There is currently no universally accepted standard treatment for patients who progress after receiving CDK4/6 inhibitors combined with endocrine therapy (CDK4/6i + ET). In the era of precision medicine, both domestic and international guidelines increasingly recommend biomarker-driven treatment strategies. However, the population covered by each biomarker is often limited, creating an urgent clinical need for more potent and broadly applicable therapies that can simplify both diagnostic testing and treatment selection.At the 2025 ASCO Annual Meeting, results from the biomarker exploratory analysis of the DESTINY-Breast06 (DB-06) study were presented, shedding new light on the critical question of optimal treatment following CDK4/6i failure. Oncology Frontier invited Professor Wenjin Yin from Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, to provide her expert interpretation.
01 No Standard Treatment Exists for the “Post-CDK4/6i” Setting
Oncology Frontier: There is still no consensus on the optimal treatment strategy after progression on CDK4/6 inhibitors. Could you walk us through the main therapeutic options currently available?
Prof. Wenjin Yin: CDK4/6 inhibitors combined with endocrine therapy have significantly improved the prognosis of patients with HR+/HER2− breast cancer—from high-risk early-stage adjuvant settings to first-line therapy in advanced disease. Many patients are now experiencing long-term survival with this regimen. However, once patients progress on CDK4/6i + ET, treatment strategies diverge, and no clear winner has emerged. The main current approaches include:
- Continuing CDK4/6 inhibition beyond progression: Supported by studies like the phase II MAINTAIN and phase III postMONARCH trials, this strategy offers some benefit compared to endocrine therapy alone. However, the overall progression-free survival (PFS) remains under six months.
- PI3K or AKT inhibitors: These are mainly used for patients with PIK3CA or AKT1 mutations or PTEN loss. Phase III trials such as SOLAR-1 and CAPItello-291 have reported promising results. However, only a small subset of patients in the SOLAR-1 study had prior CDK4/6i exposure.
- Antibody-drug conjugates (ADCs): This category includes ADCs targeting HER2 or TROP2. Among them, DB-06 is the earliest-line phase III trial. T-DXd (trastuzumab deruxtecan) is now approved for patients with HER2-low or ultra-low expression who have not received prior chemotherapy in the metastatic setting. TROP2-targeted ADCs are mainly used in patients previously treated with ET and chemotherapy.
- Other options: These include novel oral SERDs (for ESR1-mutated tumors), PARP inhibitors (for gBRCA1/2 mutations), HDAC inhibitors, mTOR inhibitors, and immune checkpoint inhibitors. However, these drugs are either not yet widely available in China or lack sufficient clinical trial data specifically in the post-CDK4/6i population.
Overall, treatment selection in the post-CDK4/6i setting is largely driven by biomarker status. Among the available options, ADCs have the broadest application. For instance, among HR+ breast cancer patients, approximately 55% may have HER2-low expression (IHC 1+ or IHC 2+/ISH−), and over 25% may have ultra-low expression (faint membrane staining at IHC 0).
In the absence of a clear standard of care, how should we select subsequent therapies for patients who have progressed on CDK4/6i + ET? Currently, there is still a lack of direct comparative evidence from randomized clinical trials to guide these decisions.
02 T-DXd Offers a New Option in the “Post-CDK4/6i” Setting
Oncology Frontier: The DB-04 and DB-06 studies have continually expanded the indications and treatment sequencing for T-DXd. Could you briefly summarize the clinical evidence behind these studies, particularly the impact of the recent DB-06 findings on clinical practice?
Prof. Wenjin Yin: T-DXd (trastuzumab deruxtecan) is an outstanding example of next-generation antibody-drug conjugates (ADCs). It has several pharmacologic advantages—such as high systemic stability, a high drug-to-antibody ratio, and a bystander effect—which allow it to break through the traditional boundaries of anti-HER2 therapies.
The DB-04 study was the first to demonstrate the clinical benefit of T-DXd in patients with HER2-low metastatic breast cancer who had previously received endocrine therapy and chemotherapy. Based on this evidence, the drug has been approved both in China and internationally for this indication and has entered routine clinical use.
At last year’s ASCO Annual Meeting, the DB-06 trial further expanded the indication for T-DXd to patients with HER2 ultra-low expression. It also moved the drug earlier in the treatment sequence—targeting patients who had received prior endocrine therapy but had not yet undergone chemotherapy in the metastatic setting. The results showed a significant improvement in progression-free survival (PFS) with T-DXd versus chemotherapy in the overall population (median PFS: 13.2 vs. 8.1 months; HR 0.62; 95% CI: 0.52–0.75; P < 0.001). Consistent benefits were observed in both HER2-low patients (13.2 vs. 5.1 months; HR 0.62) and HER2 ultra-low patients (13.2 vs. 8.3 months; HR 0.78).
Following the DB-06 results, both the 2025 NCCN Guidelines and the ESMO Online Guidelines have been updated with largely consistent recommendations. First, both guidelines have expanded the indication for T-DXd from HER2-low to include HER2 ultra-low expression. Second, they recommend earlier use of T-DXd—for patients who have failed endocrine therapy or are experiencing a visceral crisis.
