Eli Lilly is surging into a market of tens of billions.

On September 18, FDA fully approved inluriyo (imlunestrant) combined with verzenio (abemaciclib) for ESR1 mutated er+, her2- advanced or metastatic breast cancer. Patients must have disease progression after receiving at least one endocrine therapy. This is another indication covered by inluriyo.

The leap from single drug to combination therapy took Lilly less than a year. But the significance of this matter is more than Lilly.

Since fulvestrant validated the SerD mechanism, the gap of oral SerD has lasted for two decades. However, with elacestrant breaking the ice in 2023 and inluriyo single drug approval in 2025, AstraZeneca camizestrat entered the site with accelerated approval not long ago - in just three years, this track has become the main battlefield for MNC's heavy military buildup.

At the same time, the focus of competition has shifted from "whether it can be made into medicine" to the systematic game of joint strategies, treatment opportunities and population screening. ESR1 mutation detection, the deployment of cdk4/6 after treatment, and the advance of adjuvant therapy may change the pattern at each step.

Perhaps the approval of Lilly's joint plan is just the opening whistle of a new round of racing.

01. New watershed

The rise of the SerD track is not accidental. Its core driving force is the long-standing pain point of drug resistance in the clinical treatment of er+ breast cancer. About 70% of breast cancers express estrogen receptor α (ER α), so endocrine therapy has become the cornerstone, but the resistance of aromatase inhibitors and tamoxifen is almost inevitable.

One of the core drivers of drug resistance is the acquired mutation of ESR1 gene. These mutations are gradually enriched after endocrine therapy, allowing Er α to continue to activate in the absence of estrogen, driving tumor growth.
The design logic of SerD is aimed at this point. Unlike selective estrogen receptor modulators (SERMs, such as tamoxifen), SerD not only "blocks" receptors, but also induces Er α to be degraded through the ubiquitin proteasome system, weakening the starting point of the signaling pathway at the protein level.

Fulvestrant, as the first SerD, was approved in 2002 and is still the standard second-line endocrine therapy. However, intramuscular administration limits exposure and does not degrade ESR1 mutant sufficiently, which is difficult to translate into clinical benefit.

Oral SerD aims to achieve deeper and longer-lasting degradation of Er α, more convenient administration, and to form an all oral regimen with cdk4/6 inhibitors. The approval of inluriyo combined with verzenio is the clinical landing of this logic.

Supporting this approved amber-3 trial, 874 patients who had previously received aromatase inhibitor ± cdk4/6 inhibitor treatment were randomly assigned to inluriyo monotherapy, endocrine therapy (fulvestrant or exemestane) selected by the investigator, or inluriyo combined with verzenio according to 1:1 ratio.

In an exploratory subgroup analysis of 159 patients with ESR1 mutations, the median progression free survival of the combined regimen was 11.1 months and that of the single agent was 5.5 months, with a hazard ratio of 0.53; The objective response rates were 35% and 15%, respectively. In all patients (regardless of ESR1 status), the median PFS of the combined regimen was 10.9 months and that of the single agent was 5.5 months, with a hazard ratio of 0.59.

The more differentiated design of amber-3 lies in the enrollment ratio of cdk4/6 treated population. In the combined regimen group (inluriyo + verzenio, n=213), 65% of patients had previously received cdk4/6 inhibitors.

In the cdk4/6 treated subgroup, the median PFS of the combined regimen was 9.1 months and that of the single agent was 3.7 months, with a hazard ratio of 0.51. For patients with disease progression after a long duration of previous cdk4/6 inhibitor treatment, continued use of the same class of drugs combined with new endocrine drugs can still achieve clinically significant disease control.

There is a detail that needs attention behind these data. FDA clearly pointed out in the approval document that inluriyo monotherapy did not show PFS improvement relative to endocrine therapy selected by the investigator in the overall population and ESR1 undetected population, and the benefit was only observed in ESR1 mutant population.

This means that the clinical localization of inluriyo is highly dependent on the detection of ESR1 mutations, and the landing and accessibility of concomitant diagnosis will directly affect its actual scope of use.

02. MNC has its own life

While Eli Lilly verified the strategy of "cdk4/6 continue to unite after governance", other multinational pharmaceutical enterprises presented different path choices and encountered different fates in the layout of the same track.

Sanofi's lessons set the tone for the whole track. Its oral SerD amcenestrant was once ahead of schedule. In March 2022, the phase II ameera-3 study took the lead and failed to reach the primary endpoint of PFS.

Only five months later, the interim analysis of phase III ameera-5 study did not reach the preset limit of continuous dosing, and Sanofi immediately announced the termination of all clinical development of amcenestrant. This decision was regarded as a heavy blow to the prospect of oral SerD at that time.

AstraZeneca chose a strategic path of confrontation with Eli Lilly. Its camizestrat (trade name etcamah) was accelerated approved by FDA on September 4, 2026, and the indication positioning is extremely precise: during aromatase inhibitor combined with cdk4/6 inhibitor treatment, after ESR1 mutation was found by ctDNA detection, but before imaging progress, the patients can switch the endocrine treatment to camizestrat combined with the original cdk4/6 inhibitor.

Supporting this "early interception" strategy is the phase III serena-6 trial, which extended the median PFS from 9.2 months to 16 months and reduced the risk of disease progression or death by 56% (hr=0.44). FDA synchronously approved guardant360 CDX as a companion diagnosis for identifying patients with ESR1 mutations.

