giredestrant (GDC-9545) / Roche - LARVOL DELTA

Giredestrant (G) with atezolizumab (ATEZO), and/or abemaciclib (ABEMA) in patients (pts) with ER+/HER2– locally advanced/metastatic breast cancer (LA/mBC): Interim analysis (IA) from the phase I/II MORPHEUS Breast Cancer study. (ASCO 2025) - P1/2 | "Clinical Trial Registration Number: NCT04802759 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Giredestrant: Data from P3 persevERA trial (NCT04546009) in combination with palbociclib for 1L ER+/ HER2- metastatic breast cancer in H2 2025 (Roche) - Q1 2025 Results: Data from P3 evERA trial (NCT05306340) in combination with everolimus for post CDKi ER+/HER2- metastatic breast cancer in H2 2025

P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Oncology

Giredestrant: Regulatory submission in Japan for 1L-3L breast cancer in 2026 (Chugai) - Q1 FY2025 Results: Regulatory submission in Japan for 1L breast cancer in 2026; Regulatory submission in Japan for adjuvant breast cancer in 2027

Japan filing • Breast Cancer • Oncology

Giredestrant: Regulatory submissions in US/EU for post CDKi ER+/HER2- metastatic breast cancer (in combination with everolimus) in 2025 (Roche) - Q1 2025 Results: Regulatory submissions in US/EU for 1L ET sensitive ER+/HER2- metastatic breast cancer (in combination with palbociclib) in 2026; Regulatory submissions in US/EU for ER+ adjuvant breast cancer in 2027; Regulatory submissions in US/EU for 1L ER+/HER2+ breast cancer (in combination with Phesgo) in 2027; Regulatory submissions in US/EU for 1L ET resistant ER+/HER2- breast cancer in 2027

EMA filing • FDA filing • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology

ET-Based Combinations and Novel Agents in HR+/HER2- Advanced Breast Cancer (GBCC 2025) - "Tumors with alterations in the PIK3CA/AKT/PTEN pathway may be offered a pathway inhibitor such as capivasertib or alpelisib, and patients with high risk recurrence of HR+ disease with a PIK3CA mutation may benefit from early introduction of a first-line inavolisib triplet...The oral SERD elacestrant is approved as monotherapy in pretreated patients with tumors harboring an ESR1 mutation. Additional oral SERDs, including imlunestrant, camizestrant, and giredestrant, have demonstrated activity and are in registrational trials. An additional maneuver in the pretreated space includes continuation of a CDK4/6 inhibitor after prior CDK4/6 inhibitor, with activity seen from switching to abemaciclib or ribociclib from a prior agent, and novel CDK inhibitors are in trials as a next generation approach. The mTOR inhibitor everolimus remains an option for pretreated patients as well, particularly when actionable mutations are not present. The continued introduction of novel agents..."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

A Study Evaluating the Efficacy and Safety of Giredestrant Plus Everolimus Compared With the Physician's Choice of Endocrine Therapy Plus Everolimus in Participants With Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer (evERA Breast Cancer) (clinicaltrials.gov) - P3 | N=320 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial completion date: Mar 2026 ➔ Oct 2026 | Trial primary completion date: Mar 2026 ➔ Oct 2026

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

MORPHEUS BC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer (clinicaltrials.gov) - P1/2 | N=510 | Recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Apr 2026 ➔ Nov 2027

Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER

MORPHEUS BC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer (clinicaltrials.gov) - P1/2 | N=316 | Recruiting | Sponsor: Hoffmann-La Roche | N=510 ➔ 316

Enrollment change • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER

A Study to Evaluate the Efficacy and Safety of Giredestrant in Combination With Phesgo (Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf) Versus Phesgo in Participants With Locally Advanced or Metastatic Breast Cancer (heredERA Breast Cancer) (clinicaltrials.gov) - P3 | N=922 | Recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Mar 2027 ➔ Dec 2027

Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

GO39932: A Study of GDC-9545 Alone or in Combination With Palbociclib and/or Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer (clinicaltrials.gov) - P1 | N=181 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Neo-AGILE: NEOadjuvant Abemaciclib and GIredestrant TriaL in Patients with ER-positive, HER2-negative Early Breast Cancer (clinicaltrials.gov) - P2 | N=51 | Recruiting | Sponsor: Fondazione Oncotech | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

A Study Evaluating the Efficacy and Safety of Adjuvant Giredestrant Compared With Physician's Choice of Adjuvant Endocrine Monotherapy in Participants With Estrogen Receptor-Positive, HER2-Negative Early Breast Cancer (lidERA Breast Cancer) (clinicaltrials.gov) - P3 | N=4200 | Recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Dec 2025 ➔ Mar 2026

Monotherapy • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

EMPRESS: Preoperative Window Opportunity Study With Giredestrant or Tamoxifen in Premenopausal Women With ER+/HER2[-] & Ki67≥10% (clinicaltrials.gov) - P2 | N=92 | Completed | Sponsor: MedSIR | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

New Oral Selective Estrogen Receptor Degraders Redefine Management of Estrogen Receptor-Positive Breast Cancer. (PubMed, Annu Rev Med) - "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."

