Next-generation SERDs and Dominance of Verzenio

For decades, the adjuvant market of early-stage breast cancer has been mainly dominated by endocrine therapies and chemotherapy. In October 2021, the US market witnessed the entry of Eli Lilly’s CDK4/6 inhibitor, Verzenio, which is the only approved therapy for early breast cancer patients at high risk of recurrence, which is approximately 30% of the total early-stage patient pool. We expect Verzenio to garner benefits of first-mover advantage in this setting, similar to Pfizer’s Ibrance journey in first-and second-line metastatic breast cancer settings.

Although Novartis’ CDK4/6 inhibitor, Kisqali, did not prove to be significantly better in a Phase II LEADER trial in an adjuvant setting previously, we hope the drug to join the race in the future only if it provides a significant benefit in the Phase III NATALEE trial.

Another recent approval in the adjuvant setting is AstraZeneca’s PARP inhibitor, Lynparza, targeting a small population with BRCA mutation (5–10% of Breast Cancer patients). Lynparza had already taken a firm position in ovarian cancer, which had contributed to the drug sales until 2020 when it received approval in second-line metastatic castration-resistant breast cancer (2L mCRPC). The drug was earlier approved in 2018 for usage in BRCA mutated Metastatic Breast cancer patients; therefore, the addition of an adjuvant breast cancer setting led to a label expansion in March 2022.

Moving onto an emerging novel class, we can foresee the entry of a few potential Next Generation SERDs from Lilly, Sanofi, and Roche in the adjuvant/neoadjuvant setting.

After the recent failure of Sanofi’s Next Generation SERD, Amcenestrant in AMEERA-3 (Phase II trial in ESR1 mutation in metastatic breast cancer) trial, the company had decided to discontinue AMEERA-5 and AMEERA-6 as well. AMEERA-6 was being evaluated in adjuvant setting where it was supposed to face competition with the already approved CDK4/6 inhibitors.

Similarly, even Roche’s, Giredestrant recently failed in the Acelera trial (Phase II trial in ESR1 mutation in metastatic breast cancer), which marks the second stumble in this closely watched group of medicines known as Next Generation SERD. Similar to Sanofi, even Roche has not yet given up on these failed trial results. Shifting our focus toward the adjuvant setting, Roche’s Giredestrant is now being evaluated in a Phase III LIDERA trial, which is expected to complete in 2025. Earlier, Giredestrant was being evaluated in a Neoadjuvant setting along with Palbociclib in a Phase II Coopera trial. Although it did not provide much statistical significance during the interim analysis, it did become a basis for initiating the Phase III LIDERA trial in the adjuvant setting.

Roche might have flunked in trial for patients with ESR1 mutation, we can still be hopeful about its focus on adjuvant setting in high phase trials, an area that has not witnessed the usage of a SERDs (Faslodex) previously. Even after a scenario of uncertainty, if launched, we estimate Roche’s Giredestrant in combination with Palbociclib to reach US peak sales of more than USD 800 million in 2032 in the adjuvant setting and a peak sales of approximately USD 250 million if Giredestrant monotherapy gets approved separately in the Neo-adjuvant setting.

Eli Lilly’s Imlunestrant is another SERD in line, currently, in the Phase I stage of development in a neo-adjuvant setting (EMBER-2 trial). Lilly’s Imlunestrant had directly jumped from a Phase I trial to Phase III trial (EMBER-3) for ER+/HER2− advanced breast cancer patients previously treated with Endocrine therapy. We can expect Lilly to follow a similar pathway in the case of the neo-adjuvant setting, considering this space’s high unmet need. It is important to note that Lilly is one of the leading players following AstraZeneca and Radius Health when focusing on ESR1 mutation-specific trials.

We still believe that individual entry of Next-Generation SERD’s might not be able to beat Lilly’s already approved Verzenio, leading Verzenio to dominate the adjuvant market with a US peak sales of approximately USD 2 billion only in the adjuvant setting. Additionally, if Novartis’s Kisqali succeeds in this space, we will still have CDK4/6 inhibitors dominating the adjuvant market.

The scenario of Next-Generation SERDs remains skeptical due to back-to-back failures in the advanced breast cancer trials; however, we can remain hopeful for this class considering the drawbacks of Faslodex’s (old generation SERD) inconvenient route of administration and poor bioavailability. Therefore, Delveinsight estimates that this class, if successful, can garner upto USD 1.5 billion sales in the United States by 2032. For further insights, ER+/HER2− Breast Cancer – Market Insights, Epidemiology, and Market Forecast 2032 Report can be referred.