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Study: The impact of palbociclib (Ibrance) on overall survival for metastatic breast cancer patients in the PALOMA-3 trial

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Contents:

At a glance                      Questions to ask your doctor                        
Findings In-depth
Clinical trials Limitations
Media Resources


STUDY AT A GLANCE

This study is about:

Whether or not adding the drug palbociclib (Ibrance) to fulvestrant (Faslodex) treatment improves overall survival in women with advanced or ER-positive, breast cancer based on the results of the PALOMA-3 trial.

Palbociclib is a drug that blocks proteins known as CDK 4/6 proteins. These proteins can promote tumor growth. Blocking these proteins has been shown to increase progression-free survival time.

Why is this study important?

The PALOMA-3 trial previously reported significant improvement in progression-free survival (PFS) among women with breast cancer who were treated with palbociclib and fulvestrant versus fulvestrant alone. Progression-free survival is the length of time patients live without cancer getting worse (progressing). This study follows up with data on overall survival rates.

Study findings: 

  • Overall survival (OS) was not significantly different between participants treated with palbociclib plus fulvestrant and participants treated with plus fulvestrant.
     
    • The median overall survival of the 347 women on palbociclib plus fulvestrant was 34.9 months.
    • The median overall survival of the 174 women on plus fulvestrant alone was 28.0 months.
    • There was a numerical increase (6.9 months) in the average overall survival among women treated with palbociclib; however, because these results were not statistically significant, this increase may have occurred by chance.
    • 16% of the women who did not receive palbociclib in the PALOMA-3 trial, received a CDK 4/6 inhibitor in subsequent treatment, off-study. If those women are excluded from the analysis, the median overall survival for the women who received fulvestrant alone was 27.4 months.
  • No significant difference in overall survival was seen in groups stratified by endocrine therapy sensitivity, site of metastases or menopausal status.
     
  • No new adverse safety events were seen.
     
  • The time to beginning chemotherapy post-trial was significantly increased.
     
    • The average time from trial entry to first chemotherapy was 17.6 months for women on palbociclib and fulvestrant.
    • The average time from trial entry to first chemotherapy was 8.8 months for women on and fulvestrant.

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What does this mean for me?

If you have ER-positive, metastatic breast cancer, CDK4/6 inhibitors may be a treatment option. Palbociclib, ribociclib and abemaciclib are FDA-approved CDK4/6 inhibitors for use in postmenopausal women. To date, palbociclib is the only CDK4/6 inhibitor approved for use in perimenopausal or premenopausal women.  CDK4/6 inhibitors have been shown to increase progression-free survival, although they may or may not increase overall survival. While overall survival is not significantly increased, palbociclib in combination with fulvestrant also lengthens the time before chemotherapy is needed.

Of note, other CDK4/6 inhibitors have now also been approved for use with fulvestrant in this setting. In addition, CDK4/6 inhibitors are now approved for use in combination with an aromatase inhibitor as initial therapy in postmenopausal women with advanced or breast cancer.

Be aware that side effects are associated with these oral medications—70% of participants on palbociclib experienced severe neutropenia (a decrease of white blood cells that can lead to infections), which can increase the risk of infection or need to be hospitalized.

Note: On 09/13/19 the issued a safety alert that Ibrance (palbociclib), Kisqali (ribociclib), and Verzenio (abemaciclib) may cause a rare but severe inflammation of the lungs.

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References

Turner NC, Slamon DJ, Ro J, et al. "Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer." New England Journal of Medicine. Oct. 20, 2018. 79:1926-36. DOI: 10.1056/NEJMoa1810527

Finn RS, Martin M, Rugo HS, et al. "Palbociclib and Letrozole in Advanced Breast Cancer." New England Journal of Medicine. Nov. 17, 2016. 375:1925-1936. DOI: 10.1056/NEJMoa1607303

Turner NC, Ro J, André Fabian, et al. "Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer." New England Journal of Medicine. July 16, 2015. 373: 209-219. DOI: 10.1056/NEJMoa1505270

Cristofanilli M, Turner NC, Bondarenko I, et al. "Fulvestrant plus palbociclib versus fulvestrant plus for treatment of hormone-receptor-positive, metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial." The Lancet. Mar 2 2016. 17(4): 425-439. https://doi.org/10.1016/S1470-2045(15)00613-0
 

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

This article is relevant for:

People with metastatic, hormone-positive breast cancer

This article is also relevant for:

people with ER/PR + cancer

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IN-DEPTH REVIEW OF RESEARCH

Study background:

Treatment for breast cancer focuses on prolonging life and improving quality of life. Median survival with breast cancer has been reported to be 18-24 months. Extending overall survival time and progression-free survival time has been an end goal of many recent clinical trials. Longer progression-free survival, and in some cases overall survival times, have been demonstrated in recent clinical trials. These have included the addition of different classes of drugs used to treat breast cancer and expanded patient options.