Commenting on this strategy, Jake van Naarden, President of Lilly oncology, said: "I know that early interception sounds good, but the goal is not to use a new drug as soon as possible. The goal is to maximize the total time of disease control by using these two mechanisms, and wait until clinical progress before giving oral SerD, which is the evidence-based standard. ”The

The situation of Roche giredestrat is more dramatic. In the late first line, persevera trial (giredestrat combined with piperacillin) failed to reach the primary endpoint of PFS. The attempt of oral SerD to replace aromatase inhibitors in newly treated advanced patients proved to be much more difficult than expected. The efficacy baseline of aromatase inhibitors in newly treated ER positive breast cancer has been very high, "better" itself is a very high threshold.

However, Roche has produced the most significant positive results of the whole track so far in the field of adjuvant therapy. The phase III lidera trial showed that giredestrat as adjuvant therapy reduced the risk of recurrence or death of invasive disease by 30% (hr=0.70), and the 3-year invasive disease-free survival rate was 92.4% in the control group and 89.6% in the control group.

Roche has submitted an NDA for adjuvant therapy to FDA. If approved, the battlefield of oral SerD will move significantly from late second-line to adjuvant treatment -- this is a market opportunity with the largest number of patients, the longest treatment cycle, and the most test of long-term tolerance.

03. Dislocation breakthrough

The space for oral SerD therapy is expanding.

According to market data, the global scale of this track is expected to grow from 922million US dollars in 2026 to 2.516 billion US dollars in 2032, with a compound annual growth rate of about 18.2%. However, this figure may underestimate the ceiling after the adjuvant treatment scene is opened.

Roche estimates that the annual market size of hr+/her2- breast cancer in all treatment lines is between 20billion and 30billion US dollars, of which adjuvant treatment accounts for up to two thirds, which is a broader market segment than the advanced line.

Facing this largest long-term market, the layout rhythm of Chinese pharmaceutical enterprises is not consistent.

Hengrui medicine's entry point is closest to adjuvant therapy. Its oral SerD hrs-8080 has entered the phase III control study, combined with darcilib versus fulvestrant combined with darcilib, which is targeted at patients with locally advanced or metastatic breast cancer resistant to adjuvant endocrine therapy.

This design moves the intervention time point of oral SerD forward to the first late node after the failure of adjuvant therapy, and finds a relatively pre entry point between adjuvant therapy and the late posterior line.

The phase I data released by ASCO in 2026 showed that in the ESR1 mutation subgroup (32 cases evaluable), under the 300mg twice daily or 600mg once daily extended dose, the confirmed orr was 34.4%, the DCR was 75%, the median dor was 11.1 months, and the median PFS was 7.2 months; The incidence of grade 3 and above treatment-related adverse events was 20%. The common adverse events were lymphopenia and neutropenia, and there was no treatment-related death.

Other local pharmaceutical companies started from a more backward scenario and chose different differentiation paths.
Yifang bio's d-0502 is an oral SerD with advanced progress in China. It is carrying out a phase III registration trial of "head to head" with fulvestrant in China for the second-line and above treatment of er+/her2- locally advanced or metastatic breast cancer.

The selling point of d-0502 focuses on safety: in the existing clinical trials, d-0502 did not have adverse reactions such as visual impairment and bradycardia reported by the same kind of oral SerD under study, and no superimposed toxicity or pharmacokinetic interaction was observed when combined with piperacillin in phase I trials.

Sim0270 of Xiansheng pharmaceutical chose another differentiation path - penetrating the blood-brain barrier. The phase III clinical trial evaluated sim0270 combined with everolimus for cdk4/6 inhibitor treated hr+/her2- breast cancer, designed not to take ESR1 mutation status as the threshold for enrollment screening, and attempted to exempt ESR1 testing to cover a broader patient population. This design choice is in sharp contrast to AstraZeneca's strategy of highly relying on ctDNA detection.

Zhejiang Yangli pharmaceutical's tfx06 is a field that was almost blank before. According to the phase i/ii data released by ASCO in 2026, tfx06 is the first oral SerD to disclose the efficacy and safety data of fulvestrant in the treated population. All the enrolled patients had received fulvestrant, 85.7% had received CDK4 / 6 inhibitors, and 76.2% had received fulvestrant combined with CDK4 / 6 inhibitors.

Among the 42 enrolled patients, 40 were evaluable for efficacy, with a median PFS of 5.5 months, a DCR of 60.0% and a confirmed orr of 7.5% in the ESR1 mutation subgroup. The drug has been approved by CDE to carry out phase III key clinical research on April 16, 2026.

Chinese pharmaceutical companies mainly follow fast. Whether they can find a foothold in joint strategies and safety differentiation will determine their position in the next round of endocrine therapy for breast cancer. The end result of this competition is not who has the longest PFS number, but who can give it to the right patient group at the right time, with the right mechanism combination, and the patients are really willing to eat for a long time.

Reference article:
1 Eli Lilly escalates oral SERD battle with FDA approval for Inluriyo, Verzenio combo； fiercepharma
2. 7 days for a new drug: from being approved for marketing to phase III failure; Same as freehand brushwork
3 FDA approves imlunestrant in combination with abemaciclib for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer； FDA
4 Adjuvant Giredestrant Improves Invasive DFS in ER+, HER2– Early Breast Cancer； cancernetwork
5 Roche’s giredestrant reduced risk of invasive disease recurrence or death by 30% in ER-positive early-stage breast cancer； Roche
6. Stirred up breast cancer Market: fulvestrant is in the twilight, and the first SerD oral drug has reached US $1 billion; Same as freehand brushwork