A newer targeted drug combination is showing promise as a next treatment option for some people with advanced hormone receptor–positive (HR+), HER2‑negative breast cancer whose tumors are PIK3CA wild‑type and have already stopped responding to CDK4/6 inhibitor therapy.
In the phase 3 VIKTORIA‑1 trial, adding the investigational PI3K/mTOR pathway inhibitor gedatolisib to fulvestrant, with or without the CDK4/6 inhibitor palbociclib, helped patients live significantly longer without their cancer growing compared with fulvestrant alone. Across multiple analyses, the combinations roughly quadrupled median progression‑free survival, from about 2 months on fulvestrant alone to around 8–12 months with gedatolisib‑based regimens, and this benefit was seen regardless of how long patients had responded to their prior therapy. The improvement held true in patients with disease in the bones only and in those with cancer spread to other organs, with particularly strong gains in people with non–bone‑only metastases.
The study enrolled premenopausal and postmenopausal adults with HR‑positive, HER2‑negative, PIK3CA wild‑type metastatic or locally advanced breast cancer who had progressed on a CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor, but had not yet received chemotherapy or other PI3K‑pathway drugs for advanced disease. Participants were randomly assigned to receive gedatolisib plus fulvestrant and palbociclib, gedatolisib plus fulvestrant, or fulvestrant alone; patients on fulvestrant alone could switch to a gedatolisib regimen if their cancer progressed. The main goal was to see how long people lived without disease worsening, with overall survival, tumor response, safety, and quality of life as key secondary outcomes.
Side effects with gedatolisib combinations were generally manageable; the most common issue was stomatitis (mouth sores), which was usually low‑grade and could be controlled with supportive care and dose adjustments. Quality‑of‑life analyses showed that the time until significant symptom worsening was meaningfully delayed with gedatolisib‑based treatment compared with fulvestrant alone, suggesting that many patients were able to stay on therapy longer without major declines in day‑to‑day functioning. Investigators say these results support gedatolisib plus endocrine therapy—with or without palbociclib—as a potential new standard of care option in the second‑line setting for HR‑positive, HER2‑negative, PIK3CA wild‑type advanced breast cancer, pending regulatory review and longer‑term survival data.
More Reading
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References
- Pistilli B, Layman RM, Curigliano G, et al. Gedatolisib, a multitarget PI3K/AKT/mTOR inhibitor, plus fulvestrant with or without palbociclib for second-line treatment of patients with HR+/HER2-/PIK3CA-WT advanced breast cancer: updated results from the randomized, phase 3 VIKTORIA-1 trial. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract R47-04.
- Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib plus fulvestrant, with and without palbociclib, vs fulvestrant in patients with HR+/HER2-/PIK3CA wild-type advanced breast cancer: first results from VIKTORIA-1. Presented at: 2025 ESMO Annual Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA17.