Approximately 80% of breast cancers are ER-positive. For ER-positive, breast cancer, endocrine therapy including tamoxifen and aromatase inhibitors (e.g., anastrozole, letrozole or exemestane) remain a mainstay. Other pathway modulators, such as fulvestrant (Faslodex), a selective degrader, are used as second-line therapies. For pre-menopausal women, treatment may include drugs that block luteinizing-hormone-releasing hormone (e.g., buserelin or goserelin) to reduce produced by the ovaries.

In an effort to increase survival times for breast cancer patients, researchers have tested CDK4/6 inhibitors. The cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK 6) proteins can act later in the signaling pathway and are thought to promote tumor growth. Blocking the action of these proteins has been shown to increase progression-free survival time. Currently, the has approved three CDK4/6 inhibitors for treatment of advanced or breast cancer: palbociclib, ribociclib and abemaciclib.

The effectiveness of palbociclib was tested in two different phase III, randomized trials:

In the PALOMA-2 trial (Palbociclib: Ongoing Trials in the Management of Breast Cancer), postmenopausal women with advanced or breast cancer who had not prior for advanced disease were treated with either palbociclib and the aromatase inhibitor, letrozole (Femara), or and letrozole. On average, patients treated with palbociclib and letrozole had 24.8 months before metastases progress while patients in the letrozole-only group had cancer progress after 14.5 months. This was a significant extension in PFS using palbociclib as a therapy.

In the PALOMA-3 trial, participants were women with advanced or breast cancer, including those who were peri-, pre- and post-menopausal, whose disease progressed following treatment with endocrine therapy. Participants were treated with palbociclib and fulvestrant, a selective receptor down-regulator (SERD), or with a and fulvestrant. The PALOMA-3 trial previously reported significant improvement in progression-free survival (PFS) when women with breast cancer were treated with palbociclib and fulvestrant versus fulvestrant alone. On average, patients treated with palbociclib and fulvestrant had 11.2 months before metastases progress while patients in the fulvestrant only group had cancer progress after 4.6 months. This was a significant extension in PFS that also widened this secondary treatment to women of any menopausal status.

The reviewed study looks at overall survival data from the PALOMA-3 trial.

Researchers of this study wanted to know:

The impact of palbociclib (Ibrance from Pfizer) on overall survival of women with advanced or breast cancer that had progressed after prior endocrine therapy treatment. Secondary goals included looking at the impact of endocrine therapy sensitivity, visceral disease (e.g., lung or liver metastases) menopausal status, subsequent therapies, and safety.

Populations looked at in this study:

This study enrolled women with advance or ER-positive, breast cancer who had disease progression after prior endocrine therapy. The study enrolled 521 patients between Oct 7, 2013 and Aug. 26, 2014.

Post-menopausal women who were older than 60 or had a oophorectomy (surgical menopause) or were under 60 and had gone 12 months without a menstrual period. Peri- and pre-menopausal women were also enrolled and required to take goserelin to suppress ovarian function for 4 weeks prior to entering the trial and every 28 days during the trial.

Study design:

The PALOMA-3 study was a , , trial in which participants were assigned randomly to treatment with palbociclib and fulvestrant or and fulvestrant. Participants were stratified for several factors: endocrine therapy sensitivity or resistance, visceral disease (e.g., lung or liver metastases) or non-visceral disease (e.g., node, bone, chest wall metastases), and peri/pre-menopausal or post-menopausal status. Participants from each stratified group were included in each drug treatment group (palbociclib and fulvestrant group or and fulvestrant).

Study findings:  

Prior reports (reference) showed that women with advanced or breast cancer who took palbociclib in combination with fulvestrant had a statistically significant increase in progression-free survival (PFS) time compared to women who took fulvestrant alone (11.2 months versus 4.6 months).

Before the trial, a pre-specified significance level was determined based on the size of the trial and numbers of participants in each treatment group. The significance value was a two-sided p value of 0.47.

Overall survival

Overall survival is defined as the time from entry in the trial to time of death from any cause.

