Advancements in Oncology at ASCO 2025: Breast Cancer Highlights
The 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, highlighted important new developments in the management of early and metastatic breast cancer. At a satellite event on May 31, Rahul Gosain, MD, MBA, and Rohit Gosain, MD — the Oncology Brothers—reviewed key clinical trials in breast cancer in conversation with two breast oncology leaders: Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center, and Hope Rugo, MD, City of Hope Comprehensive Cancer Center.
Hormone Receptor–Positive Breast Cancer
The discussion began with a spotlight on the utility of the Oncotype DX 21-gene assay in early-stage hormone receptor (HR)–positive breast cancer. Dr. Jhaveri noted that the pivotal RxPONDER trial “was not originally designed” to address the differential benefit of adjuvant ovarian function suppression (OFS) plus endocrine therapy (ET) compared with chemotherapy followed by ET in premenopausal patients with node-positive, HR-positive breast cancer. Consequently, she generally offers chemotherapy and does not routinely order Oncotype DX for such patients. She highlighted the ongoing phase 3 NRG-BR009 (OFSET) trial, which aims to address the question of using adjuvant OFS plus ET versus chemotherapy. Dr. Rugo added that the WSG-ADAPT HR+/HER2- de-escalation trial, which utilized response in Ki-67 after preoperative ET in combination with Oncotype DX to help guide adjuvant treatment, may provide a way to identify responders to ET—as represented by a decrease in Ki-67 to 10% or less—and potentially spare them chemotherapy.
Conversation then moved to CDK4/6 inhibitors, an additional adjuvant therapy option in early-stage breast cancer. When choosing between adjuvant abemaciclib and ribociclib, Dr. Rugo usually opts for abemaciclib in patients with high-risk disease and ribociclib in patients with moderate-risk disease, including those with T2, node-negative disease with certain high-risk features. She emphasized that shared decision-making, which considers treatment toxicity, dose, and duration, is essential for patients who are eligible for both CDK4/6 inhibitors.
Dr. Rahul Gosain noted that ribociclib cannot be combined with tamoxifen due to QTc prolongation risk and is given for 3 years at 400 mg daily, “lower than the [600 mg] dosing for metastatic cancer.” Although abemaciclib can be given with tamoxifen, the combination is associated with an increased risk of thromboembolism. Dosing is the same as for metastatic cancer, and abemaciclib is given for only 2 years. Both Drs. Rugo and Jhaveri remarked that abemaciclib’s efficacy is not compromised with dose reduction, which should be considered especially in patients aged 65 or older to improve tolerability and compliance.
Transitioning to metastatic breast cancer, Dr. Jhaveri was asked about the triplet combination of inavolisib, palbociclib, and fulvestrant for patients with PIK3CA-mutated breast cancer, as studied in the practice-changing INAVO120 trial. Progression-free survival (PFS) was 17.2 months (hazard ratio [HR], 0.42), and overall survival (OS) was 34 months (HR, 0.67). Dr. Jhaveri reflected that these survival improvements over the prior standard of care are especially important, as the trial patients represented a group with poor prognosis. Patients had progressed on or within 12 months of prior ET, and over two-thirds had liver metastases, she said. She anticipated a greater interest in identifying tolerable and efficacious triplet regimens now that INAVO120 has been shown to be the first phase 3 trial of a PI3K/AKT pathway inhibitor with OS benefit.
Finally, Dr. Rugo explained that multiple studies have now shown the benefit of oral agents like selective estrogen receptor degraders (SERDs) and vepdegestrant, a proteolysis targeting chimera (PROTAC) that works through polyubiquitination and degradation of the estrogen receptor, over fulvestrant in patients whose tumors carry an acquired ESR1 mutation. She said that these therapies ideally should be given in combination with another agent, such as a CDK4/6 inhibitor or PIK3CA pathway inhibitor, in patients with endocrine-sensitive metastatic breast cancer. Currently, combinations with elacestrant are being studied. A PFS benefit of switching to an oral SERD at the time of ESR1 mutation emergence was seen in the SERENA-6 trial. The clinical implications of this strategy were a major topic at this year’s ASCO plenary session.
