giredestrant (GDC-9545)

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.

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.

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.

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.

P2, N=220, Not yet recruiting, ETOP IBCSG Partners Foundation

P2, N=550, Recruiting, Hoffmann-La Roche | Trial completion date: Sep 2026 --> Dec 2028 | Trial primary completion date: Aug 2024 --> Dec 2026

P3, N=992, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Apr 2024 --> Mar 2025

Elacestrant was approved by the US FDA on January 27, 2023, for treating postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression prior to using at least one line of endocrine therapy. In this short perspective, physicochemical properties, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interaction, and treatment-related adverse reactions of elacestrant are summarized.

GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.

Fulvestrant ± a CDK4/6i, and everolimus + exemestane are the current approved second-line regimens...Pts will use a dexamethasone mouth rinse 4 times QD for 8 weeks concurrently with study treatment...Encore from SABCS 2022 (OT2-01-07). Clinical trial information: NCT05306340.

G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P)... As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL)... G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies.

Randomization was 1:1 to giredestrant (30 mg PO daily) or PCET (fulvestrant/aromatase inhibitor). These data show that tumor response to single-agent ET is correlated with baseline ctDNA features and with tumor ER pathway activity. Interestingly, ER pathway activity was significantly lower in late-line tumors, except in ESR1m tumors. Overall, these results support the continued investigation of improved and personalized treatment options for pts with ER+, HER2– aBC.

This is the first analysis to our knowledge of PROs with a PO SERD in eBC; it showed that most pts reported minimal symptomatic AEs at frequency and severity levels that were generally numerically lower in the giredestrant + P than the A + P arm (particularly joint pain). Furthermore, there were numeric trends towards greater stability and improvement and less worsening of treatment burden in the giredestrant + P arm. Studies to further assess giredestrant’s clinical benefit are ongoing in the adjuvant setting.

It is more potent in vitro and achieves higher ER occupancy in vivo than fulvestrant...Pts are randomized 1:1 to oral 30 mg daily giredestrant or PCET (tamoxifen, anastrozole, letrozole, or exemestane; per prescribing information)...2950/4100 pts have been recruited globally. Clinical trial information: NCT04961996.

P3, N=992, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P2, N=550, Recruiting, Hoffmann-La Roche | N=400 --> 550 | Trial completion date: Mar 2026 --> Sep 2026

The only FDA-approved selective estrogen receptor degrader (SERD) fulvestrant has been used in the second line treatment to overcome aromatase inhibitor- or tamoxifen-resistance. However, fulvestrant has poor pharmacokinetic properties, which has inspired the development of a new generation of oral SERDs including amcenestrant and giredestrant...Pathway analysis of ELF3-targeted genes reveals that ELF3 may regulate cell metabolism specifically in SERD resistant cells but not in parental cells. Our study suggests that ELF3 may be a novel driver of acquired resistance to SERDs in ER+ breast cancer.

The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10 ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.