Journal • Review • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

MORPHEUS BC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer (clinicaltrials.gov) - P1/2 | N=510 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2026 ➔ Nov 2027

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER

Transformer-based modeling of Clonal Selection and Expression Dynamics reveals resistance mechanisms in breast cancer. (PubMed, NPJ Syst Biol Appl) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • ER • SNHG5

ERα dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER+ breast cancer. (PubMed, Nat Cancer) - "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."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

EMPRESS: Preoperative Window Opportunity Study with Giredestrant or Tamoxifen in Premenopausal Women with ER+/HER2[-] & Ki67≥10% (clinicaltrials.gov) - P2 | N=92 | Active, not recruiting | Sponsor: MedSIR | Recruiting ➔ Active, not recruiting | Trial primary completion date: Nov 2024 ➔ Feb 2025

Enrollment closed • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

A Study Evaluating the Efficacy and Safety of Giredestrant Combined With Palbociclib Compared With Letrozole Combined With Palbociclib in Participants With Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (persevERA Breast Cancer) (clinicaltrials.gov) - P3 | N=992 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Mar 2025 ➔ Oct 2025

Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

pionERA Breast Cancer: Phase 3 study of first-line giredestrant vs fulvestrant, + a CDK4/6 inhibitor, in patients with estrogen receptor+, HER2- locally advanced/metastatic breast cancer with resistance to prior adjuvant endocrine therapy (SABCS 2024) - "Pts will be randomized 1:1 to receive giredestrant (30 mg orally, once daily) or fulvestrant (500 mg intramuscularly on Days 1 and 15 of Cycle 1 [28-day cycles], then on Day 1 of subsequent cycles), in combination with investigator's choice of CDK4/6i (palbociclib, abemaciclib, or ribociclib administered per local prescribing information), stratified by: prior adj CDK4/6i (yes vs. no); choice of CDK4/6i; ESR1 mutation status by central testing (ESR1 mutated vs. ESR1 no mutation detected [ESR1nmd]); disease site (visceral vs. non-visceral). Reused with permission. This abstract was accepted and previously presented at the 2024 ASCO Annual Meeting."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

A Study to Evaluate the Efficacy and Safety of Giredestrant in Combination With Phesgo (Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf) Versus Phesgo in Participants With Locally Advanced or Metastatic Breast Cancer (heredERA Breast Cancer) (clinicaltrials.gov) - P3 | N=812 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Sep 2032 ➔ Dec 2030 | Trial primary completion date: Aug 2026 ➔ Mar 2027

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

MODULE 5: Oral Selective Estrogen Receptor Degraders (SERDs) for HR-Positive mBC (SABCS 2024) - "This CME symposium is sponsored by Research To Practice, and supported by educational grants from AstraZeneca Pharmaceuticals LP, Eli Lilly, Novartis, and Stemline Therapeutics Inc. Incidence of ESR1 mutations in endocrine-resistant breast cancer; optimal timing and approach to testing Results from the Phase III EMERALD trial evaluating elacestrant versus standard endocrine monotherapy for pretreated HR-positive, HER2-negative mBC; outcomes for patients with and without ESR1 mutations FDA approval of elacestrant for previously treated HR-positive, HER2-negative mBC with ESR1 mutations; optimal incorporation into clinical management algorithms Available findings with other oral SERDs (eg, camizestrant, imlunestrant, giredestrant) alone and in combination with other systemic therapies for HR-positive, HER2-negative mBC Comparative side-effect profiles of approved and investigational oral SERDs; optimal monitoring for and management of AEs Ongoing efforts evaluating oral..."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer. (PubMed, Nat Commun) - "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."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer • ACSL4 • GPX4

EndomERA: A Study of Giredestrant in Participants With Grade 1 Endometrial Cancer (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Endometrial Cancer • Oncology • Solid Tumor

A Study Evaluating the Efficacy and Safety of Giredestrant Plus Everolimus Compared With the Physician's Choice of Endocrine Therapy Plus Everolimus in Participants With Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer (evERA Breast Cancer) (clinicaltrials.gov) - P3 | N=320 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting | Trial primary completion date: Oct 2024 ➔ Mar 2026

Enrollment closed • Metastases • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2