A Phase Ia/Ib Dose-Escalation and Expansion Study Evaluating the Safety, Pharmacokinetics, and Activity of GDC-0587 as a Monotherapy and in Combination With Giredestrant in Patients With Locally Advanced Or Metastatic ER-Positive, HER2-Negative Breast Cancer Who Have Previously Progressed During or After CDK4/6 Inhibitor Therapy

This is a first-in-human, Phase Ia/Ib, dose-escalation and expansion study evaluating the safety, pharmacokinetics, and activity of GDC-0587 (cyclin-dependent kinase-4 \[CDK4\] inhibitor) as a monotherapy and in combination with giredestrant in participants with locally advanced or metastatic estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer who have previously progressed during or after CDK 4/6 inhibitor therapy.

Overview

Giredestrant (GDC‑9545) is an investigational, oral selective estrogen receptor degrader (SERD) and full ER antagonist being developed for ER‑positive/HER2‑negative breast cancer across early and advanced disease settings. It has shown antiproliferative activity in neoadjuvant early breast cancer and has mixed results in metastatic disease to date, including one negative phase II trial versus physician’s‑choice endocrine therapy and a positive phase III combination trial reported by press release in the post‑CDK4/6 inhibitor setting. (pubs.acs.org)

Mechanism of action

• Potent, non‑steroidal oral SERD that competitively binds ERα, induces receptor degradation via the proteasome, and fully antagonizes ER signaling, leading to suppression of ER‑dependent transcription and tumor cell proliferation. Preclinical studies showed activity in both ESR1 wild‑type and ESR1‑mutant models. (pubs.acs.org)

Efficacy

Early breast cancer (neoadjuvant, coopERA BC; phase II) - In a randomized neoadjuvant study (n=221), giredestrant produced a greater relative geometric mean reduction in Ki‑67 at 2 weeks than anastrozole (−75% vs −67%; p=0.043). With added palbociclib for 16 weeks, Ki‑67 suppression at surgery remained greater (−81% vs −74%), while objective response rates were similar (50% vs 49%); pathologic complete response was ~4–5% in both arms. (thelancet.com)

Previously treated advanced/metastatic disease (acelERA BC; phase II) - Randomized, open‑label study (n=303) comparing giredestrant vs physician’s‑choice endocrine therapy (mostly fulvestrant) did not meet the primary endpoint: investigator‑assessed PFS HR 0.81 (95% CI, 0.60–1.10; P=0.176); median PFS 5.6 vs 5.4 months. Prespecified subgroup analysis suggested a larger, non‑significant effect in ESR1‑mutated tumors (HR 0.60; 95% CI, 0.35–1.03). (ascopubs.org)

Post‑CDK4/6 inhibitor advanced/metastatic disease (evERA BC; phase III, combination with everolimus) - Company press release (Sept 22, 2025) reported evERA met both co‑primary endpoints, with statistically significant and clinically meaningful PFS improvement for giredestrant + everolimus vs standard endocrine therapy + everolimus in the intention‑to‑treat and ESR1‑mutated populations; OS data immature. Full peer‑reviewed results are pending. (globenewswire.com)

Other ongoing phase III programs - First‑line metastatic with palbociclib (persevERA; NCT04546009) and adjuvant early disease (lidERA; NCT04961996) are ongoing; results not yet published in peer‑reviewed venues as of October 7, 2025. (inclinicaltrials.com)

Safety

• Across studies to date, giredestrant has been generally well tolerated with a safety profile comparable to endocrine therapy controls.
• In acelERA BC (phase II), treatment‑related grade 3–4 AEs occurred in 4.0% with giredestrant vs 2.6% with control; treatment‑related serious AEs 2.0% vs 0.7%; discontinuations due to AEs 1.3% vs 2.0%. (ascopost.com)
• In coopERA BC, endocrine therapy–related AEs and grade ≥3 events were similar between giredestrant and anastrozole arms (both 6% grade ≥3 in final analysis). Patient‑reported outcomes showed manageable symptom burden. (ascopubs.org)
• Phase Ib experience (monotherapy and with palbociclib) described giredestrant as well‑tolerated; common AEs (≥10%) with monotherapy included fatigue, cough, back pain, pain in extremity, and arthralgia. (ascopubs.org)
• Press release for evERA reported the combination with everolimus was well tolerated with no new safety signals; detailed rates await full presentation/publication. (globenewswire.com)

Further reading

• Journal of Medicinal Chemistry paper describing discovery and preclinical profile of giredestrant. (pubs.acs.org)
• Lancet Oncology publication of coopERA BC neoadjuvant trial. (thelancet.com)
• Journal of Clinical Oncology publication of the phase II acelERA BC trial. (ascopubs.org)
• ASCO Meeting Abstracts for coopERA BC final analysis and PROs. (ascopubs.org)
• Phase Ib combination/monotherapy experience (ASCO abstract). (ascopubs.org)
• Company press release summarizing positive phase III evERA results (pending peer‑reviewed presentation). (globenewswire.com)