  • The median overall survival of the 347 women on palbociclib plus fulvestrant was 34.9 months.
  • The median overall survival of the 174 women on plus fulvestrant alone was 28.0 months.
  • The average 7-month difference in overall survival between women in the two treatment groups was not statistically significant (p=.09 above the predetermined significance threshold of p<=.047).

Estimated survival at 3 years

Kaplan-Meier methods were used to estimate survival at 3 years after the beginning of treatment.

  • The estimated overall survival at 3 years was 50% for women treated with palbociclib plus fulvestrant. 
  • The estimated overall survival at 3 years was 41% for women treated with plus fulvestrant. 

Post-trial treatment

After the end of the trial, 75% (389) participants continued some form of therapy. At this point, some participants switched treatment to other lines of therapy. In both trial groups, about 40% of participants were treated with some form of endocrine therapy, including other CDK4/6 inhibitors (4% of the palbociclib-plus-fulvestrant group and 16% of the placebo-plus-fulvestrant group).

Participants treated with palbociclib and fulvestrant had significantly more time before beginning chemotherapy (17.6 months from trial entry to beginning of chemotherapy) compared to participants who were treated with and fulvestrant (8.8 months from trial entry to beginning of chemotherapy). Delaying chemotherapy and its coincident side effects is likely to result in a better quality of life for patients.

At the time of data analysis:

  • Among participants in the palbociclib plus fulvestrant treatment group, 35 women were living (10% of original participants). They had survived 45.4 month on average.
  • Among participants in the plus fulvestrant treatment group, 6 women were living (3% of original participants). They had survived 44.7 months on average.

Overall survival (OS) for stratified groups

Sensitivity to endocrine therapy

Prior to enrollment, participants had experienced cancer progression after endocrine therapy, one of the criteria for participation. Endocrine sensitivity was defined as a documented clinical benefit for a patient with advanced or cancer from prior endocrine therapy (either complete, partial or stable response for at least 24 weeks) before cancer progression. While the majority of participants (79%) were endocrine therapy sensitive, 21% were endocrine therapy resistant.

Among the 410 participants with endocrine therapy sensitivity:

  • The median OS on palbociclib plus fulvestrant was 39.7 months.
  • The median OS on plus fulvestrant was 29.7 months.
  • The average 10-month difference in overall survival between women with endocrine therapy sensitivity in the two treatment groups was not statistically significant.

Among the 111 participants with endocrine therapy resistance:

  • The median OS on palbociclib plus fulvestrant was 20.2 months.
  • The median OS on plus fulvestrant was 26.2 months.
  • No benefit was shown with palbociclib treatment for women with endocrine therapy resistance.

Site of disease

People with visceral metastases (metastases to internal organs such as liver or lung) of breast cancer are known to have poorer prognoses than people with non-visceral metastases (such as to bone or muscle wall). A difference in overall survival based on site of metastases was observed in the participants of this trial as well. However, palbociclib did not significantly alter overall survival in either group.

Among the 311 participants with visceral disease:

  • The median OS on palbociclib plus fulvestrant was 27.6 months.
  • The median OS on plus fulvestrant was 24.7 months.

Among the 210 participants with non-visceral disease:

  • The median OS on palbociclib plus fulvestrant was 46.9 months.
  • The median OS on plus fulvestrant was 35.4 months.
  • The average 11-month difference in overall survival between women with non-visceral disease in the two treatment groups was not statistically significant (p=.44)

Menopausal status

Prognosis differs with menopausal status. Researchers looked at the survival in postmenopausal women separately from peri- or pre-menopausal women to determine if menopausal status impacted effectiveness of this treatment. No statistically significant improvement in overall survival was observed with either group.

Among the 413 participants who were postmenopausal:

  • The median OS on palbociclib plus fulvestrant was 34.8 months.
  • The median OS on plus fulvestrant was 27.1 months.
  • The average 9-month difference in overall survival between postmenopausal women in the two treatment groups was not statistically significant.

Among the 108 participants who were perimenopausal or premenopausal:

  • The median OS on palbociclib plus fulvestrant was 38 months.
  • The median OS on plus fulvestrant was 38 months.
  • There was no overall survival benefit of palbociclib treatment for women who were peri- or premenopausal.

Safety concerns

No new safety concerns were observed with palbociclib treatment; adverse events were similar to those observed previously. The most prominent side effect of palbociclib treatment was severe neutropenia—severely low levels of neutrophils (a class of white blood cells), which can lead to life-threatening infection. Neutropenia occurred in 70% of participants treated with palbociclib but in none of the participants on fulvestrant alone.  Other adverse events seen in less than 5% of participants included anemia, thrombocytopenia (low blood platelet count), infections, fatigue, and increased aspartate aminotransferase (an enzyme needed for heart and liver health).

