Clinical trialBreast cancer

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

N Engl J Med · 2018521 patients

Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. N Engl J Med. 2018. 379:1926-1936

Study type: Clinical trial
Study name: PALOMA-3
Design: Randomised placebo-controlled trial; prespecified overall survival analysis
Sample size: 521 patients
Source: N Engl J Med · 2018
Trial registration: NCT01942135

In plain words

In this study, women with advanced breast cancer (hormone receptor-positive and HER2-negative) whose disease had progressed on earlier hormone treatment received either palbociclib with fulvestrant or a placebo (dummy drug) with fulvestrant. Across all patients, overall survival was about 6.9 months longer in the palbociclib group, but this difference was not statistically significant. In patients who had previously responded to hormone treatment, survival was about 10 months longer and the start of chemotherapy was also delayed. No new safety problems were seen.

Key results

34.9 months (95% CI: 28.8 to 40.0) vs 28.0 months (95% CI: 23.6 to 34.6)

Median overall survival in all patients

Hazard ratio for death 0.81 (95% CI: 0.64 to 1.03); P=0.09; absolute difference 6.9 months; not statistically significant

39.7 months (95% CI: 34.8 to 45.7) vs 29.7 months (95% CI: 23.8 to 37.9)

Median overall survival in patients sensitive to previous endocrine therapy (410 patients)

Hazard ratio 0.72 (95% CI: 0.55 to 0.94); absolute difference 10.0 months

17.6 months vs 8.8 months

Median time to chemotherapy

Hazard ratio 0.58 (95% CI: 0.47 to 0.73); P<0.001

16% of patients

CDK4/6 inhibitor received after the end of trial treatment in the placebo group

Placebo + fulvestrant group

Median duration of subsequent therapies was similar in the two groups

Duration of subsequent therapies

Drugs in this study:Abemaciclib (Verzenio)Fulvestrant (Faslodex)Goserelin (Zoladex)Letrozole (Femara)Palbociclib (Ibrance)Anastrozole (Arimidex)Ribociclib (Kisqali)

Dose and schedule cards

Hormone therapy + CDK4/6 inhibitor (PALOMA-2, MONALEESA-2, MONARCH 3; after progression: PALOMA-3)

Advanced HR-positive/HER2-negative disease; first-line with an aromatase inhibitor, or with fulvestrant after prior hormone therapyOn the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Advanced HR-positive/HER2-negative disease; first-line with an aromatase inhibitor, or with fulvestrant after prior hormone therapy

Drug	Dose	Route	Schedule
One of three drugs
Palbociclib	125 mg once daily	Oral	Days 1–21
Ribociclib	600 mg once daily	Oral	Days 1–21
Abemaciclib	150 mg twice daily	Oral	Continuous
Combined with
Letrozole (or anastrozole 1 mg)	2.5 mg once daily	Oral	Continuous
Or combined with
Fulvestrant	500 mg (two 5-mL injections, one in each buttock)	IM, slowly	Days 1, 15 and 29, then monthly

Cycle length: Palbociclib and ribociclib: every 28 days; abemaciclib continuous
Duration: Until progression or unacceptable toxicity

Ribociclib: reduce to 400 mg and then 200 mg. Abemaciclib: monotherapy 200 mg twice daily.

On the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Palbociclib + fulvestrant

Palbociclib with fulvestrant.

Palbociclib 125 mg orally daily for 3 weeks followed by 1 week off (28-day cycle) + fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then on day 1 of each cycle; pre-‎ or perimenopausal women received goserelin starting at least 4 weeks before the start.

2Placebo + fulvestrant

Placebo with fulvestrant.

Placebo on the same schedule + fulvestrant 500 mg on the same schedule (and goserelin for pre-‎ or perimenopausal women).

Source of the regimen details: ClinicalTrials.gov NCT01942135 and the FDA label for Ibrance (DailyMed, section 14, PALOMA-3)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with hormone receptor-positive, HER2-negative advanced breast cancer who had disease progression or relapse during previous endocrine therapy.

Endpoints

This paper reports the prespecified overall survival analysis. Items assessed: overall survival; the effect of palbociclib by prespecified stratification factors (presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastasis, and menopausal status); efficacy of subsequent therapies after disease progression; and safety.

Safety and side effects

With a median follow-up of 44.8 months, no new safety signals were observed. The rate of grade 3 or higher adverse events is not stated in the abstract.

Clinical significance and place in guidelines

This analysis shows that adding palbociclib to fulvestrant in patients with sensitivity to previous endocrine therapy was associated with longer overall survival and about doubled the time to chemotherapy; however, in the whole trial population the overall survival difference was not significant. The status of approvals and clinical guideline recommendations should be checked in up-to-date sources, as the abstract gives no information on them.

Limitations

The overall survival difference in the whole population was not significant (P=0.09). The positive result in patients with endocrine sensitivity is a subgroup finding and should be interpreted with caution. In the placebo–fulvestrant group, 16% of patients received a CDK4/6 inhibitor after the trial regimen.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.