camizestrant (AZD9833)

P3, N=500, Not yet recruiting, AstraZeneca

P1, N=22, Completed, AstraZeneca | Recruiting --> Completed

P1, N=396, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

Fulvestrant is the first approved SERD with proven efficacy and good tolerability in clinical practice...Elacestrant is an orally bioavailable SERD that has been recently approved by the FDA for postmenopausal women with ER+, human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Other molecules of the same class currently tested in clinical trials are amcenestrant, giredestrant, camizestrant, and imlunestrant. The current review article offers a detailed pharmacological perspective of this emerging drug class, which may help with their possible future clinical applications.

P3, N=1370, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P1/2, N=204, Recruiting, AstraZeneca

P1, N=10, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2025

Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination...The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad anti-tumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi.

P1, N=28, Recruiting, AstraZeneca | Trial completion date: Nov 2023 --> Feb 2024 | Trial primary completion date: Nov 2023 --> Feb 2024

P1/2, N=804, Recruiting, AstraZeneca | N=604 --> 804

Although targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies, treatment with non-mutant selective PI3Kα inhibitors such as alpelisib is associated with significant toxicities such as hyperglycemia, due to on-target inhibition of the wild-type enzyme...Moreover, OKI-219 dosed in combination with the selective estrogen receptor degraders (SERDs) fulvestrant, elacestrant or camizestrant showed significant combination benefit leading to tumor regressions of up to 100% in the ER+ H1047R mutant breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. Dosing OKI-219 in combination with HER2-inhibitors, such as tucatinib, led to tumor regressions in the ER-HER2+ and H1047R mutant breast cancer CDX model HCC1954, also at doses where no regressions were observed with single agent treatment. These data indicate that OKI-219 offers improved efficacy and a wider therapeutic window compared to non-mutant selective PI3Kα inhibitors. OKI-219 is advancing into clinical trials.

Unlike Y537S, cells harboring mutations at the dimer interface maintain their sensitivity to Selective Estrogen Receptor Degraders (SERDs), including Fulvestrant, recently FDA-approved Elacestrant, and Camizestrant, as well as Selective Estrogen Receptor Modulators (SERMs) including Tamoxifen and Raloxifene. Collectively, our finding unveiled a new class of ER mutations that enforce receptor dimerization and activation of the ER signaling pathway. The discovery opens up a new therapeutic interventional possibility, suggesting that targeting dimerization could emerge as a new strategy to combat these malignancies.

In postmenopausal women with advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative BC and disease recurrence or progression on or after ≤1 endocrine therapy (ET) in the advanced setting, camizestrant significantly prolonged progression-free survival compared with fulvestrant in the Phase 2 SERENA-2 trial...Patients are randomized (1:1) to receive camizestrant 75 mg ± abemaciclib ± luteinizing hormone-releasing hormone (LHRH) agonist or standard ET of the investigator's choice (any aromatase inhibitor or tamoxifen) ± abemaciclib ± LHRH agonist for up to 7 years...Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 5500 patients will be randomized.

Data for camizestrant as monotherapy and in combination with palbociclib or abemaciclib have been presented previously.1–3 Here we present data from parts I and J (dose ranging and expansion, respectively), which examined camizestrant in combination with the pan-AKT inhibitor capivasertib...Prior treatment with CDK4/6 inhibitors (CDK4/6i) and/or fulvestrant was also permitted... Camizestrant 75 mg QD in combination with capivasertib 400 mg BID was well tolerated and associated with encouraging clinical and pharmacodynamic activity. These data support further evaluation of this combination in women with ER+/HER2− advanced breast cancer. Anne Armstrong had not approved the final draft of the abstract at the time of submission.

In SERENA-2, camizestrant 75 mg and 150 mg significantly prolonged progression-free survival vs fulvestrant in postmenopausal women with ER+/HER2– advanced BC with disease recurrence or progression after ET...Pts are randomized (1:1) to continue standard ET of the investigator's choice (tamoxifen or aromatase inhibitor ± luteinizing hormone-releasing hormone [LHRH] agonist) or camizestrant ± LHRH agonist for up to 60 months...Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 4300 pts will be randomized; enrollment is ongoing.

Background Camizestrant, a next-generation oral selective estrogen receptor (ER) degrader (SERD) and pure ER antagonist, has demonstrated statistically significant and clinically meaningful progression-free survival (PFS) benefit over fulvestrant at both 75 and 150 mg once-daily doses in the Phase 2 SERENA-2 (NCT04214288) study in post-menopausal women with ER+ HER2- advanced breast cancer. Together with SERENA-2, this provides strong evidence supporting 75 mg as the optimal dose of camizestrant, including for the early disease setting, and highlights the additive value of a specifically designed multi-dose pre-surgical PD study for optimal dose selection. Table 1

P3, N=5500, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1, N=28, Completed, AstraZeneca | Recruiting --> Completed

P1, N=403, Recruiting, AstraZeneca | Trial completion date: May 2024 --> Sep 2024 | Trial primary completion date: May 2024 --> Aug 2024

P2, N=135, Completed, AstraZeneca | Recruiting --> Completed

In SERENA-2, camizestrant 75 mg and 150 mg significantly prolonged progression-free survival vs fulvestrant in postmenopausal women with ER+/HER2– advanced BC with disease recurrence or progression after ET...Pts are randomised (1:1) to continue standard ET of the investigator's choice (tamoxifen or aromatase inhibitor ± LHRH agonist) or camizestrant ± LHRH agonist for up to 60 months...Secondary endpoints include invasive disease-free survival and distant relapse-free survival (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Approximately 4300 pts will be randomised; enrollment is ongoing.