Notes: Giredestrant remains investigational; no regulatory approvals are documented as of October 7, 2025. Where only press releases are available (evERA), conclusions should be considered preliminary until peer‑reviewed data are published. (globenewswire.com)

Last updated: Oct 2025

Overview

GDC-0587 (also reported as RGT-587 and RO7840736) is an investigational oral cyclin-dependent kinase 4 (CDK4) inhibitor being studied by Genentech/Roche for locally advanced or metastatic ER-positive/HER2-negative breast cancer after progression on prior CDK4/6 inhibitor therapy. (ichgcp.net)

As of the latest public trial registry updates (last updated December 19, 2025), no human efficacy or safety results have been posted for GDC-0587. (ichgcp.net)

Mechanism of action

• Target: CDK4 (ichgcp.net)
• Mechanism: small-molecule CDK4 inhibitor (cell-cycle targeted therapy intended to inhibit CDK4-mediated phosphorylation events that promote G1→S progression). (ichgcp.net)

Efficacy

• No clinical response data (e.g., ORR, CBR, PFS) have been publicly reported for GDC-0587 as of January 14, 2026.
• The ongoing first-in-human study includes activity assessments, but results are not yet available. (ichgcp.net)

Safety

• No human safety/tolerability results have been publicly reported for GDC-0587 as of January 14, 2026.
• The first-in-human trial is designed to evaluate safety and dose-limiting toxicities, but outcomes have not been posted. (ichgcp.net)

Clinical development (selected)

• NCT07214662 / GO46057 (Phase Ia/Ib; first-in-human): dose-escalation/expansion of GDC-0587 monotherapy, and GDC-0587 + giredestrant, with additional cohorts evaluating food effect and proton pump inhibitor (omeprazole) effect on exposure. Estimated enrollment 136; estimated study start December 15, 2025; status listed as not yet recruiting in the latest update. (ichgcp.net)

Further reading

• ClinicalTrials.gov record via ICH GCP mirror (NCT07214662) (ichgcp.net)
• Roche “ForPatients” trial listing (GDC-0587 in ER+/HER2- breast cancer) (forpatients.roche.com)
• Trial record summary with arm descriptions and alternate names (NCT07214662) (meddatax.com)

Last updated: Jan 2026

Inclusion Criteria:

* Agreement to adhere to the contraception requirements

* For females of childbearing potential ≤60 years of age and males: treatment with luteinizing hormone-releasing hormone (LHRH) agonist therapy beginning at least 2 weeks prior to Cycle 1, Day 1 and agreement to continue LHRH agonist therapy for the duration of the study

* Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic

* Previously documented ER+ and HER2- tumor according to American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) or European Society of Medical Oncology (ESMO) guidelines or any national guidelines with criteria conforming to ASCO/CAP or ESMO guidelines

* Disease progression during or following treatment with an approved CDK 4/6 inhibitor, with or without endocrine therapy, in the locally advanced or metastatic setting

* Measurable, or non-measurable but evaluable, disease per RECIST v1.1

* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

* Life expectancy ≥6 months

* Creatinine clearance ≥60 milliliter per minute (mL/min) (calculated through use of the Cockcroft-Gault formula)

Exclusion Criteria:

* Pregnant or breastfeeding, or intention of becoming pregnant during the study

* Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term appropriate for treatment with cytotoxic chemotherapy at time of entry into the study, as per national or local treatment guidelines

* Five or more prior lines of systemic therapy in the locally advanced or metastatic setting

* Treatment with anti-cancer therapies, including investigational therapies, within 28 days or 5 drug elimination half-lives, whichever is shorter, prior to initiation of study drug

* Treatment with an approved oral endocrine therapy within 7 days prior to initiation of study drug or treatment with fulvestrant or an approved/investigational CDK inhibitor within 21 days prior to initiation of study drug

* History of Grade ≥3 adverse event attributed to prior CDK inhibitor therapy that resulted in permanent discontinuation of prior CDK inhibitor therapy

* Poor peripheral venous access

* Malabsorption condition or other gastrointestinal (GI) conditions/surgeries that the investigator assesses may significantly interfere with enteral absorption

* Major surgical procedure within 28 days prior to initiation of study drug

* Untreated, active CNS metastases

* Infection requiring systemic (i.e., oral, IV, or intramuscular) antibiotics, chronic infection requiring treatment within 1 year prior to screening, or any evidence of current infection

* History of malignancy within 3 years prior to screening, except for cancer under investigation in this study

* Known history of a clinically significant abnormal ECG