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The PALOMA-3 clinical trial showed that a new CDK4/6 inhibitor in combination therapy improved progression-free survival of women treated for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in women with prior disease progression after endocrine therapy. This XRAYS reviews a newly published study in the New England Journal of Medicine that looks at overall survival in the original PALOMA-3 study. (1/23/19)
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Whether or not adding the drug palbociclib (Ibrance) to fulvestrant (Faslodex) treatment improves overall survival in women with advanced or metastatic ER-positive, HER2-negative 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.
The PALOMA-3 trial previously reported significant improvement in progression-free survival (PFS) among women with metastatic 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.
If you have ER-positive, HER2-negative 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 metastatic 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 FDA 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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Treatment for metastatic breast cancer focuses on prolonging life and improving quality of life. Median survival with metastatic 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 metastatic breast cancer and expanded patient options.
Approximately 80% of breast cancers are ER-positive. For ER-positive, HER2-negative breast cancer, endocrine therapy including tamoxifen and aromatase inhibitors (e.g., anastrozole, letrozole or exemestane) remain a mainstay. Other estrogen pathway modulators, such as fulvestrant (Faslodex), a selective estrogen 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 estrogen produced by the ovaries.
In an effort to increase survival times for metastatic 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 estrogen 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 FDA has approved three CDK4/6 inhibitors for treatment of advanced or metastatic breast cancer: palbociclib, ribociclib and abemaciclib.
The effectiveness of palbociclib was tested in two different phase III, double-blinded randomized trials:
In the PALOMA-2 trial (Palbociclib: Ongoing Trials in the Management of Breast Cancer), postmenopausal women with advanced or metastatic breast cancer who had not prior systemic therapy for advanced disease were treated with either palbociclib and the aromatase inhibitor, letrozole (Femara), or placebo 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 first-line therapy.
In the PALOMA-3 trial, participants were women with advanced or metastatic 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 estrogen receptor down-regulator (SERD), or with a placebo and fulvestrant. The PALOMA-3 trial previously reported significant improvement in progression-free survival (PFS) when women with metastatic 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.
The impact of palbociclib (Ibrance from Pfizer) on overall survival of women with advanced or metastatic breast cancer that had progressed after prior endocrine therapy treatment. Secondary goals included looking at the impact of endocrine therapy sensitivity, visceral metastatic disease (e.g., lung or liver metastases) menopausal status, subsequent therapies, and safety.
This study enrolled women with advance or metastatic ER-positive, HER2-negative 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 bilateral 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.
The PALOMA-3 study was a prospective, double-blinded, placebo-controlled trial in which participants were assigned randomly to treatment with palbociclib and fulvestrant or placebo and fulvestrant. Participants were stratified for several factors: endocrine therapy sensitivity or resistance, visceral metastatic disease (e.g., lung or liver metastases) or non-visceral metastatic 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 placebo and fulvestrant).
Prior reports (reference) showed that women with advanced or metastatic 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 is defined as the time from entry in the trial to time of death from any cause.
Estimated survival at 3 years
Kaplan-Meier methods were used to estimate survival at 3 years after the beginning of 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 placebo 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:
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 metastatic 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:
Among the 111 participants with endocrine therapy resistance:
Site of metastatic 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 metastatic disease:
Among the 210 participants with non-visceral metastatic disease:
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:
Among the 108 participants who were perimenopausal or premenopausal:
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).
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 placebo 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.
CDK4/6 inhibitors are a promising addition to the arsenal of tools available for treating metastatic 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 metastatic breast cancer.
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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 placebo for treatment of hormone-receptor-positive, HER2-negative 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