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CTRI Number  CTRI/2024/03/064777 [Registered on: 26/03/2024] Trial Registered Prospectively
Last Modified On: 22/06/2026
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study   Efficacy and safety of Giredestrant, in patients with advanced breast cancer 
Scientific Title of Study
Modification(s)  		 A phase III, randomized, open-label study evaluating efficacy and safety of Giredestrant compared with Fulvestrant, both combined with a CDK4/6 inhibitor, in patients with estrogen receptor-positive, HER2-negative advanced breast cancer with resistance to prior adjuvant endocrine therapy 
Trial Acronym  PionERA 
Secondary IDs if Any
Modification(s)  
Secondary ID  Identifier 
CO44657_Version 3 dated 06 Sep 2024  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query
Modification(s)  
Name  Dr Jyotii Poddaar 
Designation  Lead- Clinical Operations 
Affiliation  Roche Products India Private Limited 
Address  Roche Products (India) Pvt. Ltd. 146-B, 166 A, Unit No. 7, 8, 9 8th Floor, R City Office, R City Mall

Mumbai
MAHARASHTRA
400086
India 
Phone  9136064373  
Fax    
Email  jyotii.poddaar@roche.com  
 
Details of Contact Person
Public Query
Modification(s)  
Name  Heta Khokhani 
Designation  Manager-Clinical Operations 
Affiliation  Roche Products India Private Limited 
Address  Roche Products (India) Pvt. Ltd. 146-B, 166 A, Unit No. 7, 8, 9 8th Floor, R City Office, R City Mall

Mumbai
MAHARASHTRA
400086
India 
Phone  9892440927  
Fax    
Email  heta.khokhani@roche.com  
 
Source of Monetary or Material Support  
F Hoffmann La Roche Ltd, CH-4070, Basel, Switzerland 
 
Primary Sponsor  
Name  F Hoffmann La Roche Ltd 
Address  Grenzacherstrasse 124, CH-4070 Basel, Switzerland 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
Roche Products India Pvt Ltd  146-B, 166 A, Unit No. 7, 8, 9, 8th Floor, R City Office, R City Mall Lal Bahadur Shastri Marg, Ghatkopar, Mumbai 
 
Countries of Recruitment     Argentina
Australia
Austria
Belgium
Brazil
Canada
Chile
China
Colombia
Costa Rica
Finland
France
Germany
Greece
Guatemala
Hong Kong
Hungary
India
Israel
Italy
Kenya
Mexico
New Zealand
Peru
Poland
Portugal
Romania
Singapore
Slovenia
South Africa
Spain
Taiwan
Thailand
Turkey
United Kingdom
United States of America
Other  
Sites of Study
Modification(s)  
No of Sites = 7  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Minish Jain   Grant Medical Foundation, Ruby Hall Clinic   40, Sassoon Raod, Pune- 411001
Pune
MAHARASHTRA 		 91

minishjainresearch009@gmail.com 
Dr Satheesh CT  HealthCare Global Enterprises Limited  #8, P.Kalinga Rao Road, HCG Towers, Sampangi Ram Nagar, Bangalore, 560027
Bangalore
KARNATAKA 		 91

drsatheeshct@gmail.com 
Dr Narayanankutty Warrier  MVR Cancer Centre and Research Institute   Vellalasseri, Chuloor, Near NIT, Chathamangalam, Pin 673601, Kozhikode
Kozhikode
KERALA 		 91

drnkwarrier@mvrccri.co 
Dr Rona Joseph P  Regional Cancer Centre  Medical College PO, Trivandrum, Kerala
Thiruvananthapuram
KERALA 		 91

ronsjsph@gmail.com 
Dr Tushar Patil  Sahyadri Hospitals Pvt Ltd.  33/34B, Makarand Bhave Path, Erandwane, Pune-411004. Maharashtra, India
Pune
MAHARASHTRA 		 9552522556

tussipats@hotmail.com 
Dr Sewanti Limaye  Sir HN Reliance Foundation Hospital and Research Centre  Prarthana Samaj, Raja Rammohan Roy Rd, Girgaon, Mumbai, Maharashtra 400004
Mumbai
MAHARASHTRA 		 91

sewanti.limaye@rfhospital.org 
Dr Vijay Patil  Sunact Cancer Institute  Sunact Cancer Institute, 4th floor, Tieten Medicity Hospital, Kasarvadavali, Ghodbunder Road, Thane West – 400 615
Thane
MAHARASHTRA 		 9136129135

