Comparative study of ribociclib and palbociclib in patients with advanced hormone receptor-positive/HER2-negative/HER2-Enriched breast cancer - HARMONIA trial

INTERVENTION: Trade Name: KISQALI 200 MG Product Name: Ribociclib Product Code: LEE011 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Ribociclib CAS Number: ‐ Current Sponsor code: LEE011 Other descriptive name: RIBOCICLIB SUCCINATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ Trade Name: IBRANCE 75 MG Product Name: Palbociclib Product Code: PD‐0332991 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Palbociclib CAS Number: ‐ Current Sponsor code: PD‐0332991 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Trade Name: IBRANCE 100 MG Product Name: Palbociclib Product Code: PD‐0332991 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Palbociclib CAS Number: ‐ Current Sponsor code: PD‐0332991 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Trade Name: IBRANCE 125 MG Product Name: Palbociclib Product Code: PD‐0332991 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Palbociclib CAS Number: ‐ Current Sponsor code: PD‐0332991 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 125‐ CONDITION: Patients with advanced hormone receptor‐positive/HER2‐negative/HER2‐Enriched breast cancer Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: To compare PFS of ribociclib plus endocrine therapy over palbociclib plus endocrine therapy with respect to PFS in patients with advanced hormone receptor‐positive, HER2‐negative and HER2‐E breast cancer. Primary end point(s): Progression‐free survival using RECIST 1.1 criteria, as assessed by local radiologists/investigators Secondary Objective: •To compare the two treatment arms with respect to Progression on next‐line therapy (PFS2) in the HER2‐E cohort; •To compare the two treatment arms with respect to overall survival in the HER2‐E cohort; •To evaluate the two treatment arms with respect to overall response rate (ORR) and clinical benefit rate (CBR) in the HER2‐E cohort. ; •To describe time to response and duration of response in each treatment arm in the HER2‐E cohort.; •To evaluate the safety and tolerability of ribociclib and palbociclib in combination with endocrine therapy in the HER2‐E cohort; •To evaluate patient reported outcomes for health‐related quality of life in the two treatment arms of the HER2‐E cohort. Timepoint(s) of evaluation of this end point: Image testing will be done mandatory, every 8 weeks (+/‐ 7 days) for the first 12 months, then every 12 weeks (+/‐ 7 days) SECONDARY OUTCOME: Secondary end point(s): PFS2, defined as the time from randomization to first documented progression on next‐line therapy or death, whichever occurs first; OS ; Overall response and clinical benefit as defined by RECIST 1.1. ; Time to response and duration of response per RECIST 1.1; Occurrence /severity of AEs, laboratory abnormalities, discontinuation rates, dose reductions/interruptions ; ; Time to 10% deterioration in the global health status/QOL scale score of the EORTC QLQ‐C30; Change from baseline in the global health status/QOL scale score of the EORTC QLQ‐C30; Change from baseline in the fatigue scale score of the FACT‐G score of FACIT Fatigue Scale (Version 4) Timepoint(s) of evaluation of this end point: 1.Follow up for PFS2 and OS will be every 6 months; 2.Image testing will be done mandatory, every 8 weeks (+/‐ 7 days) for the first 12 months, then every 12 weeks (+/‐ 7 days); 3.Safety (incidence of AEs) will be monitored continuously, until 30 days after discontinuation; 4.Patient reported outcomes will be done every two cycles for the first 12 months, then every three cycles INCLUSION CRITERIA: 1. Male/female patients =18 years of age 2. HR‐positive and HER2‐negative breast cancer by local testing 3. ECOG performance status of 0 to 1. 4. Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer. 5. Availability of FFPE tumor block for biomarker analysis, obtained during metastatic period. 6. HER2‐E or Basal‐like subtype as per central PAM50 analysis. 7. Measurable disease or non‐measurable (but evaluable), as defined by RECIST v1.1. 8. Adequate hematologic and end‐organ function 9. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures. 10. Women of childbearing potential must have confirmed negative serum pregnancy test. 11. Women of CBP must be willing to use highly effective methods of contraception. 12. Postmenopausal OR Pre/perimenopausal status as defined in protocol 13. Patients must