Orserdu (elacestrant)

P2, N=140, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Not yet recruiting --> Recruiting

The analysis commenced with elacestrant (2022) and fulvestrant (2004), concluding in the fourth quarter of 2024. For fulvestrant, increased vigilance is necessary regarding cancer metastasis and adverse events impacting the hematological and lymphatic systems. It is recommended that targeted monitoring be enhanced in clinical practice in accordance with the distinct characteristics of each drug.

P3, N=1520, Not yet recruiting, West German Study Group

Elacestrant demonstrated durable benefit in real-world clinical practice, particularly in earlier lines and in patients with prolonged prior ET exposure. Despite coexisting ESR1 and PI3K-pathway mutations, TTNT remained clinically meaningful, reinforcing the role of elacestrant in personalized ET sequencing strategies prior to chemotherapy, antibody-drug conjugates, or targeted combinations.

We demonstrated that CDD-1274 induced proteasomal degradation of ERα variants in breast cancer cell lines and caused Y537S ERα degradation more effectively than elacestrant in a palbociclib-resistant cell line. These findings establish that CDD-1274 potently blocks ligand-dependent and ligand-independent ER signaling in endocrine-resistant breast cancer cells and could be further optimized for developing a new class of ERα degraders for endocrine therapy-resistant breast cancer.

In ESR1-mutant MBC, elacestrant treatment durations support the routine use of elacestrant monotherapy in appropriately selected patients. For patients with concurrent ESR1 and PI3K-pathway mutations, single-agent activity was comparable to outcomes observed in phase III studies.

Importantly, ferroptosis inducers potentiated the effects of the selective estrogen receptor degraders fulvestrant and elacestrant, which are the standard of care for breast cancers carrying ESR1 mutations. These findings, validated both in preclinical models and in patient-derived material, identify a combinatory therapeutic approach in the setting of ET resistance and establish ACSL4 as an important biomarker to recognize ER+ breast cancers susceptible to ferroptosis induction.

In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway-the transactivation of jointly regulated ERα-SP1 target genes such as the mTOR regulator DEPTOR We show that silencing mutant p53 restores the ability of ERα to transactivate ERα-SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line.

P1/2, N=73, Recruiting, Stemline Therapeutics, Inc. | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

P2, N=174, Recruiting, Northwestern University | Not yet recruiting --> Recruiting | Trial completion date: Jul 2025 --> Jul 2027 | Trial primary completion date: Jul 2024 --> Jul 2026

Sapanisertib plus fulvestrant provided the greatest PFS benefit (HR 0.34, 95% CI 0.14-0.82) but had a high discontinuation rate (>15%). Among the approved therapies, ribociclib plus ET (HR 0.57, 95% CI 0.39-0.84), capivasertib plus fulvestrant (HR 0.62, 95% CI 0.51-0.75), and elacestrant (HR 0.70, 95% CI 0.55-0.89) demonstrated superior efficacy...Ipatasertib and alpelisib showed the greatest benefits in patients with PI3K/PTEN/AKT alterations. Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan and sacituzumab govitecan, outperformed standard chemotherapy, albeit with higher toxicity...Grant Assignment Decree No. 1369 adopted on 01.09.2023 by the Italian Ministry of University and Research (MUR).

P2, N=75, Recruiting, Memorial Sloan Kettering Cancer Center