Study: Breast cancer outcomes improved with CDK4/6 inhibitor treatment
A study showed that people with metastatic breast cancer who took an oral drug known as a CDK4/6 inhibitor combined with hormone therapy did better than people who took hormone therapy alone. The drug combination improved the length of time before cancer worsened or returned. After six years of treatment, people who took this drug combination lived longer compared to those who took hormone therapy alone. (Posted 4/5/23)
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Most relevant for: People with HR-positive HER2-negative advanced breast cancer. It may also be relevant for:
- people with ER/PR + cancer
- men with breast cancer
Strength of Science: Medium-High
Research Timeline: Post Approval
What was the research about?
A large research study known as PALOMA-3 looked at how well a drug called Ibrance (palbociclib) works when combined with hormone therapy (fulvestrant) for people with breast cancer that was hormone sensitive (). In 2019, researchers shared early results from the study, which seemed to show that some people who received the two drugs together did better than people who received hormone treatment alone. However, these results were too early for researchers to say for certain that the drug combination worked better than hormone therapy alone.
This follow-up report from 2022 looked at overall survival (how long participants lived) for a longer period of time. The report also looked at whether some groups of people benefitted more from the drug combination.
Researchers looked at results for all participants and for different subgroups of participants.
In this updated report, overall survival continued to be better for people who were treated with Ibrance plus fulvestrant compared to people treated with fulvestrant alone:
- 35 months for people on Ibrance plus fulvestrant
- 28 months for people on fulvestrant alone
While the combination of fulvestrant plus Ibrance improved overall survival, the difference—a benefit of seven months at six years—was not statistically significant. (The overall survival reported in 2019 was the same for both groups.)
The benefit for participants who did not previously have chemotherapy
Among people who had not received prior chemotherapy, overall survival at 6 years was 40 months for people on Ibrance plus fulvestrant compared to 30 months for people on fulvestrant alone, a benefit of 10 months. This result was statistically significant.
|fulvestrant alone||Ibrance plus fulvestrant|
|Full group||28 months||35 months|
|No chemotherapy||30 month||40 months|
What does this mean for me?
If you have , metastatic breast cancer, treatment with a CDK4/6 inhibitor such as Ibrance combined with fulvestrant may be a treatment option. The combination of Ibrance plus fulvestrant increases the time before breast cancer returns or becomes worse compared to fulvestrant alone. While the research suggests that this drug combination may also increase how long patients live, the results are not statistically significant.
Note: The issued a safety alert in September 2019, that the CDK4/6 inhibitors Ibrance (palbociclib), Kisqali (ribociclib) and Verzenio (abemaciclib) may cause a rare but severe inflammation of the lungs.
- What treatment therapy or therapies are best for me?
- Should I consider treatment with a CDK4/6 inhibitor for my breast cancer?
- What side effects might I have with a CDK4/6 inhibitor?
- Should I have testing of my tumor?
- Are there clinical trials enrolling participants with breast cancer that are appropriate for me?
The following studies look at treatment for people with ER-positive breast cancer.
- NCT04673448: Combining the Dostarlimab and Niraparib for Advanced or Breast, Ovarian or Pancreatic Cancer with an Inherited or Tumor Mutation. This study is looking at the effectiveness of combining the , and the dostarlimab for treating people with an inherited mutation (found with genetic testing) or a tumor mutation (found through tumor testing) who have advanced breast, pancreatic or ovarian cancer.
- NCT05501886: Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or HR+/HER2- Breast Cancer (VIKTORIA-1). This study is looking at the efficacy and safety of the selective receptor degrader (SERD) gedatolisib plus fulvestrant with or without palbociclib for the treatment of patients with locally advanced or HR+/HER2- breast cancer following progression on or after CDK4/6 and aromatase inhibitor therapy.
- NCT04975308: A Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer. This study will evaluate the efficacy and safety of the selective receptor degrader (SERD) imlunestrant, how it works compared to standard hormone therapy, and how well imlunestrant with abemaciclib works compared to imlunestrant in participants with breast cancer that is ER-positive and .
- NCT05065411: Efficacy & Safety Evaluation of Enobosarm in Combo With Abemaciclib in Treatment of ER+HER2- Breast Cancer. This study will look at the efficacy and safety of a drug known as a Selective Androgen Receptor Modulator (SARM) enobosarm in combination with abemaciclib to treat receptor-positive (ER+), metastatic breast cancer that tests positive for the presence of androgen receptors.
