giredestrant (GDC-9545)

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

Giredestrant was well tolerated and clinically active in patients who progressed on prior ET. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.

The Phase Ia/b GO39932 study (NCT03332797) investigated GIR ± palbociclib (palbo) and ± a luteinizing hormone-releasing hormone agonist for patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer who had disease progression on prior endocrine therapies. The E–R results also indicate that GIR may have a relevant wide therapeutic window. Overall, these data support the 30 mg clinical dose of GIR that was selected, with a favorable risk–benefit profile, for further clinical studies.

METHODS Pts (n = 303) were randomized 1:1 to GIR or PCET (75% of pts had fulvestrant [FUL]; 25%, an aromatase inhibitor). ESR1 MAF declined to a greater degree with GIR compared with cTF, which is consistent with the larger magnitude of PFS benefit seen with GIR in pts with ESR1m tumors. The specific ESR1 variants D538G and Y537X showed greater sensitivity to GIR compared with PCET or FUL.

100 mg G + 125 mg palbociclib on a 21-D on/7-D off schedule was also explored. Although cells became resistant to ER-targeted drugs, they acquired sensitivity to EGFR/MAPK inhibitors e.g., gefitinib, cobimetinib. CONCLUSIONS We identified molecular features associated with LTB to G and revealed a set of oncogenic pathways associated with FP pts on tx; demonstrating that these pathways represent acquired dependencies and potential therapeutic targets for SERD-resistant tumors and FP pts.

Prior fulvestrant (FUL) was received by 53% of patients in the GIR + INAVO arm (n = 8). Safety summary Data are % of patients. AE, adverse event; GIR, giredestrant; INAVO, inavolisib; TRAE, treatment-related adverse event; tx, treatment.

Selection criteria include pts: a) with HR+/HER2- EBC at high risk of relapse, b) on adjuvant treatment with endocrine therapy (ET) for at least 2 years with 3 additional years of planned ET, c) no prior treatment with cyclin-dependent kinases 4/6 inhibitors or fulvestrant, and d) had surgery for their primary BC in the last 5 years...Pts with positive ctDNA without radiological disease progression (PD) will be allocated to 1 of the treatment arms (n=10): A) standard ET; B) giredestrant; C) giredestrant + abemaciclib; or D) giredestrant + inavolisib (if PIK3CA mutation)...Key secondary objectives include the proportion of pts with 90% decrease in baseline ctDNA at 6, 9, and 12 months, 70%, and 50% decrease in ctDNA at 3, 6, 9, and 12 months, and treatment safety and tolerability. A cohort expansion up to 20 pts in 1 or 2 arms will occur if at 3 months a 90% ctDNA decrease is observed in at least 30% of pts and if, after 3 additional months, a 90% ctDNA decrease is maintained in at least 20% of pts.

P3; Not yet recruiting --> Recruiting

P3, N=4100, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P3; N=1050; Not yet recruiting; Sponsor:Hoffmann-La Roche

P2, N=550, Recruiting, Hoffmann-La Roche | Trial primary completion date: Dec 2026 --> May 2028

Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials.

Table: 395P Conclusions Encouraging activity was seen with G + IPAT in pts with disease progression on 1–2 lines of ET (including a CDK4/6i), especially in pts with AKT signalling alterations. G + IPAT was well tolerated, with no unexpected safety signals.

Background The phase II acelERA BC study (NCT04576455) compared the oral, selective ER antagonist and degrader (SERD) giredestrant (G) with physician's choice of endocrine therapy (PCET) in previously treated ER+, HER2– aBC...In pts with ESR1m, distinct signalling and mutational profiles were observed, dependent on RP status and prior CDK4/6i. Additional observations will inform ongoing pt selection and drug combination research.