welford in a Monday note to investors.Dive Insight:Wall Street analysts have high expectations for datopotomab deruxtecan, which is part of a lucrative alliance between AstraZeneca and Daiichi and is in clinical testing for several cancer types. Jefferies analysts have forecasted that, if approved, the drug could generate $9.4 billion in yearly sales at its peak, with $1.2 billion coming in breast cancer alone.But the future of datopotomab deruxtecan, or dato-dxd for short,is now unclear.In lung cancer,it similarly delayed disease progression in a Phase 3 trial,but didnt extend survival, even among those who had been expected to benefit the most from treatment. That result, which was disclosed earlier this month, led analysts at the investment bank Stifel to speculate that the FDA might delay an approval decision and convene a panel of outside advisers.Dato-dxd could now face a more complex path to market in breast cancer too.Overall survival was one of the two main goals of its breast cancer trial and is the FDAs gold standard for the approval of a cancer drug. Though comparing drugs across trials can be difficult, Jefferies analyst Welford noted that dato-dxds benefit on tumor progression was also broadly in-line with what was observed in testing of Gileads similar rival drug Trodelvy.The results, then, could give Gilead a leg up against a potential competitor, according to RBC Capital Markets analyst Brian Abrahams. The FDA could conceivably reject dato-dxd altogether.But even if it doesnt, the companies wouldnt be able to claim a survival benefit compared to chemotherapy, which Trodelvy was able to achieve in testing, he wrote.Furthermore, doctors sometimes retest patients HER2 status after disease progression. If theyre found to have low, but still detectable levels of the protein, clinicians could steer them towards AstraZeneca and Daiichis Enhertu, which is already marketed for breast cancer.After a slow start, Trodelvy sales grew to $1.1 billion in 2023. Its now Gileads fastest-growing drug, with year-over-year sales growing 30% through the first six months of 2024. '