Ribociclib vs. Palbociclib for Breast Cancer

(HARMONIA Trial)

Recruiting at 70 trial locations

Overseen By Juan M Ferrero-Cafiero, PharmD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: SOLTI Breast Cancer Research Group

Must be taking: Endocrine therapy

Must not be taking: CDK4/6 inhibitors

Disqualifiers: Chemotherapy for advanced cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 62 months

456 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Ribociclib or Palbociclib for breast cancer?

Research shows that Ribociclib and Palbociclib are effective in treating hormone receptor-positive, HER2-negative advanced breast cancer. Ribociclib has been reviewed for its safety and efficacy, while Palbociclib, when combined with fulvestrant, improved outcomes in patients with metastatic breast cancer. ^{1 2 3 4 5}

What safety information is available for Ribociclib and Palbociclib in breast cancer treatment?

Ribociclib and Palbociclib are generally considered safe for treating certain types of breast cancer, but they can cause side effects. Common side effects include low white blood cell counts, fatigue, and nausea. These drugs have been studied in various settings, and while they are effective, patients should be monitored for these potential adverse effects. ^{1 6 7 8 9}

How do Ribociclib and Palbociclib differ from other breast cancer drugs?

Ribociclib and Palbociclib are unique because they are oral drugs that inhibit cyclin-dependent kinases 4 and 6, which help control cell division, potentially improving survival and quality of life in patients with hormone receptor-positive, HER2-negative metastatic breast cancer. They are used in combination with endocrine therapy and have different safety and tolerability profiles compared to other similar drugs. ^{1 3 7 10 11}

What is the purpose of this trial?

HARMONIA is an international, multicenter, randomized, open-label and phase III study. The primary objective of this study is to demonstrate that the combination of ribociclib with endocrine therapy (letrozole or fulvestrant) is superior to palbociclib with endocrine therapy (letrozole or fulvestrant) in prolonging progression-free survival in patients with advanced HR+/HER2- and HER2-E breast cancer. The study will enroll approximately 456 patients with HER2-E disease from approximately 95 sites worldwide. In addition, the HARMONIA trial will include an exploratory cohort of patients with HR+/HER2- and Basal-like disease treated with paclitaxel +/- Tislelizumab. This cohort does not have a predefined sample size and the objective is only exploratory, given the suggested lack of efficacy of the combinations of hormone therapy and CDK4/6 inhibitors in this subgroup of patients. Enrolment into the basal-like cohort will stop once the HER2-E disease cohort is fully enrolled.

Research Team

Lisa Carey

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Aleix Prat, MD

Principal Investigator

Hospital Clínic of Barcelona / SOLTI

Dan G Stover, MD

Principal Investigator

Stefanie Spielman Comprehensive Breast Center

Tomás Pascual, MD

Principal Investigator

Hospital Clínic of Barcelona / SOLTI cancer research group

Eligibility Criteria

This trial is for women with advanced HR+/HER2- breast cancer, specifically the HER2-E or Basal-like subtype. They must have a tumor block available for analysis, measurable disease by RECIST v1.1 standards, good blood and organ function, an ECOG status of 0 to 1, and be able to follow the trial procedures. Women who can become pregnant must use effective contraception and not have used CDK4/6 inhibitors or chemotherapy for advanced cancer before.

Inclusion Criteria

Women who could become pregnant need to have a negative pregnancy test within a week before starting the study.

My breast cancer is either HER2-E or Basal-like subtype.

I can carry out all my daily activities without help.

Exclusion Criteria

I have been treated with CDK4/6 inhibitors before.

I have had chemotherapy for advanced breast cancer before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ribociclib or palbociclib in combination with endocrine therapy (letrozole or fulvestrant) to assess progression-free survival

Up to 62 months

Follow-up

Participants are monitored for safety, adverse events, and overall survival after treatment

Up to 62 months

Exploratory Cohort

An exploratory cohort of patients with HR+/HER2- and Basal-like disease treated with paclitaxel +/- Tislelizumab

Treatment Details

Interventions

• Palbociclib
• Ribociclib

Trial Overview The HARMONIA study is testing whether Ribociclib combined with endocrine therapy (Letrozole or Fulvestrant) works better than Palbociclib with the same endocrine therapy in extending progression-free survival in patients with advanced breast cancer within the HER2-E subtype. It's an open-label phase III trial enrolling about 456 patients worldwide.