Notably, for patients with germline BRCA mutations (gBRCA), the NCCN Guidelines recommend PARP inhibitors (PARPi) as first-line therapy. T-DXd is then considered for HER2-low/ultra-low patients without gBRCA mutations. In contrast, the ESMO Guidelines do not clearly distinguish between these subgroups. Instead, they broadly recommend HER2 and gBRCA testing to guide subsequent endocrine-based targeted therapy (ET ± TT). As for patients who are positive for both HER2 and gBRCA biomarkers, there is still no clear guidance from the major guidelines on whether to prioritize ADCs or targeted therapies.
Additionally, based on findings from the INAVO120 study, the ESMO Online Guidelines have added a new recommendation for CDK4/6i + PI3K inhibitor + ET as first-line therapy in patients who experience early relapse after adjuvant therapy (i.e., recurrence within 12 months). As PI3K inhibitors move earlier in the treatment sequence, patients who have failed multiple targeted therapies may accumulate a broader range of resistance mutations. Therefore, selecting therapies with broader activity and greater resistance-overcoming potential will be essential in later lines of treatment.
03 Decoding the Biomarker Analysis of DB-06
Oncology Frontier: At the recently concluded 2025 ASCO Annual Meeting, new exploratory biomarker analyses from the DB-06 study were presented. Could you walk us through these findings?
Prof. Wenjin Yin: As mentioned earlier, post-CDK4/6i treatment strategies increasingly rely on biomarker-driven drug selection. These biomarkers often include genes associated with tumorigenesis and drug resistance. An important question is whether T-DXd can deliver strong efficacy in patients harboring these commonly observed clinical biomarkers.
The exploratory biomarker analysis from the DB-06 study, presented at ASCO 2025, showed that in patients with alterations in the PI3K/AKT pathway (57.6% vs. 41.5%), ESR1 mutations (60.2% vs. 32.1%), or BRCA1/2 mutations (80% vs. 39.3%), the objective response rate (ORR) was significantly higher in the T-DXd group compared to the treatment of physician’s choice (TPC) group.
Progression-free survival (PFS) was also improved across these biomarker subgroups:
· In patients with PI3K/AKT pathway mutations: 13.2 vs. 7.1 months (HR 0.65, 95% CI: 0.48–0.87)
· In those with ESR1 mutations: 11.3 vs. 7.0 months (HR 0.64, 95% CI: 0.49–0.83)
· In BRCA1/2-mutant patients: 21.4 vs. 5.6 months (HR 0.14, 95% CI: 0.05–0.33)
These findings suggest that T-DXd demonstrates potent efficacy and an ability to overcome resistance mechanisms in HR+/HER2− metastatic breast cancer, even in the presence of various pathogenic or resistance-related mutations.
Additionally, for PFS2—a metric reflecting the time from randomization to progression on the next line of therapy or death—the T-DXd group showed consistent benefit across key biomarker subgroups:
· PI3K/AKT pathway mutations: 19.5 vs. 13.6 months (HR 0.59, 95% CI: 0.44–0.79)
· ESR1 mutations: 19.4 vs. 13.7 months (HR 0.58, 95% CI: 0.43–0.77)
· BRCA1/2 mutations: 33.7 vs. 11.8 months (HR 0.17, 95% CI: 0.06–0.42)
These results suggest that patients treated with T-DXd may have a lower risk of developing complex cross-resistance (“crosstalk”) that could compromise the effectiveness of subsequent therapies.
In summary, the exploratory biomarker data from DB-06 show that T-DXd provides consistent therapeutic benefits across multiple resistance and oncogenic mutations, with potential advantages both upfront (in overcoming resistance) and downstream (in avoiding cross-resistance).
04 A Clearer Answer Emerges for the Post-CDK4/6i Setting
Oncology Frontier: Based on the exploratory analysis from the DB-06 study and current clinical evidence, do you believe we now have clearer guidance on selecting optimal therapies in the post-CDK4/6i setting?
Prof. Wenjin Yin: As previously mentioned, determining the optimal treatment for patients with both HER2-low or ultra-low expression and other biomarkers remains challenging due to a lack of head-to-head clinical trial evidence. However, by reviewing findings from various studies, we can indirectly observe that T-DXd tends to show more favorable outcomes—both in terms of longer progression-free survival (PFS) and greater hazard ratio (HR) reductions. Of course, these promising trends still need to be confirmed through future prospective research.
In the exploratory analyses from DB-06, T-DXd demonstrated median PFS nearing or exceeding one year in patients with:
- PI3K/AKT pathway alterations (13.2 months),
- ESR1 mutations (11.3 months),
- and especially BRCA1/2 mutations, where PFS reached 21.4 months.
By comparison, previously reported median PFS with other targeted therapies or novel oral SERDs in phase III trials has typically ranged from only 3 to 7 months. The 21.4-month PFS seen in BRCA-mutant patients—though based on a small exploratory subgroup—is particularly striking and may significantly influence treatment decisions made by clinicians and patients alike.
As more clinical data are generated, we can anticipate updates to national and international guidelines. But based on the current body of evidence, for HR+/HER2-low or ultra-low patients who have failed endocrine therapy and have not received chemotherapy, T-DXd appears to be a highly favorable treatment option, regardless of biomarker status.
We look forward to seeing future real-world data and prospective controlled studies to further validate and refine these findings.
About Prof. Wenjin Yin
Prof. Wenjin Yin is the Deputy Director of the Department of Breast Surgery at Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine.