- NCT05306340: A Study Evaluating the Efficacy and Safety of Giredestrant Plus Everolimus Compared With Exemestane Plus Everolimus in Participants With Receptor-Positive, , Locally Advanced or Breast Cancer (evERA Breast Cancer). This study will evaluate the efficacy and safety of the selective receptor degrader (SERD) giredestrant, plus everolimus compared with exemestane plus everolimus in people with receptor ER-positive, locally advanced or breast cancer who have had previous treatment with a CDK4/6 inhibitor and hormone therapy.
- NCT03344965: Expanded - Treating Breast Cancer in People without gBRCA Mutations. This study will look at whether is also effective for treating breast cancer in people who do not have an inherited mutation. The study is enrolling people with an in or an acquired (tumor) mutation in or .
- NCT03685331: , Palbociclib and Fulvestrant for BRCA-Associated, ER/PR+/HER2-Negative Breast Cancer. This study is looking at the side effects and best dose of palbociclib when given with and fulvestrant for people with HR+/HER2-negative mBC who have a or mutation.
- NCT04072952: ARV-471 Alone and in Combination With Palbociclib in Patients With ER+/HER2- Locally Advanced or Breast Cancer. This is a dose escalation and expansion study to learn the safety and tolerability of ARV-471 alone and combined with palbociclib in people with ER+/HER2- locally advanced or breast cancer who have received prior hormonal therapy and chemotherapy in the locally advanced/metastatic setting.
- NCT04448886: Sacituzumab Govitecan +/- Pembrolizumab In HR+ / - MBC. This research study is evaluating the safety and effectiveness of Sacituzumab Govitecan with or without Pembrolizumab in HR+/HER2- breast cancer.
- NCT04563507: Combined Immunotherapies in ER+ Breast Cancer. Patients receiving standard therapy for HR+ Breast cancer(BC) (letrozole+palbociclib) are randomly assigned to also receive Stereotactic Body Radiation Therapy(SBRT) to each lesion.
- NCT04895358: Pembrolizumab Plus Chemotherapy Versus Plus Chemotherapy for HR+/HER2- Inoperable or Breast Cancer (KEYNOTE-B49). The study will look at the safety and efficacy of pembrolizumab plus chemotherapy compared to chemotherapy alone in the treatment of HR+/HER2- locally recurrent inoperable or breast cancer.
- NCT04946864: A Study to Investigate the Safety, Tolerability, of APG-2575 as a Single Agent or in Combination for Breast Cancer. This is an study of APG-2575 as a single agent in patients with advanced or in combination with anti-cancer agents such as the CDK4/6 inhibitor palbociclib in patients with ER+/HER2- mBC who have progressed or relapsed after therapy.
Other clinical trials for people with breast cancer can be found here.
Strengths and limitations
- This update followed participants for another 2 years. The collection of long-term data can confirm how well this drug combination treatment worked for participants who received it. Sometimes, long-term follow-up can also reveal additional side effects or interactions with other treatments.
- This is the first study to look at whether circulating tumor mutations can help identify those who would benefit the most from a CDK4/6 inhibitor (Ibrance).
- In studies where participants tend to live longer, it is often hard to show that treatment significantly improved their overall survival. In this study, the researchers still do not know if the trend of increased overall survival among participants who received Ibrance plus fulvestrant was due to the treatment, some other factor or chance.
- Because the researchers looked at small numbers of participants in subgroups (chemotherapy and circulating tumor ), they did not have enough data to conclude that improvement in overall survival was due to treatment rather than chance.
Several studies have shown that the CDk4/6 inhibitors palbociclib (Ibrance), ribociclib (Kisquali) and abemaciclib (Verzenio) increase survival for people with , advanced breast cancer. Somewhat longer overall survival has been seen with abemaciclib in the MONACH2 trial and with ribociclib in the MONALEESA-3 trial (participants did not have prior chemotherapy in either trial).
- MONARCH-2 trial: at 4 years, overall survival was:
- 47 months with abemaciclib plus fluvestrant
- 37 months with fluvestrant alone
- MONALEESA-3 trial: at 4.5 years, overall survival was:
- 54 months with ribociclib plus fulvestrant
- 42 months with fulvestrant alone
However, no head-to-head comparison of these three CDK4/6 inhibitors has been done as yet. All three CDK4/6 inhibitors are FDA-approved for postmenopausal people. Currently, Ibrance is the only CDK4/6 inhibitor approved for perimenopausal or premenopausal women.