vijaypgi@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 7  
Name of Committee  Approval Status 
HCG Central Ethics Committee  Approved 
Human Ethics Committee, RCC   Approved 
IEC of Sir H N Reliance Foundation Hospital and RC   Approved 
Institutional Ethics Committee, MVR Cancer Centre  Approved 
Poona Medical Research Foundation  Approved 
Sahyadri Hospitals Ltd. Ethics committee  Approved 
Vedant Hospital Institutional Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI
Modification(s)  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: C509||Malignant neoplasm of breast of unspecified site,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Fulvestrant  Participants in the control arm will receive intramuscular (IM) fulvestrant 500 mg IM on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle. 
Intervention  Giredestrant  Participants in the experimental arm will receive giredestrant 30 mg orally (PO) once a day (QD) on Days 1−28 of each 28-day cycle 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Female 
Details  1. Signed Informed Consent Form
2. Age more than or equal to 18 years.
3. Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent.
4. Documented ER plus tumor according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or ESMO guidelines or any national guidelines with criteria conforming to ASCO/CAP or ESMO guidelines, defined as more than or equal to 1 percent of tumor cells stained positive, assessed locally based on the most recent tumor biopsy (or archived tumor sample)
5. Documented HER2 tumor according to ASCO/CAP or ESMO guidelines or any national guidelines with criteria conforming to ASCO/CAP or ESMO guidelines, assessed locally based on the most recent tumor biopsy (or archived tumor sample)
6. Confirmed ESR1 mutation status (mutation detected [ESR1m] vs. no mutation detected [ESR1nmd]) in baseline ctDNA, as assessed through central lab testing of a blood sample freshly collected at screening, using the investigational FMI F1LCDx assay. A valid central testing result using investigational F1LCDx is always required; in localities where FMI central testing is not available, samples will be submitted to an alternative, Sponsor-designated central laboratory. Participants without a valid ESR1 mutation status central result (i.e., unknown ESR1 mutation status that cannot be classified as ESR1m or ESR1nmd) are not eligible. Eligible ESR1 mutations are defined as short variants known to affect protein function occurring within amino acids 310 to 547.
7. Consent to provide and confirmed availability of the most recently collected and representative tumor tissue specimen suitable for biomarker testing with associated pathology (i.e., archived formalin-fixed paraffin-embedded tissue block [preferred] or 15 to 20 slides containing unstained, freshly cut, serial sections).
8. Participants who have relapsed with prior standard adjuvant ET with an AI (i.e., anastrozole, letrozole, or exemestane) and/or a SERM (i.e., tamoxifenor toremifene), on-treatment after more than or equal to 12 months or off-treatment within 12 months of completion (i.e., treatment-free interval less than 12 months). If neo/adjuvant ET included a CDK4/6i, relapse should have occurred more than or equal to 12 months since completion of CDK4/6i treatment.
9. No history of systemic anti-cancer therapy for locally advanced or metastatic disease.
10. Measurable disease as defined per RECIST v.1.1 or non-measurable bone-only disease which must be evaluable defined as having at least one predominantly lytic bone lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) which can be followed (soft tissue component not required). Tumor lesions previously irradiated or subjected to other locoregional therapy will be deemed measurable only if disease progression at the treated site after completion of therapy is clearly documented.
11. Considered appropriate for treatment with ET (e.g., CDK4/6i in combination with fulvestrant) at time of entry into the study, recommended as per national or local treatment guidelines
12. Life expectancy of more than 6 months
13. ECOG Performance Status 0 to 1
14. Adequate organ function as defined by the following criteria: ANC more than or equal to 1.5x10 to the power of 9/L (1500/microL); Platelet count more than or equal to 100x10 to the power of 9/L (100,000/microL); Hemoglobin more than or equal to 90g/L (9g/dL). The blood counts are to meet the specified criteria without transfusion or growth factor support, unless it is clear that the bone marrow function is adequate and that any aberration has a clear and correctable cause, and the correction undertaken. AST and serum ALT less than or equal to 3xupper limit of normal (ULN); for participants with liver metastases: AST and ALT less than or equal to 5xULN. Serum bilirubin less than or equal to 1.5xULN; for patients with Gilbert syndrome: less than or equal to 3xULN. Estimated creatinine clearance more than or equal to 30 mL/min as calculated per institutional guidelines.
15. INR (or PT) less than 1.5x ULN and PTT (or aPTT) less than 1.5x ULN (except for participants receiving anticoagulation therapy). For participants receiving warfarin, a stable INR between 2 and 3 is required. For participants receiving heparin, PTT (or aPTT) between 1.5 and 2.5xULN (or patients va 
 
