The development of next-generation antibody-drug conjugates (ADCs) and selective estrogen receptor degraders (SERDs) is revolutionizing breast cancer treatment, offering patients significantly improved outcomes compared to earlier therapeutic approaches. These advances represent a major shift in the treatment paradigm, with novel agents demonstrating superior efficacy and broader clinical applicability.
HER2-Directed ADCs Lead the Transformation
The evolution from first-generation to next-generation HER2-directed ADCs has yielded remarkable clinical benefits. Trastuzumab deruxtecan has emerged as the superior HER2 ADC, demonstrating dramatic improvements over trastuzumab emtansine in the phase 3 DESTINY-Breast03 trial. The median progression-free survival was 28.8 months with trastuzumab deruxtecan compared to 6.8 months with trastuzumab emtansine, representing a 4-fold improvement in disease control.
"That's 4 times longer than with [trastuzumab emtansine]; that's pretty spectacular," noted Shanu Modi, MD, section head of the HER2 Breast Program at Memorial Sloan Kettering Cancer Center. The confirmed objective response rate reached 78.5% with trastuzumab deruxtecan versus 35.0% with trastuzumab emtansine, with complete responses observed in 21.1% and 9.5% of patients, respectively.
The superiority of trastuzumab deruxtecan was further validated in the DESTINY-Breast02 trial, where patients who had previously received trastuzumab emtansine achieved a median progression-free survival of 17.8 months compared to 6.9 months with treatment of physician's choice. Median overall survival reached 39.2 months versus 26.5 months, establishing trastuzumab deruxtecan as the preferred second-line therapy for HER2-positive metastatic breast cancer.
Technological Advances Drive Improved Efficacy
Next-generation ADCs incorporate several technological improvements that explain their enhanced therapeutic performance. As Neelima Vidula, MD, from Harvard Medical School explained, these agents feature "cleavable linkers, a higher drug-to-antibody ratio, and increased membrane permeability, which likely explains their increased efficacy."
Trastuzumab deruxtecan exemplifies these advances with its higher drug-to-antibody ratio, high potency topoisomerase I inhibitor payload, tetrapeptide-based cleavable linker, and bystander antitumor effect. Unlike trastuzumab emtansine, which requires active lysosomal function for payload release, trastuzumab deruxtecan's less stable linker allows for effective drug delivery even in resistant cell populations.
Expanding Target Landscape with Novel ADCs
TROP2-Directed Therapies
Datopotamab deruxtecan, a TROP2-directed ADC with a topoisomerase I inhibitor payload, has shown promising activity in heavily pretreated patients. In the TROPION-PanTumor01 trial, the agent achieved a 34% objective response rate in HER2-negative breast cancer patients, with an extended follow-up showing 52% response rate in patients without prior topoisomerase I inhibitor exposure.
The agent demonstrated manageable safety, with treatment-emergent adverse events reported in 98% of patients, though grade 3 or higher treatment-related adverse events occurred in only 23% of patients. No cases of treatment-related interstitial lung disease were reported.
HER3-Targeted Approach
Patritumab deruxtecan, targeting HER3 which is overexpressed in 30% to 50% of breast cancers, showed meaningful activity across multiple breast cancer subtypes. In the U31402-A-J101 study, the agent achieved objective response rates of 30.1% in hormone receptor-positive, HER2-negative disease, 42.9% in HER2-positive disease, and 22.6% in triple-negative breast cancer.
Oral SERDs Address Endocrine Resistance
The development of oral SERDs represents a significant advancement for patients with estrogen receptor-positive breast cancer who develop resistance to standard endocrine therapy. Elacestrant became the first oral SERD to demonstrate significant survival improvement over standard-of-care therapy in a phase 3 study.
In the EMERALD trial, elacestrant achieved progression-free survival rates of 34.3% at 6 months and 22.3% at 12 months, compared to 20.4% and 9.4% respectively with standard-of-care therapy. The benefit was particularly pronounced in patients with ESR1 mutations, where 6-month progression-free survival rates were 40.8% with elacestrant versus 19.1% with standard care.
The superior bioavailability of oral SERDs compared to fulvestrant translates into greater clinical efficacy. Camizestrant, another next-generation oral SERD, has shown meaningful efficacy and tolerability in the SERENA-2 trial and is advancing through pivotal phase 3 studies.
Clinical Implementation Challenges
The expanding arsenal of effective ADCs presents new challenges for clinical practice. "A clinically critical and emerging problem for clinicians is how do we best select and sequence these ADC therapies," Modi noted, highlighting the overlapping patient populations eligible for multiple ADCs.
For hormone receptor-positive, HER2-negative patients, treatment selection may be guided by HER2 expression levels, with trastuzumab deruxtecan appropriate for IHC 1+ or 2+ patients based on DESTINY-Breast04 data, while sacituzumab govitecan may be preferred for IHC 0 patients based on TROPiCS-02 findings.
Future Directions
The success of these next-generation therapies is driving exploration into earlier treatment settings and combination approaches. Trastuzumab deruxtecan is being investigated in neoadjuvant settings and in combination with pertuzumab and immunotherapy agents. The TRIO-US B-12 TALENT trial demonstrated the feasibility of delivering 6 to 8 cycles of trastuzumab deruxtecan in the neoadjuvant setting, with objective response rates of 68% as monotherapy and 58% in combination with anastrozole.
As Modi emphasized, "Fundamentally, we need a greater understanding of the mechanisms of resistance. This will allow us to really advance the field" and enable more personalized treatment approaches. The development of novel predictive biomarkers and comparative studies will be essential for optimizing the clinical impact of these transformative therapies.