Participant Groups

Group I: Ribociclib + Endocrine Therapy Experimental Treatment 1 Intervention

Ribociclib + Fulvestrant or Letrozole

Group II: Palbociclib + Endocrine Therapy Experimental Treatment 1 Intervention

Palbociclib + Fulvestrant or Letrozole

Group III: Paclitaxel +/- Tislelizumab - Exploratory cohort Experimental Treatment 1 Intervention

Additional experimental Cohort that includes patients with Basal-Like intrinsic subtype.

Palbociclib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in European Union as Ibrance for:

• HR-positive, HER2-negative locally advanced or metastatic breast cancer

Approved in Canada as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in Japan as Ibrance for:

• HR-positive, HER2-negative advanced or recurrent breast cancer

Who Is Running the Clinical Trial?

SOLTI Breast Cancer Research Group

Lead Sponsor

Trials

44

Recruited

8,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Alliance Foundation Trials, LLC.

Collaborator

Trials

25

Recruited

27,200+

Findings from Research

Ribociclib, a CDK 4/6 inhibitor, significantly improves median progression-free survival (PFS) in women with HR+/HER2- metastatic breast cancer when used in combination with endocrine therapy, with PFS ranging from 8 to 13 months across three phase III trials.

The treatment is well tolerated, particularly in elderly patients, and while it has some dose-limiting toxicities like neutropenia and QTc prolongation, it maintains health-related quality of life and reduces pain scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. Rascon, K., Flajc, G., De Angelis, C., et al.[2020]

In a study of 521 premenopausal and postmenopausal patients with endocrine-resistant metastatic breast cancer, those treated with palbociclib and fulvestrant showed a higher rate of prolonged benefit (29%) compared to those on placebo and fulvestrant (15%).

Long-term responders to palbociclib-fulvestrant tended to have less disease burden at baseline and lower rates of certain mutations, but no specific molecular or clinical factors were identified as predictors of long-term benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in PALOMA-3. Cristofanilli, M., DeMichele, A., Giorgetti, C., et al.[2022]

In a phase II study involving 12 patients with HER2+ metastatic breast cancer and brain metastases, palbociclib combined with trastuzumab showed no significant responses, with the best outcome being stable disease in 6 patients and a median progression-free survival of only 2.2 months.

The study found that patients with stable or responding systemic disease had lower circulating tumor DNA (ctDNA) variant allele fractions and fewer alterations compared to a larger cohort, suggesting that ctDNA levels may correlate with disease progression in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Single-arm Study of Palbociclib in Patients With HER2-positive Breast Cancer With Brain Metastases and Analysis of ctDNA in Patients With Active Brain Metastases. Shah, AN., Santa-Maria, CA., Mukhija, D., et al.[2023]

In a phase II trial involving 71 patients with HER2-positive advanced breast cancer, the combination of palbociclib and trastuzumab showed promising progression-free survival rates, particularly in estrogen receptor-positive patients, with rates of 42.8% and 46.4% for different cohorts.

The treatment was generally safe, but a high incidence of grade 1-2 (97.7%) and grade 3-4 (84.4%) toxicities was observed, with neutropenia being the most common severe side effect, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial. Ciruelos, E., Villagrasa, P., Pascual, T., et al.[2021]

In the FLIPPER trial, the combination of palbociclib and fulvestrant significantly improved progression-free survival (PFS) in postmenopausal women with HR+/HER2- advanced breast cancer compared to placebo and fulvestrant.

Patient-reported outcomes indicated that while global health status and quality of life (QoL) were maintained during treatment with palbociclib/fulvestrant, the time to deterioration in QoL was longer with placebo/fulvestrant, suggesting that palbociclib/fulvestrant is a beneficial treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. Tibau, A., Martínez, MT., Ramos, M., et al.[2023]

In a study of 396 female patients with hormone receptor positive, HER2-negative metastatic breast cancer receiving CDK4 and 6 inhibitors, the most common adverse events were neutropenia, diarrhea, and fatigue, with varying frequencies depending on the specific drug used.

