At the 2026 ASCO Annual Meeting, Professor Claudio Vernieri from the Fondazione IRCCS Istituto Nazionale dei Tumori (Italy) presented the key findings of the PALMARES-2 study. Among patients with HR+/HER2− metastatic breast cancer, only about 20% continued first-line endocrine therapy (ET) plus a CDK4/6 inhibitor beyond first progression, achieving a median real-world progression-free survival (rwPFS) of 10.5 months and a median real-world overall survival (rwOS) of 71.3 months. The study also suggested that adding local treatment—particularly radiotherapy—was associated with improved outcomes.To discuss the clinical implications of these real-world findings, Oncology Frontier invited Professor Claudio Vernieri and Professor Man Li from the Second Affiliated Hospital of Dalian Medical University to share their perspectives on CDK4/6 inhibitor continuation beyond progression, patient selection, the role of local therapy, and future applications in Chinese clinical practice.
Oncology Frontier: In the PALMARES-2 study, only 18.7% of 2,434 patients with disease progression continued the same first-line ET plus CDK4/6 inhibitor regimen, achieving a median rwPFS of 10.5 months and a median rwOS of 71.3 months. Why do you think fewer than 20% of patients in routine practice received this strategy?
Professor Claudio Vernieri:
Our subgroup analysis showed that approximately one in five patients with HR+/HER2− metastatic breast cancer continued the same first-line ET plus CDK4/6 inhibitor after disease progression, most often combined with local treatment. These patients achieved a median rwPFS of 10.5 months, suggesting that a meaningful subset of patients can still derive nearly an additional year of benefit from continued CDK4/6 inhibition after first progression.
These findings are particularly important because PALMARES-2 represents the largest real-world study conducted in the current treatment era examining this strategy. The patients selected for continuation therapy tended to be younger, more often premenopausal, and had more favorable disease characteristics, including higher ER and PR expression, predominant bone metastases, and fewer liver metastases.
Multivariable analysis identified several factors independently associated with greater benefit from treatment continuation, including high ER and PR expression, low Ki-67, good performance status, and concurrent local treatment. Based on these findings, continuing ET plus CDK4/6 inhibition should be considered for patients with biologically less aggressive disease whose progression is limited to a small number of lesions that can be effectively managed with local therapy, particularly radiotherapy.
Oncology Frontier: In China, what proportion of patients receive CDK4/6 inhibitor continuation beyond progression, and what are the main barriers to wider adoption?
Professor Man Li:
Real-world studies from China, including analyses from our own institution, suggest that only 8%–15% of patients continue CDK4/6 inhibitors after progression on first-line ET plus CDK4/6 inhibition. The rate is around 15% in major tertiary breast cancer centers but closer to 8% in regional hospitals.
Several factors contribute to this lower utilization.
First, evidence has been limited. Until recently, no large randomized studies supported CDK4/6 inhibitor continuation beyond progression. Previous small studies suggested only about five months of PFS benefit. The PALMARES-2 results presented at ASCO provide much stronger evidence, demonstrating more than ten months of median PFS and offering clinicians greater confidence in this approach.
Second, tumor biology influences patient selection. Many patients progressing on first-line therapy develop widespread visceral disease, experience reduced hormone receptor expression, or harbor resistance-associated alterations such as PI3K, ESR1, AKT, or PTEN mutations, making continued CDK4/6 inhibition less appropriate.
Finally, economic factors remain a major obstacle. CDK4/6 inhibitor continuation beyond progression is not currently reimbursed by China’s national insurance system, creating a significant financial burden for many patients.
Nevertheless, for younger patients with high ER/PR expression, low tumor burden, low Ki-67, and bone-only metastases, continuation beyond progression remains an important treatment option.
Oncology Frontier: When should clinicians continue the same ET plus CDK4/6 inhibitor together with local therapy, and when should they switch treatment?
Professor Claudio Vernieri:
Our multivariable analysis demonstrated that concurrent local treatment, particularly radiotherapy, was strongly associated with improved outcomes. Local therapy effectively controls isolated progressing lesions while allowing continuation of a systemic treatment that remains active against disease elsewhere.
This concept is also supported by the AVATAR phase II trial from Australia. That study enrolled patients with extracranial oligoprogressive disease receiving ET plus CDK4/6 inhibitors. Patients underwent stereotactic ablative radiotherapy (SABR) while continuing systemic therapy and achieved a median PFS of 9.5 months, remarkably similar to the benefit observed in PALMARES-2.
Although additional prospective evidence is needed, these findings suggest that controlling isolated resistant lesions with local therapy while maintaining an otherwise effective systemic regimen can safely delay treatment escalation without compromising overall survival.
Professor Man Li:
Careful patient selection is essential.
Continuation should be considered for patients with oligoprogressive disease, generally involving three or fewer metastatic sites confined to bone, soft tissue, or lymph nodes, without widespread new lesions. Patients should also have favorable biology, including high ER and PR expression, low Ki-67, limited tumor burden, and a durable initial response lasting at least one year.
Local treatments such as stereotactic radiotherapy, radiofrequency ablation, or surgery provide opportunities to eradicate resistant lesions while preserving systemic benefit.
Conversely, patients with rapidly progressive disease, high tumor burden, extensive visceral metastases involving the liver, lung, or brain, high Ki-67, or loss of hormone receptor expression should switch promptly to alternative endocrine therapy, chemotherapy, or antibody-drug conjugates (ADCs). Patients whose first-line PFS was shorter than one year are also less likely to benefit from continuing the same CDK4/6 inhibitor.
Oncology Frontier: Two-thirds of patients continuing therapy received radiotherapy. Do you think radiotherapy mainly controls local progression and allows systemic therapy to continue, or does it also synergize biologically with CDK4/6 inhibitors?
Professor Claudio Vernieri:
This is an excellent question.
There is strong biological and preclinical evidence supporting synergy between radiotherapy and CDK4/6 inhibitors. CDK4/6 inhibition arrests cell-cycle progression, making tumor cells more susceptible to radiation-induced damage.
However, in PALMARES-2 and AVATAR, progression occurred while patients were already receiving CDK4/6 inhibitors, indicating that those specific lesions had developed resistance. Therefore, in this clinical setting, I believe radiotherapy primarily functions by eliminating resistant lesions while continued systemic therapy maintains control of disease that remains sensitive. The local control effect is likely more important than any biological synergy in this particular context.
Oncology Frontier: Should CDK4/6 inhibitor continuation plus local therapy eventually be incorporated into Chinese clinical guidelines?
Professor Man Li:
I was very encouraged by the PALMARES-2 results, and I believe similar studies should now be conducted in Chinese patients.
Although these findings are not yet sufficient to change national guidelines, they fill an important evidence gap and provide clinicians with a valuable new treatment strategy. The key message is not that every patient should continue CDK4/6 inhibition beyond progression, but rather that careful patient stratification is essential.
Patients with oligometastatic disease, low tumor burden, treatment duration of at least one year on first-line therapy, high ER expression, low Ki-67, and metastases limited to bone, soft tissue, or lymph nodes appear to be the best candidates.
In contrast, patients with rapidly progressive disease, extensive visceral metastases, first-line PFS shorter than one year, or declining hormone receptor expression should undergo molecular testing for alterations such as PI3K pathway, ESR1, or BRCA mutations to guide subsequent targeted therapy. Those without actionable alterations may be better served by chemotherapy or ADCs.
Going forward, we hope to generate robust Chinese real-world data while integrating liquid biopsy, molecular profiling, and next-generation sequencing to optimize treatment sequencing for patients with advanced breast cancer.
Professor Man Li
Professor Claudio Vernieri
