A Phase Ib/II Multicenter, Open-Label, Randomized Study Evaluating the Safety, Pharmacokinetics, and Activity of GDC-4198 Alone and in Combination With Giredestrant in Comparison With Abemaciclib and Giredestrant in Participants With Locally Advanced or Metastatic Estrogen Receptor-Positive, HER2-Negative Breast Cancer Who Have Previously Progressed During or After a CDK4/6 Inhibitor

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-4198 (also known as RGT-419B; Roche code RO7840734) is an investigational, oral small‑molecule cyclin‑dependent kinase inhibitor being developed for hormone receptor–positive, HER2‑negative (HR+/HER2−) advanced or metastatic breast cancer, including disease that has progressed on prior CDK4/6 inhibitor plus endocrine therapy. Genentech (Roche) acquired Regor Therapeutics Group’s next‑generation CDK inhibitor portfolio, including RGT‑419B, in September 2024 and is sponsoring subsequent development as GDC‑4198/RO7840734. (prnewswire.com)

Mechanism of action

GDC‑4198/RGT‑419B is described as a next‑generation CDK inhibitor with high potency against CDK4, additional activity against CDK2, and relative selectivity versus CDK6. The profile aims to address resistance to approved CDK4/6 inhibitors and potentially reduce hematologic toxicity. (aacrjournals.org)

Efficacy

Early human data (Phase 1a, single‑agent dose‑escalation; interim analysis) in post‑menopausal patients with HR+/HER2− advanced/metastatic breast cancer previously treated with endocrine therapy and at least one CDK4/6 inhibitor reported: - Partial responses in 2 of 7 patients with measurable disease in the first three dose cohorts (25–150 mg once daily), for a 28.6% RECIST v1.1 PR rate; clinical benefit rate 44% at the June 30, 2023 cutoff. (aacrjournals.org)

Press materials summarizing the same study later noted 3 partial responses among 12 treated patients and that 6 patients remained on treatment for more than 24 weeks; these figures should be interpreted as preliminary and derived from company communications. (en.prnasia.com)

No randomized efficacy results are available as of October 7, 2025.

Safety

In the Phase 1a interim analysis, the most common treatment‑emergent adverse events (all causality) were nausea, decreased neutrophils/lymphocytes, and diarrhea. At the data cutoff, no grade ≥3 treatment‑related adverse events, no dose‑limiting toxicities, no ocular toxicity, and no discontinuations due to study drug were reported. (aacrjournals.org)

Company press summaries of the same dataset similarly stated no dose‑limiting toxicities and no discontinuations due to adverse events. (en.prnasia.com)

Clinical development status

• First‑in‑human Phase 1 study (NCT05304962): RGT‑419B as monotherapy and in combination with endocrine therapy in HR+/HER2− advanced or metastatic breast cancer after prior CDK4/6 inhibitor; recruiting/active with sites in the United States. (cdek.pharmacy.purdue.edu)
• Phase Ib/II study (GO46021; NCT07100106): GDC‑4198 alone and with giredestrant versus abemaciclib plus giredestrant in HR+/HER2− locally advanced/metastatic breast cancer post‑CDK4/6 inhibitor; first posted August 3, 2025; recruiting. Primary completion is estimated for July 31, 2030. (ichgcp.net)

Further reading

• First‑in‑human Phase 1a abstract (SABCS 2023; published in Cancer Research 2024): mechanism, preliminary efficacy, and safety details. (aacrjournals.org)
• Acquisition announcement and development handoff to Genentech/Roche. (prnewswire.com)
• Phase 1 trial record (RGT‑419B monotherapy and combos), NCT05304962. (cdek.pharmacy.purdue.edu)
• Phase Ib/II randomized study record, NCT07100106 (GDC‑4198 ± giredestrant vs abemaciclib + giredestrant). (ichgcp.net)

Notes: GDC‑4198, RGT‑419B, and RO7840734 refer to the same program at different sponsors/stages. Data reported to date are early‑phase and subject to change as ongoing trials mature.

Last updated: Oct 2025

Inclusion Criteria:

* Histologically and/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 after treatment with an approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and endocrine therapy (ET) in the locally advanced or metastatic setting.

* Measurable or non-measurable evaluable, disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)

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

* Life expectancy ≥ 6 months

Exclusion Criteria:

* 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.

* Have received more than one-line of therapy for locally advanced or metastatic disease.

* Have received prior chemotherapy for metastatic breast cancer

* 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 (ET) within 7 days prior to initiation of study drug; treatment with fulvestrant or an approved CDK4/6 inhibitor within 21 days prior to initiation of study drug.

* Poor peripheral venous access

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

* History of malignancy within 3 years prior to screening, except for cancer under investigation in this study and malignancies with a negligible risk of metastasis or death.