Editor’s Note:For patients with hormone receptor–positive (HR+) advanced breast cancer who progress after treatment with CDK4/6 inhibitors, should clinicians choose antibody–drug conjugates (ADCs) or a combination of targeted therapy plus endocrine therapy (ET)? At the 2025 Summer Breast Cancer Forum · Northern Salon, the “Debate” session addressed this very question. Professor Ning Xie of Hunan Cancer Hospital and Professor Lingzhi Xu of the Second Affiliated Hospital of Dalian Medical University presented evidence-based arguments for ADCs and for targeted therapy + ET, respectively. In this Oncology Frontier feature, they further elaborate on their viewpoints. 

Presenting the Case for ADCs

Professor Ning Xie:favor ADCs, and my reasoning is grounded in efficacy and safety profiles, guideline recommendations, and accessibility. For example, comparing the data from DESTINY-Breast06 with CAPItello-291, ADCs show clear advantages in median progression-free survival (PFS), second PFS (PFS2), and objective response rate (ORR), regardless of whether patients carry ESR1 mutations or PAM pathway alterations. ADCs also offer good accessibility, with manageable and controllable adverse effects. This makes them a strong choice across a broad patient population.

That said, we cannot deny that carefully selected patients may still benefit from targeted therapy combined with endocrine therapy. Debate is one thing, but clinical practice is another: what matters most is tailoring treatment to the individual. ADCs and targeted therapy + ET should be viewed as complementary strategies. For patients with actionable targets who are still candidates for endocrine therapy, targeted therapy plus ET remains a valuable option. Conversely, for patients who are not suitable for endocrine therapy or require rapid disease control, ADCs may be the more appropriate first choice. Together, these approaches can make treatment planning for HR+ advanced breast cancer more rational and effective across the entire disease course.

Making the Case for Targeted Therapy + Endocrine Therapy

Professor Lingzhi Xu: Although ADCs have shown impressive efficacy in studies such as DESTINY-Breast04 and DESTINY-Breast06, the precision medicine paradigm suggests that patients with actionable targets may derive greater benefit from targeted therapy combined with endocrine therapy. For example, in ESR1-mutated disease, the EMBER-3 trial evaluated the novel oral selective estrogen receptor degrader (SERD) imlunestrant plus abemaciclib, achieving a median PFS of 11.1 months.

For patients with PIK3CA mutations, timely identification of those likely to experience CDK4/6 inhibitor failure allows us to consider approaches such as the INAVO120 study: triplet therapy with the PI3K inhibitor inavolisib plus a CDK4/6 inhibitor and fulvestrant, which achieved a median PFS of 17.2 months (investigator-assessed). These data suggest that while ADCs shine with strong efficacy and visibility, targeted therapy combined with endocrine therapy still has a meaningful role in clinical practice.

Professor Ning Xie

Director, Joint Oncology Center Hunan Cancer Hospital – Hunan Third People’s Hospital

Professor Lingzhi Xu

MD, Associate Chief Physician, Doctoral Supervisor Breast Oncology Department, Second Affiliated Hospital of Dalian Medical University