giredestrant (GDC-9545)

P3, N=922, Recruiting, Hoffmann-La Roche | Trial primary completion date: Mar 2027 --> Dec 2027

P1, N=181, Active, not recruiting, Genentech, Inc. | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

P1/2, N=316, Recruiting, Hoffmann-La Roche | N=510 --> 316

P2, N=51, Recruiting, Fondazione Oncotech | Not yet recruiting --> Recruiting

P3, N=4200, Recruiting, Hoffmann-La Roche | Trial primary completion date: Dec 2025 --> Mar 2026

P1/2, N=510, Recruiting, Hoffmann-La Roche | Trial primary completion date: Apr 2026 --> Nov 2027

P2, N=92, Completed, MedSIR | Active, not recruiting --> Completed

There are currently five oral SERDs in published and ongoing clinical trials-elacestrant, camizestrant, giredestrant, imlunestrant, and amcenestrant-with more in development. They offer a reasonably well-tolerated oral therapy option with low discontinuation rates in studies. This review summarizes the currently available literature on this new class of drugs.

ESR1-mutant tumors generally retained luminal features and higher ERα activity and exhibited an anti-proliferative response to the ERα antagonist giredestrant. ESR1-mutant tumors acquired mixed-lineage features following treatment. Lineage heterogeneity in advanced ER+ breast cancer may underpin the differential benefit of investigational ERα therapeutics observed in ESR1-mutant versus NMD contexts.

When applied to cells treated with either giredestrant, a selective estrogen receptor (ER) antagonist and degrader, or palbociclib, a CDK4/6 inhibitor, pathways dynamically associated with resistance are revealed. Clustering based on partial least squares regression found that high baseline expression of both SNHG25 and SNCG genes was the primary marker of positive selection to co-treatment and thus potentially associated with innate resistance - an aspect that traditional differential analysis methods missed. In conclusion, TraCSED enables associating features with phenotypes in a time-dependent manner from scRNA-seq data.

P1/2, N=510, Recruiting, Hoffmann-La Roche | Trial completion date: Oct 2026 --> Nov 2027

P2, N=92, Active, not recruiting, MedSIR | Recruiting --> Active, not recruiting | Trial primary completion date: Nov 2024 --> Feb 2025

P3, N=992, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Mar 2025 --> Oct 2025

P3, N=812, Recruiting, Hoffmann-La Roche | Trial completion date: Sep 2032 --> Dec 2030 | Trial primary completion date: Aug 2026 --> Mar 2027

Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer.

P2, N=30, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P3, N=320, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Oct 2024 --> Mar 2026

This thermal analysis method was used as a surrogate for chromatography as a rapid, effective in-process check method for impurity quantitation to enable the timely release of the final reworked clinical batch. Post release, the % w/w oligomer value determined by calorimetry was in excellent agreement to that obtained by size exclusion chromatography.

Oral SERDs constitute an exciting new drug class. Ongoing and future research will further refine the role of these drugs next to standard endocrine treatments and targeted therapies.

P2, N=176, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2028 --> May 2028 | Trial primary completion date: May 2028 --> Feb 2028

P3, N=992, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Mar 2027 --> Mar 2028

P2; Recruiting --> Active, not recruiting

P2, N=303, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Jun 2024 --> Jun 2025

heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC.

P2, N=176, Active, not recruiting, Hoffmann-La Roche | N=550 --> 176

P2; Not yet recruiting --> Recruiting

Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) as monotherapy or when combined with the VEGF-targeted tyrosine kinase inhibitor, lenvatinib, have demonstrated promising response rates in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively...Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity in relapsed recurrent EC, and other solid tumors (e.g. NSCLC, HCC) as monotherapy and as part of combinatorial therapy...In AFT-50A, pts may be eligible for one of the following doublets: Atezo+talazoparib (tumors with genomic loss of heterozygosity (gLOH ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB-H). The Atezo+bevacizumab (biomarker unmatched) and Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered tumors) cohorts have completed accrual...AFT-50B pts will be eligible for inavolisib (PIK3CAm/PTEN and AKT1wt-altered tumors) + letrozole or giredestrant + abemaciclib (RB1wt, estrogen receptor positive tumors)...As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 20 sites in the US with a target of 25 sites nationwide.

P2, N=550, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

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.

P2, N=303, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Mar 2024 --> Jun 2024

P2, N=220, Recruiting, ETOP IBCSG Partners Foundation | Not yet recruiting --> Recruiting

P2, N=220, Not yet recruiting, ETOP IBCSG Partners Foundation | Initiation date: Dec 2023 --> Mar 2024

P2, N=30, Recruiting, Hoffmann-La Roche | N=45 --> 30 | Trial completion date: Oct 2024 --> Dec 2025 | Trial primary completion date: Oct 2024 --> Dec 2025

P2; Trial completion date: Mar 2028 --> Dec 2028 | Initiation date: Sep 2023 --> Dec 2023 | Trial primary completion date: Dec 2024 --> Dec 2028

P2, N=92, Recruiting, MedSIR

P1, N=181, Active, not recruiting, Genentech, Inc. | Phase classification: P1a/1b --> P1

P3, N=4200, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development.

P3, N=4200, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P2, N=92, Recruiting, MedSIR | Not yet recruiting --> Recruiting

P2, N=303, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Nov 2023 --> Mar 2024