Limitations:

This study has several limitations stemming from the relatively small group of participants.

First, small but real differences in overall survival would not be detectable with the number of participants enrolled. Although the numbers of participants enrolled were sufficient to determine progression-free survival (published previously), this trial is underpowered to address overall survival, particularly in some of the stratified groups.  This is the largest limitation of this study and leads to several questions about whether or not there are small but actual difference in overall survival. The authors emphasize the numerical increase in OS, however the lack of statistical significance means that this increase may be due to chance and may not be repeatable (or it may be a true small difference). This study cannot determine which is the case. The authors acknowledge this point and suggest that the increase in overall survival may have been statistically significant with a larger number of trial participants. Further analysis of a larger pool of participants is needed to clarify this issue.

Second, after the trial, 16% of surviving participants who had been assigned to the plus fulvestrant group subsequently took CDK inhibitors once they were no longer in the PALOMA-3 study. This confounds the analysis. While the researchers took this information into account in their statistical evaluation, it leaves some question as to the potential differences in overall survival between the two groups.

Third, palbociclib plus fulvestrant did not improve the overall survival of people with endocrine therapy resistance. This conclusion is limited by the relatively small number of participants (111) with documented endocrine therapy resistance. A small but real effect would be undetectable.

Fourth, the longer overall survival observed in older, postmenopausal women versus peri- or premenopausal women may reflect differences in the proportion of women with endocrine therapy resistance tumors in these groups: 30% of peri- or premenopausal women had endocrine therapy resistance tumors, whereas 19% of post-menopausal women had endocrine therapy resistance tumors.

Conclusions:

CDK4/6 inhibitors are a promising addition to the arsenal of tools available for treating breast cancer. Palbociclib in combination with fulvestrant provides longer progression-free survival than previously possible. Furthermore, this is the first CDK inhibitor approved for use in peri- or premenopausal women. While overall survival is not significantly increased, it does provide a significantly longer time before disease progression and before chemotherapy is needed, which likely enhances quality of life for those with breast cancer.

Share your thoughts on this XRAYS article by taking our brief survey.

Posted 1/23/19

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) guidelines for the treatment of advanced or ER-positive breast cancer include the following:

Genetic testing

  • All people diagnosed with breast cancer meet guidelines for genetic counseling and testing. 

NCCN preferred treatment options

The NCCN lists the following preferred treatments for ER-positive and breast cancer:

  • for people with or mutations:
    • Lynparza () or () for people with an inherited or mutation. 
  • therapy
    • A combination of hormonal therapy (aromatase inhibitor or Fulvestrant) + with a CDK4/6 inhibitor:
      •  abemaciclib (Verzenio), palbocicib (Ibrance) or ribociclib (Kisqali). 
  • For second-, third- or later lines of therapy:
    • 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 with HER2-low ( 1+ or 2+) tumors, who received chemotherapy for disease and whose 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 a or mutation.
    • A combination of everolimus and hormonal therapy.
    • Hormonal therapy alone.
    • Trodelvy (sacituzumab govitecan-hziy) for , after prior treatment, including hormone therapy, a CDK4/6 inhibitor and at least two lines of chemotherapy (including a taxane).

Updated: 03/21/2023

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • What treatment therapy or therapies are best for my circumstance?
  • Are there combination therapies that I should consider?
  • Should I consider treatment with a CDK4/6 inhibitor for my breast cancer?
  • What are the pros and cons of various treatments for my breast cancer?
  • Are there clinical trials enrolling participants with breast cancer that are appropriate for me?

Open Clinical Trials
Open Clinical Trials

The following studies look at treatment for people with ER-positive breast cancer.  

Other clinical trials for people with breast cancer can be found here.

Updated: 12/22/2023

Open Clinical Trials
Open Clinical Trials

The following studies are looking at treatment for people with advanced

 

Updated: 02/01/2024

Peer Support
Peer Support

The following organizations offer peer support services for people with, or at high risk for breast cancer:

Updated: 05/07/2024

Who covered this study?

The Hippocratic Post

Palbociclib targets advanced breast cancer This article rates 2.5 out of 5 stars

BBC.com

Treatment may extend advanced breast cancer survival This article rates 1.0 out of 5 stars

How we rated the media

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