ExclusionCriteria 
Details  1. Disease recurrence during the first 12 months of adjuvant ET.
2. Prior systemic therapy for metastatic breast cancer eg prior chemotherapy immunotherapy or biologic therapy for locally advanced unresectable or metastatic disease.
3. Prior treatment with a SERD eg fulvestrant novel oral proteolysis targeting chimera complete ER antagonist CERAN or novel SERM other than tamoxifen toremifene.
4. Treatment with any investigational therapy within 28 days prior to randomization or within 5 half lives of the investigational drugs whichever is longer.
5. Radiotherapy or any other anti cancer therapy within 2 weeks before randomization. Participants who received prior radiotherapy to more than or equal to 25 percentage of bone marrow or hematopoietic stem cell or bone marrow transplantation are not eligible regardless of when.
6. Major surgical procedure or significant traumatic injury within 28 days prior to randomization. Anticipation of need for a major surgical procedure during the course of the study.
7. Exposure to strong CYP3A4 inhibitors strong CYP3A4 inducers and moderate CYP3A inducers for participants who will receive abemaciclib only within 14 days or 5 drug elimination half lives whichever is longer prior to initiation of study treatment.
8. Advanced symptomatic, visceral spread that is at risk of life threatening complications in the short term including massive uncontrolled effusions pleural pericardial peritoneal or pulmonary lymphangitis appropriate for treatment with cytotoxic chemotherapy at time of entry into the study as per national or local treatment guidelines.
9. History of other malignancy within 5 years prior to screening except for cancers with very low risk of recurrence including but not limited to appropriately treated carcinoma in situ of the cervix non melanoma skin carcinoma papillary thyroid cancer treated with surgery or Stage I endometrial cancer.
10. Known active uncontrolled or symptomatic CNS metastases carcinomatous meningitis or leptomeningeal disease. Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy eg radiotherapy surgery are clinically stable and have not been treated with anticonvulsants or corticosteroids within 2 weeks prior to randomization.
11. Active cardiac disease or history of cardiac dysfunction including any of the following History within 2 years of screening or presence of idiopathic symptomatic bradycardia or resting heart rate less than 50 bpm at screening. Patients on stable dose of a beta blocker or calcium channel antagonist for preexisting baseline conditions eg hypertension may be eligible if resting heart rate is at least 50 bpm. History of angina pectoris or symptomatic coronary heart disease within 12 months prior to study entry. History of documented congestive heart failure New York Heart Association Class III to IV or cardiomyopathy. QT interval based on mean value of triplicate ECGs corrected through use of Fridericias formula QTcF. More than 470 ms for female participants intended to be treated with palbociclib or abemaciclib. More than 450 ms for male participants intended to be treated with any CDK4 6i and for female participants intended to be treated with ribociclib. History of long or short QT syndrome Brugada syndrome or known history of corrected QT interval prolongation or torsades de pointes. Presence of an abnormal ECG that is clinically significant in the investigators opinion including complete left bundle branch block second or third degree heart block sick sinus syndrome. Participants with first degree heart block may be eligible following consultation with a cardiologist and determination that no additional cardiac risks are present. Participants with pacemakers to treat more severe heart blocks and other arrhythmias are eligible. Participants with history of well controlled atrial fibrillation are eligible. History within 12 months of screening or presence of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as significant structural heart disease eg severe left ventricular systolic dysfunction restrictive cardiomyopathy, hypertrophic cardiomyopathy infiltrative cardiomyopathy moderate to severe valve disease or family history of long QT syndrome. Clinically significant electrolyte abnormalities eg hypokalemia hypomagnesemia hypocalcemia should be corrected prior to enrollment.
12. Clinically significant history of liver disease consistent with Child Pugh Class B or C including active viral infection or other hepatitis eg hepatitis B virus HBV or hepatitis C virus HCV current alcohol abuse or cirrhosis or positive test for viral hepatitis.
13. Known HIV infection. Screening HIV test should be performed as allowed per local regulations.
14. Serious infection requiring oral or IV antibiotics or other clinically significant infection within 14 days prior to randomization. Participants who fully recovered from serious or clinically significant infections at least 14 days prior to randomization are eligible.
15. Active inflammatory bowel disease, chronic diarrhea short bowel syndrome or major upper gastrointestinal GI surgery including gastric resection potentially affecting enteral absorption or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea.
16. Malabsorption syndrome or other condition that would interfere with enteral absorption.
17. Inability or unwillingness to swallow pills or receive IM injections.
18. Any serious medical condition or abnormality in clinical laboratory tests that in the investigators judgment precludes the individuals safe participation in and completion of the study.
19. Known allergy or hypersensitivity to any of the study drugs or any of their excipients.
20. For pre or perimenopausal female or male participants known hypersensitivity to LHRH agonists or any of their excipients.
21. Pregnancy or breastfeeding or intention of becoming pregnant during the study or within 98 days after the final dose of study treatment based on local prescribing information for fulvestrant patients may be advised to use an effective means of contraception for up to 2 years after the last dose of fulvestrant. Female participants of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment. 
 
