Breast cancer is the most common malignancy in the world, with 2.26 million new cases in 2020, accounting for 11.7% of the total incidence of cancer.
Breast cancer is one of the sex hormone receptor dependent tumors, its occurrence and development is closely related to estrogen and progesterone, estrogen in the body and the estrogen receptor of breast cancer cells to stimulate the proliferation of cancer cells. Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer, accounting for about 75 percent.
Endocrine therapy combined with CDK4/6 inhibitors is the first-line treatment for ER-driven advanced breast cancer. However, many patients with advanced breast cancer develop resistance to CDK4/6 inhibitors and existing endocrine therapies, while accumulating many mutations, causing treatment difficulties.
Mutations in the estrogen receptor 1 (ESR1) gene are the most common mechanism of endocrine therapy resistance, usually occurring in about 30% of patients treated with aromatase inhibitors.
Selective estrogen receptor depressants (SERDs) reduce the stability of ER by binding to ER on the surface of cancer cells, inducing them to be degraded by the cell's normal protein degradation mechanism, thereby reducing ER levels and inhibiting the growth of cancer cells.
Moreover, different from modulators that inhibit the activity of estrogen, SERD can theoretically inhibit the function of ER more comprehensively by mediating the degradation of ER, and may solve the drug resistance caused by ER mutation.
However, there is currently only one SERD approved globally, known as fluvezetan. Fulvestrant (Faslodex), developed by Astrazeneca, has been approved for use in postmenopausal breast cancer patients whose disease has progressed after treatment with anti-estrogen drugs such as tamoxifen. And in combination with the CDK4/6 inhibitor pipersilil (Ibrance) for patients with HR+/ HER2-metastatic breast cancer who are receiving or have received endocrine therapy but whose disease has progressed.
Faslodex is a blockbuster drug in Astrazeneca's oncology pipeline, but sales have fallen off a cliff in recent years as patents expire. At present, Chia Tai Tianqing, Hausen Pharmaceutical, Hangzhou Jiuyuan has obtained the approval for the production of fluweisetn injection generic drug.
Due to the disadvantages of fluvestran, such as inconvenient administration mode (intraperitoneal injection), insufficient drug exposure (unable to achieve the maximum effective exposure) and poor efficacy in ESR1 mutation
Elacestrant
elacestrant, a once-daily oral SERD developed by Menarini /Radius for the treatment of ER+/HER2 -- advanced or metastatic breast cancer, was granted priority review approval by the FDA in August with a PDUFA date of February 17, 2023.
OP-1250
OP-1250, an oral small-molecule drug developed by OlemaOncology that combines full estrogen receptor antagonist (CERAN) and SERD activity, was granted fast-track status by the FDA in July this year for the treatment of patients with metastatic breast cancer with ER+ and HER2-. These patients had previously received one or more endocrine therapies (at least one of which combined with a CDK4/6 inhibitor) for disease progression.
D-0502
The oral D-0502 independently developed by Yifang Biologic also progressed rapidly, and has entered the phase 3 clinical stage. According to the company's prospectus, D-0502 has shown good antitumor activity and safety in preclinical studies and clinical trials, and is expected to become a "best-in-class" oral SERD-targeting drug.
Most of the above SERDs are administered orally, and the types of drugs are no longer limited to small molecules. Arvinas' ARV-471 and ice SPAR's AC682 are ER-targeted proteolytic targeted chimera (PROTAC) protein depressants.
However, the development of SERDs was not smooth. Sanofi announced the termination of amcenestrant's global clinical development program in August after the failure of the AMEERA-3 and AMEERA-5 phase 2 clinical trials.
Moreover, a Phase 2 acelERA of Roche Giredestrant in breast cancer failed in April, missing the primary endpoint for PFS.
However, it is worth noting that the recent oral SERD breakthrough! Clear the cloud of SERD target development.
Astrazeneca today announced that its next generation oral selective estrogen receptor suppressor (SERD) camizestrant (AZD9833) in the treatment of estrogen receptor positive (ER+) locally progressive or metastatic breast cancer patients reached its primary endpoint in a Phase 2 clinical study of SERENA-2. Clearing the cloud of oral SERD targets, and encouraging the development of this target.
The study was a multicenter, randomized, open-label trial of 240 patients to evaluate the efficacy and safety of camizestrant versus fluvestrant in patients with advanced ER+/ HER2-breast cancer who had previously received endocrine therapy.
Results: Patients in the camizestrant group (75mg and 150mg) achieved a statistically significant and clinically significant improvement in PFS compared with those in the fluvestrant group (500mg). In addition, camizestrant was well tolerated and safety was consistent with previous reports, with no new safety signals found.
camizestrant, a novel oral SERD and selective ERα antagonist developed independently by Astrazeneca, has shown anticancer activity in a range of preclinical models, including ER-activated mutations.
camizestrant is currently in two ongoing phase 3 studies, including the Sina-4 study, which is expected to enroll 1,402 patients, to evaluate the efficacy and safety of camizestrant combined with piperoxil versus anastozole combined with piperoxil in first-line treatment of HR+ locally advanced or metastatic breast cancer.
The Sina-6 study, which is expected to enroll 302 patients, aims to evaluate the efficacy and safety of camizestrant in combination with CDK4/6 inhibitors (piperoxil or abesili) in first-line treatment of HR+ metastatic breast cancer patients with detectable ESR1 mutations.
On the whole, the industry is very optimistic about SERDs. Multinational pharmaceutical companies such as Astrazeneca and Roche, as well as domestic companies such as Hengrui Pharmaceutical and Simsen Pharmaceutical are actively laying out their positions in this field. And that dominance is about to be broken, with Elacestrant expected to be approved for sale next year. Jefferies analysts estimate the oral SERD market, if successful, to be worth at least $7 billion to $8 billion.