SERD plus Palbociclib resulted in higher rates of AEs (p<0.01). Table: 481P Characterization of ESR1mut and response to SERD (Amcenestrant, Elacestrant, and Camizestrant) Conclusions Our study supports the favorable safety profile of the new generation oral SERD and presents its efficacy according to ESR1mut. Further studies shall assess the potential biomarker role of individual ESR1mut.

P1/2, N=604, Recruiting, AstraZeneca | Trial completion date: Jan 2026 --> Jul 2026 | Trial primary completion date: Jan 2026 --> Jul 2026

P3, N=5500, Not yet recruiting, AstraZeneca

P2, N=241, Active, not recruiting, AstraZeneca | Trial completion date: May 2023 --> Mar 2024

P1, N=10, Active, not recruiting, AstraZeneca | Trial primary completion date: Dec 2023 --> Jul 2022

P3, N=300, Recruiting, AstraZeneca | Trial primary completion date: Jul 2024 --> Jan 2025

Camizestrant is a next-generation oral selective estrogen receptor degrader (SERD) that in a phase II study significantly improved progression-free survival (PFS) over fulvestrant (also a SERD) in ER+/HER2- ABC. The aim is to treat ESR1m clones and extend the duration of control of ER-driven tumor growth, delaying the need for chemotherapy. The primary end point is PFS; secondary end points include chemotherapy-free survival, time to second progression event (PFS2), overall survival, patient-reported outcomes and safety.

P3, N=4300, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting | Trial completion date: Sep 2036 --> May 2036

There is also a paucity of data regarding the efficacy of older regimens, such as everolimus + exemestane, post-CDK4/6 inhibition. In this setting of high unmet need, several clinical trials of novel drugs have recently reported encouraging the addition of the AKT-inhibitor capivasertib to fulvestrant demonstrated a significant improvement in progression-free survival (PFS); the oral selective estrogen receptor degrader (SERD) elacestrant prolonged PFS compared to traditional ET in a phase 3 trial, particularly among patients with detectable ESR1 mutations; finally, PARP inhibitors are available treatment options for patients with pathogenic BRCA1/2 germline mutations. Overall, a plethora of novel endocrine and biologic treatment options are finally filling the gap between first-line ET and later line chemotherapy. In this review article, we recapitulate the activity of these novel treatment options and their potential role in future treatment algorithms.

P3, N=4300, Not yet recruiting, AstraZeneca

Compared with standard fulvestrant, it significantly prolonged progression-free survival in postmenopausal women with advanced estrogen receptor-positive, HER2-negative breast cancer. Camizestrant also bested fulvestrant in subgroup analyses of patients who previously received a CDK4/6 inhibitor, had visceral metastases, or had ESR1 mutations.

P3, N=300, Recruiting, AstraZeneca | Trial completion date: Jun 2026 --> Nov 2027 | Trial primary completion date: Sep 2023 --> Jul 2024

P1, N=10, Active, not recruiting, AstraZeneca | Trial completion date: Nov 2022 --> Dec 2023 | Trial primary completion date: Nov 2022 --> Dec 2023

P1, N=402, Recruiting, AstraZeneca | N=305 --> 402 | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

No abstract available

Parts A/B and C/D (escalation/expansion) examined camizestrant as monotherapy and in combination with palbociclib respectively and have been presented previously.1,2 Here we present data from parts G/H which examined camizestrant in combination with abemaciclib...There was no limit on the number of lines of prior endocrine treatment in the advanced setting; previous treatment with CDK4/6 inhibitors (CDK4/6i) and fulvestrant was permitted... Camizestrant 75 mg QD in combination with abemaciclib 150 mg BID was well tolerated with encouraging clinical activity. The inclusion of this regimen in the ongoing Phase 3, SERENA-6 trial 3, of camizestrant combined with CDK4/6i versus an aromatase inhibitor, will further clarify the role of this combination in the treatment of patients with ER+/HER2− advanced breast cancer with tumors expressing ESR1 mutations.

P3, N=1342, Recruiting, AstraZeneca | Trial primary completion date: Nov 2025 --> Aug 2026

P2, N=132, Recruiting, AstraZeneca | N=92 --> 132

The L391F mutation resulted in an increased binding affinity for Lasofoxifene (LAS) (dAff -0.34), Giredestrant (GIR) (dAff -0.18), Elacestrant (ELA) (dAff -0.08) and Amcenestrant (AMC) (dAff -0.41), while a decreased binding affinity was observed for 4OH-Tamoxifen (TAM) (dAff 0.01), Imlunestrant (IML) (dAff 0.15), Fulvestrant (FUL) (dAff 0.43), and Camizestrant (CAM) (dAff 0.02). The study suggests that genomic variability in drug targets detectable through ctDNA may modulate therapeutic response. Preclinical models are under development to investigate the combined endocrine resistance mechanism suggested by the significant co- occurrence between ESR1 mutations in SERDs/SERMs docking sites and ESR1 hotspot mutations and provide valuable additional insights for drug development and future treatment algorithms.