Equinox Group’s analysis of the Enhertu + Perjeta combination in first-line HER2+ breast cancer predicts a peak-year patient share of 46% in that setting. Our finding is based on initial results from the Destiny-Breast09[1] trial and the expected competitive environment. FDA approval in first-line is likely by the end of 2025[2].

The core of our analysis compares the net clinical improvement of the Enhertu regimen vs. the current standard of care, Perjeta + Herceptin + paclitaxel. Using our rigorous, data-driven methodology, we find that the Enhertu regimen reduces medical need by 14.6%.

History shows that drugs with a 10% or greater reduction in need typically go on to dominate their segment. Enhertu’s improvement in this population is similar to Tagrisso’s advantage in first-line EGFR+ NSCLC.

The graphic quantifies that net clinical improvement, and shows the contribution of each clinical attribute. The biggest driver is efficacy, primarily progression-free survival (40.7 months for the Enhertu regimen vs. 26.9 months for the SOC). Because the median overall survival data is not yet mature, we have made a conservative assumption about that value for Enhertu. Moreover, the Enhertu regimen spares patients paclitaxel, greatly reducing the frequency of neutropenia and offering a cleaner side effect profile. While the Enhertu regimen costs more, that modest disadvantage is overwhelmed by the clinical benefits.

[1] Tolaney et al. 2025

[2] Daiichi Sankyo Press Release, July 2025

Conclusion: Enhertu achieves impressive clinical innovation versus Kadcyla, the current SOC, in second-line HER2+ metastatic breast cancer, and in the newly defined HER2-low metastatic breast cancer population at second or later lines of therapy versus chemo.

Enhertu (trastuzumab deruxtecan, AstraZeneca) was approved[1] in December 2019 for HER2+ unresectable or metastatic breast cancer patients who have received multiple prior anti-HER2 treatments. In May 2022 the FDA approved Enhertu in second line HER2+ breast cancer, based on results from the DESTINY-Breast03[2] trial, which show impressive efficacy in the second-line setting in HER2+ unresectable or metastatic breast cancer.

In these patients, Enhertu boasts a significant increase in progression-free survival compared to the current standard of care (SOC), trastuzumab emtansine (Kadcyla) (25.1 vs. 9.6 months), and a notable improvement in overall response rate (79.7% vs. 43.6%). Coupled with a hazard ratio for death of 0.55, Enhertu appears poised to take over from Kadcyla in second-line HER2+ metastatic breast cancer.

The waterfall chart above shows that Enhertu’s improvements in efficacy far outweigh its slightly worse side effect profile when compared to Kadcyla. The jump in efficacy, as well as its trickle-down effect on mortality and morbidity, deliver a strong clinical innovation score of 25.9%. Drugs with clinical innovation above 10% usually dominate their segments; Enhertu’s improvement in this population is similar to Tagrisso’s advantage in second-line EGFR+ NSCLC.

We expect Enhertu to dominate treatment in this setting within two years.

Moreover, the FDA recently granted Enhertu Breakthrough Therapy Designation in patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who received a prior systemic therapy in the metastatic setting or developed disease recurrence within six months of completing adjuvant chemotherapy. HR+ patients should additionally have received or be ineligible for endocrine therapy.

The DESTINY-Breast04[3] trial studied Enhertu versus investigator’s choice chemotherapy (e.g., eribulin) in 2L+ HER2-low metastatic breast cancer. Enhertu offers a significant increase in progression-free survival (9.9 vs. 5.1 months) and median overall survival (23.4 vs. 16.8 months) compared to chemo, and a dramatic improvement in overall response rate (52.3% vs. 16.3%). This trial could portend a paradigm shift in breast cancer classification, targeting the entirety of HER2 expression.

The waterfall chart below shows that Enhertu’s improvements in efficacy in HER2-low patients, and resultant impact on mortality and morbidity, offer strong clinical innovation of 14% compared to chemotherapy.