Method of Generating Random Sequence   Stratified randomization 
Method of Concealment   Not Applicable 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
To evaluate the efficacy of
giredestrant compared with
fulvestrant (both combined with CDK4/6i) in the ESR1m subgroup and FAS 		 PFS, defined as time from randomization to first
occurrence of Progressive disease, as determined by the investigator according to RECIST v1.1, or death from any cause during the study whichever occurs first.  
 
Secondary Outcome  
Outcome  TimePoints 
To evaluate the efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the ESR1nmd subgroup  Progression free survival, defined as time from randomization to first occurrence of progressive disease, as determined by the
investigator according to RECIST v1.1, or death from any cause during the study (whichever occurs first) 
To evaluate efficacy of giredestrant compared with fulvestrant (both combined with CDK4 or 6i) in the in ESR1m & ESR1nmd, subgroups & in the FAS  Overall Survival (OS), defined as the time from randomization to
death from any cause
 
To evaluate the efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the ESR1m, ESR1nmd subgroups & in the FAS  Confirmed objective response rate is the proportion of participants with a complete response (CR) or partial response (PR) on two consecutive occasions more than or equal to 4 weeks apart 
To evaluate the safety of giredestrant compared with fulvestrant in the FAS, and in the choice of CDK4/6i subgroups  Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0. Change from baseline in selected vital signs and in clinical laboratory test results

 
To evaluate efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the in ESR1m & ESR1nmd, subgroups & in the FAS  Duration of Response is from the first occurrence of a documented objective response to PD  
To evaluate efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the in ESR1m & ESR1nmd, subgroups & in the FAS  Clinical Benefit Rate is from the first occurrence of a documented objective response to PD, as determined by the investigator according to RECIST v1.1 
To evaluate the efficacy of giredestrant compared with fulvestrant (both combined with
CDK4/6i) in the ESR1m & ESR1nmd subgroups & in the FAS 		 Time to Chemotherapy is time from randomization until the start date of chemotherapy or death from any cause, whichever occurs first 
To evaluate the efficacy of giredestrant compared with
fulvestrant (both combined with CDK4/6i) in the ESR1m &
ESR1nmd subgroups & in the FAS 		 Time to confirmed deterioration (TTCD) in pain severity, time from randomization to the first documentation of a more than or equal to 2 point increase from baseline on the worst pain item score from the BPI-SF held for two consecutive timepoints, or a more than or equal to 2 point increase followed by death attributable to cancer progression with 28 days from the last assessment 
To evaluate the efficacy of
giredestrant compared with
fulvestrant (both combined with
CDK4/6i) in the ESR1m &
ESR1nmd subgroups & in the
FAS 		 Time to confirmed deterioration (TTCD) in pain presence & interference, time from randomization to the first documentation of a more than or equal to 10 point increase from baseline in the EORTC QLQ C30 linearly transformed pain scale score held for two consecutive timepoints, or a more than or equal to 10 point increase followed by death attributable to cancer progression with 28 days from the last assessment 
To evaluate the efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the ESR1m & ESR1nmd subgroups & in the FAS  Time to confirmed deterioration in physical functioning, role functioning & global health status or QoL, from randomization to the first documentation of a more than or equal to 10 point decrease from baseline in the EORTC QLQ C30 linearly transformed PF scale score, RF scale score or GHS or QoL scale score, respectively, held for two consecutive timepoints, or a more than or equal to 10 point decrease followed by death attributable to cancer progression with 28 days from the last assessment.  
 
Target Sample Size   Total Sample Size="1050"
Sample Size from India="15" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   15/05/2024 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  11/12/2023 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="3"
Months="3"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Open to Recruitment 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   N/A 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary   The proposed Phase III study is designed to demonstrate a statistically significant and clinically meaningful progressionfree survival (PFS) benefit of giredestrant compared with fulvestrant, each combined with the investigator’s choice of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) between palbociclib, abemaciclib and ribociclib, as first-line (1L) treatment of estrogen receptorpositive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC) resistant to adjuvant endocrine therapy (ET), a patient group considered to have a particularly high unmet need.
Available data support that giredestrant can provide meaningful clinical benefit to patients with ER+ HER2- aBC resistant to prior adjuvant ET. In the mBC setting, giredestrant demonstrated clinical efficacy in terms of clinical benefit rate (CBR), objective response rate (ORR) and duration of response (DOR) both as single agent (GO39932, WO42312/acelERA BC) and in combination with the CDK4/6i palbociclib (GO39932), as well as a favorable trend in PFS versus AI/fulvestrant which was more pronounced in patients with ESR1m tumors (WO42312/acelERA BC, Martin Jimenez et al. 2022).
 
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