• Data from two early stage trials show giredestrant’s encouraging anti-tumour effect and tolerable safety profile in both the early and advanced settings
• Further monotherapy data and in combination with a CDK4/6 inhibitor are expected to be presented at upcoming medical meetings later this year
• Comprehensive giredestrant clinical development programme underway, with ongoing enrolment in two phase II studies and one phase III study
• An estimated 1.6 million people are diagnosed with hormone receptor-positive breast cancer every year; more effective and tolerable medicines are needed

Basel, 4 June 2021 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced 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. 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) Annual Meeting, which will be held June 4-8, 2021.

“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 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.

About Roche
Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve people’s lives. The combined strengths of pharmaceuticals and diagnostics, as well as growing capabilities in the area of data-driven medical insights help Roche deliver truly personalised healthcare. Roche is working with partners across the healthcare sector to provide the best care for each person.
Roche is the world’s largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. In recent years, Roche has invested in genomic profiling and real-world data partnerships and has become an industry-leading partner for medical insights.

Founded in 1896, Roche continues to search for better ways to prevent, diagnose and treat diseases and make a sustainable contribution to society. The company also aims to improve patient access to medical innovations by working with all relevant stakeholders. More than thirty medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and cancer medicines. Moreover, for the twelfth consecutive year, Roche has been recognised as one of the most sustainable companies in the Pharmaceuticals Industry by the Dow Jones Sustainability Indices (DJSI).

The Roche Group, headquartered in Basel, Switzerland, is active in over 100 countries and in 2020 employed more than 100,000 people worldwide. In 2020, Roche invested CHF 12.2 billion in R&D and posted sales of CHF 58.3 billion. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com.

All trademarks used or mentioned in this release are protected by law.

References
[1] Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;0:1-41.
[2] Tomas R and Barrios C. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol 2015;7(6):304-20.
[3]Moore HM et al. Evaluation of pharmacodynamic (PD) and biologic activity in a preoperative window-of-opportunity (WOO) study of giredestrant(GDC-9545) in postmenopausal patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2–) operable breast cancer (BC). Presented at ASCO Annual Meeting 2021, June 4-8. Abstract #577.
[4] Jhaveri KL et al. Safety and activity of single-agent giredestrant (GDC-9545) from a phase Ia/b study in patients (pts) with estrogen receptor-positive (ER+), HER2-negative locally advanced/metastatic breast cancer (LA/mBC). Presented at ASCO Annual Meeting 2021, June 4-8. Abstract #1017.
[5] Dustin D, et al. ESR1 mutations in breast cancer. Cancer 2019;125(21):3714-28.
[6] Clinicaltrials.gov. A Study Evaluating the Efficacy, Safety, and Pharmacokinetics of Giredestrant Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer (coopERA Breast Cancer). [Internet; cited 2021 June ]. Available from: https://clinicaltrials.gov/ct2/show/NCT04436744.
[7] Clinicaltrials.gov. A Study Evaluating the Efficacy and Safety of Giredestrant Compared With Physician's Choice of Endocrine Monotherapy in Participants With Previously Treated Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (acelERA Breast Cancer). [Internet; cited 2021 June]. Available from: https://clinicaltrials.gov/ct2/show/NCT04576455.
[8] Clinicaltrials.gov. 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). [Internet; cited 2021 June]. Available from: https://clinicaltrials.gov/ct2/show/NCT04546009.
[9] Zhao M, Ramaswamy B. Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer. World J Clin Oncol 2014;5(3):248-62.
[10] Finitsis D, et al. Interventions to promote adherence to endocrine therapy among breast cancer survivors: A meta-analysis. Psycho-Oncology 2019;28:255-63.
[11] U.S Food and Drug Administration. Fast Track. [Internet; cited 2021 June]. Available from: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track.
[12] Metcalfe C, et al. GDC-9545: A novel ER antagonist and clinical candidate that combines desirable mechanistic and pre-clinical DMPK attributes. Presented at: San Antonio Breast Cancer Symposium; 2018 December 4-8; San Antonio, Texas, USA. Abstract #P5-04-07.
[13] Jhaveri K, et al. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-9545, in postmenopausal women with estrogen receptor-positive (ER+) HER2-negative(HER2-) metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium; 2019 December 10-14; San Antonio, Texas, USA. Abstract #PD7-05.
[14] Lim E, et al. A phase Ib study to evaluate the oral selective estrogen receptor degrader GDC-9545 alone or combined with palbociclib in metastatic ER-positive HER2- negative breast cancer. Presented at: ASCO virtual Meeting; 2020 May 29 – June 30. Abstract #1023.
[15] Clinicaltrials.gov. A Study of Giredestrant (GDC-9545) in Postmenopausal Women With Stage I-III Operable, Estrogen Receptor-Positive Breast Cancer. [Internet; cited 2021 June]. Available from: https://clinicaltrials.gov/ct2/show/NCT03916744.
[16] Clinicaltrials.gov. 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. [Internet; cited 2021 June]. Available from: https://clinicaltrials.gov/ct2/show/NCT03332797.

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