HER2-Positive Breast Cancer
Dr. Jhaveri opened this discussion by addressing anthracycline use in early-stage HER2-positive disease, noting ongoing trials like CompassHER2 that may support de-escalation. “I would be very comfortable not giving an anthracycline for many of our patients … I think we’re refining it more and more,” she said, emphasizing a shift toward more personalized regimens as more clinical trial data become available.
In metastatic HER2-positive disease, the DESTINY-Breast09 (DB09) trial comparing first-line continuous trastuzumab deruxtecan (T-DXd) plus pertuzumab to the CLEOPATRA regimen (taxane, trastuzumab, and pertuzumab) sparked debate. Dr. Rahul Gosain raised a key clinical dilemma for management of responders: “Are you going to keep these patients on T-DXd forever?” Dr. Jhaveri noted that DB09 allowed for maintenance strategies in cases of toxicity, including ET or anti-HER2 therapy alone, depending on estrogen receptor status. However, she emphasized the need for more data on long-term outcomes and patient-reported experiences.
Dr. Rugo highlighted the curative potential of HER2-targeted therapy, referencing CLEOPATRA’s 8-year PFS. “We all have patients who are cured of metastatic HER2-positive disease,” she said, contrasting this with the rarity of durable responses in triple-negative breast cancer (TNBC). Both experts agreed that the central nervous system activity and high response rate of T-DXd—such as the 21% complete response rate in DESTINY-Breast03—make it a compelling first-line option, but questions remain about optimal sequencing and duration. “We answer one question, and that same answer generates three additional questions,” Dr. Jhaveri reflected.
Triple-Negative Breast Cancer
The conversation then turned to T1c TNBC, where Dr. Rugo advocated the philosophical advantage of neoadjuvant chemotherapy, saying “‘knowledge is power’” in regard to understanding tumor response. Dr. Rugo indicated a preference for docetaxel and carboplatin for many patients with early-stage TNBC, whereas Dr. Jhaveri voiced confidence in the effectiveness of anthracycline-based regimens. The importance of supportive care, including scalp cooling, was reinforced.
Regarding metastatic TNBC, a press release of results from the ASCENT-04 trial, describing a 3-month improvement in PFS (11.2 vs 7.8 months) for sacituzumab govitecan (SG) plus pembrolizumab over chemotherapy plus pembrolizumab, was discussed. Dr. Jhaveri noted that only 5% of patients in ASCENT-04 had prior checkpoint inhibitor exposure, raising questions about sequencing in patients who relapse after KEYNOTE-522. “We’ve been utilizing a treatment-free interval of 12 months” to select which patients might benefit from re-treatment with pembrolizumab, Dr. Jhaveri said. Dr. Rugo indicated she might consider the ASCENT-04 regimen even sooner than 12 months after relapse following KEYNOTE-522, given the effectiveness of SG and potential benefits both in regard to efficacy and reduced toxicity in comparison to chemotherapy. Dr. Rahul Gosain highlighted a recent press release updating results from the ASCENT-03 trial, which demonstrated a statistical benefit of SG alone over chemotherapy in first-line metastatic TNBC, bringing a consensus that SG either with or without pembrolizumab will likely become a standard of care for first-line therapy in metastatic TNBC.
Key Takeaways
The concluding remarks highlighted three main takeaways: First, INAVO120 is the first phase 3 PI3K/AKT inhibitor trial to show an OS benefit in HR-positive, HER2-negative metastatic breast cancer. Second, the novel SERD vepdegestrant showed PFS benefit in a phase 3 clinical trial in ESR1-mutated, HR-positive metastatic breast cancer. Third, the ASCENT-04 and ASCENT-03 trials both demonstrated the efficacy of SG (either with or without pembrolizumab, respectively) in the first-line treatment of metastatic TNBC. All panel participants highlighted the importance of adverse event management to enhance quality of life for patients with breast cancer.