The study found that while the overall incidence of adverse events was lower than in clinical trials, the rates of dose reductions and treatment holds due to these events were higher, suggesting that clinicians may be actively managing side effects to help patients continue their therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting. Price, GL., Sudharshan, L., Ryan, P., et al.[2022]

Palbociclib, ribociclib, and abemaciclib have similar efficacy in treating hormone-receptor positive, HER2 negative metastatic breast cancer, as shown in a review of 8 trials involving 2799 patients.

However, safety profiles differ: ribociclib and abemaciclib have lower rates of severe neutropenia compared to palbociclib, but abemaciclib is associated with higher gastrointestinal toxicity and treatment discontinuation rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis. Desnoyers, A., Nadler, MB., Kumar, V., et al.[2020]

In a study of 160 older patients (≥65 years) with metastatic breast cancer, neutropenia was the most common reason for dose modifications of palbociclib (97%) and ribociclib (69%), highlighting the importance of monitoring blood cell counts during treatment.

The findings suggest that starting doses of palbociclib and ribociclib can be safely reduced for patients aged 75 years and older or those with an ECOG performance status of ≥2, which may help manage the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PROPSEA, safety evaluation of palbociclib and ribociclib in older patients with breast cancer: A prospective real-world TOG study. Avcı, O., İriağaç, Y., Çavdar, E., et al.[2023]

Palbociclib is a selective inhibitor of CDK4 and CDK6, which are crucial for cell cycle regulation, and has been approved in the US for use with letrozole as a first-line treatment for advanced breast cancer in postmenopausal women.

Ongoing clinical trials are exploring palbociclib's efficacy in various cancer types, including non-small cell lung cancer and other solid tumors, indicating its potential as a versatile treatment option in oncology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib: first global approval. Dhillon, S.[2018]

Palbociclib and Ribociclib, when combined with Letrozole, demonstrated significant improvements in progression-free survival (PFS) for patients with hormone receptor-positive metastatic breast cancer, based on data from major clinical trials.

Despite their efficacy, the combination therapies were not cost-effective in Iran, with incremental cost-effectiveness ratios exceeding the acceptable threshold, making Letrozole monotherapy the most cost-effective option for first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-utility analysis of Palbociclib + letrozole and ribociclib + letrozole versus Letrozole monotherapy in the first-line treatment of metastatic breast cancer in Iran using partitioned survival model. Darvishi, A., Daroudi, R., Fazaeli, AA.[2023]

Ribociclib (RIBO) combined with letrozole (LET) showed a statistically significant improvement in progression-free survival (PFS) compared to letrozole alone, with a hazard ratio of 0.524, indicating it may be a more effective treatment for advanced breast cancer than palbociclib (PALBO) when adjusted for patient characteristics.

While the direct comparison of RIBO and PALBO did not yield statistically significant differences in PFS or overall survival, the results favored RIBO, suggesting it could be a preferable option in hormone receptor-positive, HER2-negative advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect treatment comparison of ribociclib and palbociclib in HR+, HER2- advanced breast cancer. Tremblay, G., Chandiwana, D., Dolph, M., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in PALOMA-3. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

A Phase II Single-arm Study of Palbociclib in Patients With HER2-positive Breast Cancer With Brain Metastases and Analysis of ctDNA in Patients With Active Brain Metastases. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis. [2020]

8. Netherlands pubmed.ncbi.nlm.nih.gov

PROPSEA, safety evaluation of palbociclib and ribociclib in older patients with breast cancer: A prospective real-world TOG study. [2023]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Palbociclib: first global approval. [2018]

10. Germany pubmed.ncbi.nlm.nih.gov

Cost-utility analysis of Palbociclib + letrozole and ribociclib + letrozole versus Letrozole monotherapy in the first-line treatment of metastatic breast cancer in Iran using partitioned survival model. [2023]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect treatment comparison of ribociclib and palbociclib in HR+, HER2- advanced breast cancer. [2022]