PALOMA-3: What the Breast Cancer Trial Found

The problem this trial addressed

Hormone-receptor-positive breast cancer grows using estrogen. Blocking that signal works well, sometimes for years. Then it stops working.

For a long time, the answer when hormone therapy failed was to move to chemotherapy. PALOMA-3 tested a different idea: add a second drug that attacks the cell cycle directly, and see whether hormone therapy can be made to work again.

The two drugs

Fulvestrant is an injected hormone therapy. It attaches to the estrogen receptor and causes the cell to destroy it, so estrogen has nothing left to signal through.

Palbociclib is a CDK4/6 inhibitor, taken as a capsule. CDK4 and CDK6 are enzymes that push a cell from its resting phase into copying its DNA. Blocking them stalls the cell before it can divide.

The reasoning is that hormone signaling and the cell cycle are two points on the same chain. Blocking only one leaves the other available.

The design

521 patients with advanced hormone-receptor-positive, HER2-negative breast cancer that had relapsed or worsened during previous hormone therapy.

They were assigned 2 to 1: palbociclib plus fulvestrant, or placebo plus fulvestrant. It was double-blind, so neither patients nor their doctors knew which. Premenopausal and perimenopausal women also received goserelin, which shuts down ovarian estrogen production.

The primary measure was progression-free survival, judged by the treating investigator. Results appeared in the New England Journal of Medicine in 2015, at a preplanned interim analysis after 195 events.

What it showed

Median progression-free survival was 9.2 months with palbociclib plus fulvestrant (95% CI 7.5 to not estimable), against 3.8 months with fulvestrant alone (95% CI 3.5 to 5.5).

The hazard ratio was 0.42 (95% CI 0.32 to 0.56, P<0.001) — roughly a 58% lower risk of the cancer progressing or the patient dying at any given moment. Time before progression was about two and a half times longer.

The main cost was blood counts. Severe neutropenia occurred in 62.0% of the palbociclib group against 0.6% on placebo, and low white cells in 25.2% against 0.6%. Despite that, febrile neutropenia — fever while counts are low, the dangerous version — was rare and equal at 0.6% in both groups. Only 2.6% stopped palbociclib because of side effects, against 1.7% on placebo.

What happened to survival

This is the part that headlines usually skip. The final overall survival analysis was published in 2018.

Median overall survival was 34.9 months with palbociclib plus fulvestrant against 28.0 months with fulvestrant alone: a 6.9-month difference, hazard ratio 0.81 (95% CI 0.64 to 1.03, P=0.09). That did not reach statistical significance.

Among the 410 patients whose cancer had responded to previous hormone therapy, median survival was 39.7 against 29.7 months, a 10.0-month difference with a hazard ratio of 0.72. The authors also reported that time until chemotherapy became necessary was 17.6 months against 8.8 months.

So the honest summary is: clearly longer before the cancer grew, considerably longer before chemotherapy was needed, and a survival difference that pointed the right way without meeting the statistical bar for the whole group.

Living with a CDK4/6 inhibitor

Neutropenia in 62% of patients is not a footnote. In practice it means regular blood tests, and dose interruptions or reductions are routine rather than a sign something has gone wrong.

Call your team, the same day, if you have:

• A temperature at or above 100.4°F (38°C), or chills and shaking.
• A sore throat, cough, burning on urination, or any new sign of infection.
• Unusual bruising, or bleeding that will not stop.
• Breathlessness, or new or worsening cough — inflammation of the lungs is uncommon but recognized with this drug class.
• Extreme fatigue that is a clear change from your baseline.

Our breast cancer page covers how receptor status is tested and what it means for treatment choices.

What this trial cannot tell you

• The headline result is progression-free survival. The final overall survival analysis did not reach significance for the whole trial group, so this study did not establish that people live longer.
• The published result was a preplanned interim analysis after 195 events, at relatively early follow-up.
• Progression was assessed by the treating investigator rather than by blinded independent review, which can shade results in an open assessment.
• The comparison arm was fulvestrant on its own, which is now rarely used that way in this setting, so the size of the advantage over current practice is not what this trial measured.
• Everyone enrolled had hormone-receptor-positive, HER2-negative cancer that had already progressed on hormone therapy. Nothing here applies to other subtypes. Trial phases explains what phase 3 endpoints do and do not settle.

Sources

This article was written from the sources below, which were checked on the source-check date shown above.

• Turner NC and colleagues, "Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer," New England Journal of Medicine, 2015 (PMID 26030518): https://pubmed.ncbi.nlm.nih.gov/26030518/
• Turner NC and colleagues, "Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer," New England Journal of Medicine, 2018 (PMID 30345905): https://pubmed.ncbi.nlm.nih.gov/30345905/
• National Cancer Institute, Breast Cancer Treatment (PDQ), health professional version: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq

How this page was made

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. It is not a diagnostic service, does not recommend treatments, and is not for emergencies.

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