On June 4, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported the presentation of new and updated data on giredestrant (formerly known as GDC-9545), an investigational next generation oral selective oestrogen receptor degrader (SERD), in people with hormone receptor (HR)-positive, HER2-negative breast cancer (Press release, Hoffmann-La Roche, JUN 4, 2021, View Source [SID1234583529]). Breast cancer is now the most common cancer in the world, with HR-positive being the most common subtype representing 70% of cases.1,2 Data from these studies will be presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which will be held June 4-8, 2021.

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"We’re encouraged by the results of these ongoing giredestrant studies which form part of a comprehensive clinical development programme in HR-positive breast cancer," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "Prolonged treatment durations and risk of relapse can represent significant challenges for patients, therefore a need remains for more effective and tolerable treatment options."

The data from two phase I studies presented at ASCO (Free ASCO Whitepaper) show giredestrant’s promising clinical activity and safety profile in HR-positive, HER2-negative breast cancer:

NCT03916744: Interim analysis of this window of opportunity study in the post-menopausal, neoadjuvant (preoperative) setting showed giredestrant’s consistent and compelling activity.3

The pharmacodynamic effect of giredestrant was assessed using the Ki67 proliferation biomarker, which indicates the ability of a therapy to suppress tumour growth.
Giredestrant showed promising impact on tumour cell proliferation after ~14 days of treatment; a mean reduction of Ki67 of 78% (95% CI:72-83); 55% of tumours exhibited complete cell cycle arrest defined as Ki67 ≤2.7%.
The safety profile of giredestrant in the neoadjuvant setting was consistent with its mechanism of action and there were no discontinuations due to adverse events (AEs).

NCT03332797: Updated data from this phase I study in the locally advanced/metastatic breast cancer setting showed that giredestrant as a monotherapy was well-tolerated, and had promising clinical activity, irrespective of the type of prior therapy or the presence of ESR1 mutations (mutations in the ESR1 gene are important mechanisms of resistance to hormone therapy).4,5

At 30mg, a 20% overall response rate was seen in patients with measurable disease at baseline, and clinical benefit rates of 55% and 76% were observed in the overall and ESR1 mutant subgroups, respectively.
Giredestrant showed notable activity in the ESR1 mutant subgroup indicating that giredestrant overcomes ESR1 mutations.
Giredestrant was well-tolerated at all doses (10–250mg); there were no dose limiting toxicities with giredestrant monotherapy; AEs were generally low grade.
A standardised once-daily 30mg dose has been selected for the giredestrant development programme, both as a monotherapy and in combination studies.

We are currently enrolling patients into two phase II studies (CoopERA and AcelERA) evaluating giredestrant in neoadjuvant oestrogen receptor (ER)-positive early breast cancer, and previously treated locally advanced or metastatic breast cancer respectively, as well as one phase III study (PersevERA), evaluating giredestrant plus palbociclib against letrozole plus palbociclib in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer.6,7,8

The mainstay of treatment is to block oestrogen, but the side effects of this have a very significant impact on quality of life and can greatly affect treatment adherence.9,10 With giredestrant, we are striving to provide a more tailored, more effective and less debilitating treatment for HR-positive breast cancer.

Giredestrant received U.S. Food and Drug Administration (FDA) Fast Track Designation (FTD) for ER-positive, HER2-negative, second and third-line metastatic breast cancer on 15 December 2020. A FTD is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.11

About giredestrant
Giredestrant is a next generation investigational SERD, designed to fully block ER signalling with robust receptor occupancy. Oestrogen encourages HR-positive breast cancer cells to grow by attaching to the ER. Giredestrant works by blocking this receptor to prevent the action of oestrogen, and in the process causes the receptor to be degraded. This investigational medicine has also shown efficacy regardless of ESR1 mutation status (mutations in the ESR1 gene are important mechanisms of resistance to hormone therapy).5,9,12,13

Orally given, giredestrant delivers a strong clinical efficacy and safety profile and has shown superior pre-clinical potency over other SERDs in development.12,14 The oral administration of giredestrant has the potential to transform the treatment experience for patients, offering greater convenience and a less painful option compared to therapies administered via intramuscular injection.

Giredestrant has a comprehensive development programme across a broad range of settings and treatment combinations for patients with HR-positive, HER2-negative breast cancer. A standardised once-daily 30mg dose has been selected for the giredestrant development programme, both as a monotherapy and in combination studies.

About NCT0391674415
An open-label, short-term window study due to explore the safety, pharmacokinetics, pharmacodynamics, and activity of giredestrant in around 75 post-menopausal women with untreated stage I-III ER-positive/HER2-negative early breast cancer. The primary endpoint of the study will be the change in Ki67 scores (a measure of how quickly cancer cells are proliferating) between biopsies taken before and after treatment. Secondary endpoints include safety outcomes and plasma concentration of giredestrant.

About NCT0333279716
An ongoing phase Ia/b first-in-human, multi-centre, open-label, dose escalation, dose expansion study. The study is exploring the safety, pharmacokinetics, pharmacodynamics, and activity of giredestrant as a single agent, and in combination with palbociclib and/or luteinizing hormone-releasing hormone agonist, in 181 people with locally advanced or metastatic ER-positive/HER2-negative breast cancer. Primary endpoints of the study include the maximum tolerated dose of giredestrant and as well as safety outcomes. Secondary endpoints include plasma concentration levels of giredestrant and palbociclib over time, objective response rate, clinical benefit rate and duration of response.