Note: The issued a safety alert on September 13, 2019, that Ibrance (palbociclib), Kisqali (ribociclib) and Verzenio (abemaciclib) may cause a rare but severe inflammation of the lungs.
The National Comprehensive Cancer Network (NCCN) brings together national expert panels that create guidelines for cancer treatment. NCCN guidelines for the treatment of advanced or ER-positive breast cancer include the following:
- All people diagnosed with breast cancer meet guidelines for genetic counseling and testing.
NCCN preferred treatment options
The NCCN lists the following as preferred treatments for ER-positive and breast cancer:
- for people with or mutations:
- The NCCN lists Lynparza () or () for people with an inherited or mutation.
- First line therapy
- The NCCN lists as the preferred treatment combination of hormonal therapy (aromatase inhibitor or Fulvestrant) + with a CDK4/6 inhibitor:
- abemaciclib (Verzenio), palbocicib (Ibrance) or ribociclib (Kisqali).
- The NCCN lists as the preferred treatment combination of hormonal therapy (aromatase inhibitor or Fulvestrant) + with a CDK4/6 inhibitor:
- For second, third or later lines of therapy, the NCCN lists the following targeted therapies or combinations treatments:
- a combination of hormonal therapy (aromatase inhibitor or Fulvestrant) plus with a CDK4/6 inhibitor for people who have not previously received a CDK4/6 inhibitor
- Enhertu (trastuzumab deruxtecan) for people whose tumors are HER2-low ( 1+ or 2+), who received chemotherapy in the setting and their cancer no longer responds to hormonal therapy
- Piqray (apelisib) for cancers that test positive for a PIK3CA-mutation
- Oserdu (elacestrant) for , cancers that test positive for an ESR1 mutation
- Lynparza () or () for BRCA1/BRCA2 for tumors with or mutation
- a combination of everolimus and hormonal therapy
- hormonal therapy alone
- Trodelvy (sacituzumab govitecan-hziy) for , cancers after prior treatment including hormone therapy, a CDK4/6 inhibitor and at least two lines of chemotherapy (including a taxane)
The following studies are looking at treatment for people with advanced .
- NCT05252390: NUV-868 Alone and in Combination With PARP Inhibitors in Patients With Advanced .This study will test the safety and effectiveness of the experimental drug NUV-868 alone and combined with a in people with advanced . This study is open to people whose cancer stopped responding or progressed on PARP inhibitors.
- NCT05169437: () in patients with inherited or tumor mutations in advanced (PAVO). PAVO is a Phase II study investigating if the niraparib is safe and effective for people with an advanced solid tumor who have an inherited gene mutation or a tumor with a mutation.
- NCT02264678: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents. This is a study of ceralasertib administered orally in combination with chemotherapy regimens and/or novel anticancer agents to patients with advanced cancer. The study is enrolling people with inherited mutations, including , , , , , and people with tumors that are HRD-positive.
- NCT04644068: Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies (PETRA). This research is designed to learn whether treatment with a new , AZD5305, used alone or in combination with anti-cancer agents is safe, tolerable and has anti-cancer activity in patients with advanced . The study is open to people who have previously been treated with PARP inhibitors.
- NCT04267939: ATR Inhibitor Plus Study in Advanced and Ovarian Cancer. This study will look at how well people with advanced respond to treatment with the BAY1895344 in combination with the . This study is open to people with inherited mutations in , , and other genes. Contact the study coordinator for information about eligibility for people with mutations in other genes.
- NCT04657068: Treatment with ATR Inhibitor for Advanced or Solid Tumors. This study will look at how well a new oral known as an ATR inhibitor works on advanced or with mutations in genes that are linked to damage repair. This study is open to people who have an inherited or acquired or mutation or whose tumors are HRD-positive. This study is open to people whose cancer stopped responding or progressed on PARP inhibitors.
The following organizations offer peer support services for people with, or at high risk for breast cancer:
- FORCE peer support:
- Our Message Boards allow people to connect with others who share their situation. Once you register, you can post on the Diagnosed With Cancer board to connect with other people who have been diagnosed.
- Our Peer Navigation Program will match you with a volunteer who shares your mutation and situation.
- Connect online with our Private Facebook Group.
- Join our virtual and in-person support meetings.
- Other organizations that offer breast cancer support: