Ribociclib vs. Palbociclib for Breast Cancer

(HARMONIA Trial)

Not currently recruiting at 80 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining ribociclib (Kisqali) with hormone therapy is more effective than palbociclib (Ibrance) with hormone therapy in slowing advanced breast cancer that is HR+/HER2- and HER2-E. It seeks participants with this specific type of breast cancer who have not previously used CDK4/6 inhibitors. An exploratory part of the trial involves those with the basal-like subtype, testing paclitaxel with or without Tislelizumab. Participants should have breast cancer that has spread or cannot be cured with surgery and must be willing to follow the trial's schedule and procedures. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ribociclib, when combined with hormone therapy, is generally well-tolerated by patients. Although some side effects may occur, they are usually manageable and reversible through dose adjustments, allowing patients to continue treatment longer. Ribociclib effectively treats advanced breast cancer and suits various age groups.

Long-term research indicates that palbociclib remains safe when used with hormone therapy, making it a reliable option for patients with hormone receptor-positive breast cancer. Some side effects, such as a low white blood cell count, have been observed. However, these side effects are known and generally do not outweigh the benefits for most patients.

Both treatments have undergone thorough study in breast cancer patients and have their own potential side effects. Overall, they are considered safe and effective for treating advanced breast cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Ribociclib and Palbociclib for breast cancer because these treatments offer a targeted approach by inhibiting specific proteins, CDK4 and CDK6, which play a crucial role in cell division. Unlike traditional chemotherapy, which can affect both healthy and cancerous cells, these drugs specifically target cancer cell growth. This means potentially fewer side effects and a more personalized treatment for patients with hormone receptor-positive breast cancers. Additionally, when combined with endocrine therapy, these drugs have shown promise in slowing disease progression, offering new hope for improved outcomes.

What evidence suggests that this trial's treatments could be effective for breast cancer?

In this trial, participants will receive either ribociclib or palbociclib combined with endocrine therapy. Previous studies have shown that ribociclib combined with hormone therapy yields promising results for treating advanced HR+/HER2- breast cancer. Patients taking ribociclib lived longer without their cancer worsening, with an average time of about 27.3 months before disease progression. Palbociclib has also proven effective, with real-world studies showing it reduced the risk of disease progression by 30% in a large group of patients. In a study comparing different treatments, the average time before disease progression for palbociclib was around 19.3 months. Both treatments have demonstrated the ability to extend the lives of patients with this type of breast cancer, with ribociclib showing slightly longer times before disease worsening in clinical settings. ^{2 3 6 7 8}

Who Is on the 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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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 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]

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]

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]

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]

Citations

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Real-world effectiveness of palbociclib plus an aromatase ... In a large (n = 2888), heterogeneous population in the United States, palbociclib plus ET was associated with a 30% reduction in risk of disease ...

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Real-World Outcomes Support Use of First-Line Palbociclib ... Real-world data from the UK, Spain, and Germany support palbociclib plus endocrine therapy as effective for HR-positive/HER2-negative advanced ...

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Real-world effectiveness of palbociclib plus endocrine therapy ... Together with prior clinical trial and real-world data, this study helps support the use of palbociclib + ET for patients with HR+/HER2– ABC.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0960977625004655

metastatic breast cancer: A Flatiron Health database analysis In the current study, approximately 15 % of patients treated with palbociclib had a reduced starting dose (100/75 mg/day); per protocols, this did not occur in ...

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Real-world study of overall survival with palbociclib plus ... Progression-free survival (95% CI) is 19.3 (17.5–20.7) versus 13.9 (12.5–15.2) months, respectively (hazard ratio, 0.70 [95% CI, 0.62–0.78]; P < ...

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Long‐Term Pooled Safety Analysis of Palbociclib in ... This 5-year, long-term analysis demonstrated that palbociclib plus ET has a consistent and stable safety profile and is a safe treatment for patients with HR+/ ...

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Overall Survival With Palbociclib Plus Letrozole in ... The median OS was 53.9 months (95% CI, 49.8 to 60.8) with palbociclib plus letrozole versus 51.2 months (95% CI, 43.7 to 58.9) with placebo plus ...

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Real-world safety of palbociclib in breast cancer patients in ... This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia.