Palbociclib, a reversible and selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, is an antineoplastic agent.1, 21
Palbociclib is used in combination with an aromatase inhibitor or fulvestrant for the treatment of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative advanced or metastatic breast cancer.1, 15, 21
Palbociclib is also used in combination with inavolisib and fulvestrant for the treatment of endocrine-resistant, PIK3CA -mutated hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.1, 21, 28
Initial Therapy for Advanced Breast Cancer
Palbociclib is used in combination with an aromatase inhibitor for the initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.1, 21
This indication for palbociclib is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (PALOMA-2) in postmenopausal women with previously untreated estrogen receptor-positive, HER2-negative, advanced or metastatic breast cancer.1, 21, 22, 23, 24 In this study, 666 patients were randomized (stratified according to disease site, disease-free interval, and prior neoadjuvant or adjuvant endocrine therapy) in a 2:1 ratio to receive either palbociclib (125 mg orally once daily for 3 consecutive weeks of each 4-week cycle) in combination with letrozole (2.5 mg orally once daily continuously) or placebo in combination with letrozole.1, 21, 22 Patients were treated until disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of patient consent occurred.1, 21 The primary measure of efficacy was progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria.1, 21 Additional outcomes included objective response rate, overall survival, median duration of response, and clinical benefit response (complete/partial response or stable disease).22
The majority of patients (98%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and 78% of patients were white.1, 21 Approximately one-half (48%) of patients received prior chemotherapy, 56% received neoadjuvant or adjuvant endocrine therapy prior to diagnosis of advanced breast cancer, and 37% had not received prior systemic therapy in the neoadjuvant or adjuvant setting.1, 21 The majority of patients (97%) had metastatic disease and 49 or 23% of patients had visceral or bone-only disease, respectively.1, 21
The median follow-up was 23 months.22 Patients receiving palbociclib in combination with letrozole had a longer median progression-free survival (24.8 versus 14.5 months) compared with patients receiving placebo in combination with letrozole.1, 21, 22 The objective response rate (for patients with measurable disease) was 55.3 or 44.4% for palbociclib or placebo, respectively.1, 21 The median overall survival was 53.8 or 49.8 months for palbociclib or placebo, respectively.1, 21 The median duration of response was 22.5 or 16.8 months, and the rate of clinical benefit response was 84.9 or 70.3% for palbociclib or placebo, respectively.22 At a median follow-up of 38 months, median progression-free survival was 27.6 or 14.5 months for palbociclib and placebo, respectively.23 Benefits of palbociclib on progression-free survival were seen across all subgroups evaluated (e.g., visceral, nonvisceral, bone-only or no bone-only disease, measurable or nonmeasurable disease).23 At a median follow-up of 90.1 months, the median overall survival was 53.9 or 51.2 months for palbociclib or placebo, respectively.24
Previously Treated Advanced Breast Cancer
Palbociclib is used in combination with fulvestrant for the treatment of hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer in patients with disease progression following endocrine therapy.1, 15, 21, 25
This indication for palbociclib is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (PALOMA-3) in women with hormone receptor-positive, HER2-negative, metastatic breast cancer.1, 15 A total of 521 patients were randomized (stratified according to sensitivity to endocrine therapy, menopausal status, and presence of visceral metastases) in a 2:1 ratio to receive either palbociclib (125 mg orally once daily for 3 consecutive weeks of each 4-week cycle) in combination with fulvestrant (500 mg IM on days 1 and 15 during cycle 1 and then on day 1 of each 4-week cycle thereafter) or placebo in combination with fulvestrant.1, 15 Patients were treated until disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of patient consent occurred.1, 15 Premenopausal or perimenopausal patients received goserelin acetate for at least 4 weeks prior to and during the study.1, 21 The primary measure of efficacy was progression-free survival as assessed by the investigator according to RECIST criteria.1, 15 Additional outcomes included objective response rate, clinical benefit (complete/partial response or stable disease) and overall survival.1, 21 The median age of patients was 57 years.1 All patients enrolled in the study had a baseline ECOG performance status of 0 or 1.1 The majority of patients (80%) were postmenopausal and 60 or 23% of patients had visceral or bone-only disease, respectively.1 All patients enrolled in the study received prior systemic therapy, 75% of patients received prior chemotherapy, and 25% of patients had not received prior therapy for metastatic disease.1
The median follow-up was 8.9 months.15 Patients receiving palbociclib in combination with fulvestrant had a longer median progression-free survival (9.5 versus 4.6 months) compared with patients receiving placebo in combination with fulvestrant.1, 15, 21 The objective response rate for patients with measurable disease was 24.6 or 10.9% for palbociclib or placebo, respectively, with a clinical benefit of 67 or 40%, respectively.1, 15, 21 At a median follow-up of 73.3 months, the median overall survival was 34.8 months with palbociclib and 28 months with placebo.25 The 6-year overall survival was 19.1 or 12.9% for palbociclib or placebo, respectively.25
Previously Treated or Following Recurrence of Advanced Breast Cancer
Palbociclib is used in combination with inavolisib and fulvestrant for the treatment of endocrine-resistant, PIK3CA -mutated hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.1, 21, 28
This indication for palbociclib is based principally on the results of a randomized, double-blind, placebo-controlled study (INAVO120 trial) in adult women (with any menopausal status) and men with PIK3CA -mutated hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer.1, 21, 28 Enrolled patients experienced disease recurrence or progression during or within 12 months after completion of adjuvant endocrine therapy and had not received prior systemic therapy for their condition.1, 21, 28 A total of 325 patients were randomized (stratified according to presence of visceral metastases, endocrine resistance, and geographic region) in a 1:1 ratio to receive either palbociclib (125 mg orally once daily on days 1 to 21 of each 28-day cycle) in combination with fulvestrant (500 mg IM on days 1 and 15 during cycle 1 and then approximately every 4-weeks thereafter) and inavolisib (9 mg orally once daily on days 1 to 28 of each 28-day cycle) or placebo in combination with palbociclib and fulvestrant.1, 21, 28 Patients were treated until disease progression, unacceptable toxicity, death, or withdrawal of patient consent occurred.1, 21, 28 The primary measure of efficacy was progression-free survival as assessed by the investigator according to RECIST criteria.1, 21, 28 Additional outcomes included overall survival, objective response rate, and duration of response.1, 21 The median age of patients was 54 years and 98% were female; 59% White, 38% Asian, 6% Hispanic or Latino, and 0.6% Black or African American.1 A majority of patients enrolled in the study (99%) had a baseline ECOG performance status of 0 or 1.1 The most commonly administered adjuvant endocrine therapies were tamoxifen (57%) and aromatase inhibitors (50%).1
The median follow-up was 34.2 months in the palbociclib/inavolisib/fulvestrant combination group and 32.3 months in the palbociclib/fulvestrant/placebo group in the final analysis.28 Patients receiving palbociclib in combination with fulvestrant and inavolisib had a longer median progression-free survival (17.2 versus 7.3 months) compared with patients receiving placebo in combination with palbociclib and fulvestrant.28 An objective response was seen in 62.7 or 28% of patients in the palbociclib/inavolisib/fulvestrant or palbociclib/fulvestrant/placebo groups, respectively.28 The median overall survival was 34 months with palbociclib/inavolisib/fulvestrant and 27 months with palbociclib/fulvestrant/placebo.28 The median duration of response was also improved with palbociclib/inavolisib/fulvestrant (19.2 versus 11.1 months).28
Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer
An estimated 20 to 25% of all breast cancer cases are human epidermal growth factor receptor 2-positive (HER2+), with nearly 50% of these patients also hormone receptor-positive (HR+).10001 Patients with HR+/HER2+ metastatic breast cancer† generally have a worse prognosis than patients with HR+/HER2- disease and are more apt to exhibit resistance to therapy.10001 In guidelines, the basis of treatment for patients with HR+/HER2+ breast cancer is HER2-targeted therapy in combination with chemotherapy or endocrine therapy.10001 Ongoing research is evaluating various combinations of drug regimens in this patient population including the use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.10001
The phase 3, randomized, open-label, international PATINA trial evaluated the efficacy and safety of the addition of the CDK4/6 inhibitor, palbociclib, to standard first-line maintenance therapy after induction chemotherapy in patients with histologically confirmed HR+/HER2+ metastatic breast cancer and no prior therapy.10002 Enrolled patients had no evidence of disease progression following completion of induction therapy (i.e., 6 to 8 cycles, including trastuzumab +/- pertuzumab and taxane/vinorelbine).10002 A total of 518 patients were randomly assigned to palbociclib 125 mg orally once daily for 21 consecutive days with trastuzumab +/- pertuzumab + endocrine therapy or trastuzumab +/- pertuzumab + endocrine therapy alone.10002 Trastuzumab and pertuzumab were administered per standard of care; therapeutic options for endocrine therapy included fulvestrant or an aromatase inhibitor.10002 Therapy was administered until disease progression or intolerable toxicity.10002 The primary study endpoint was investigator-assessed progression-free survival (PFS), which was performed at a median follow-up of 53 months.10002 The data cutoff for the final PFS analysis was October 15, 2024.10002 The key secondary endpoint was overall survival (OS).10002
At baseline, the median age of patients was 53.4 years (range: 44.2 to 61.4), 99.4% were female, and the majority were White (91.7%), with 3.5% Black or African American and 2.1% Asian Indian/Chinese/other Asian.10002 Over 97% of patients received pertuzumab and almost 90% of patients were administered an aromatase inhibitor as endocrine therapy.10002 A complete or partial response to induction therapy occurred in 68.5% of patients by investigator assessment, with stable disease present in 31.5% of patients.10002
The addition of palbociclib significantly improved PFS by 26% compared with the control arm.10002 The median PFS was 44.3 months in the palbociclib arm and 29.1 months in the control arm (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.58 to 0.94).10002 At the time of the analysis, OS remained immature; median overall survival was not evaluable in the palbociclib arm and was 77 months in the control arm.10002 The 5-year overall survival rates were 74.3% versus 69.8% in the palbociclib and control arms, respectively.10002 The confirmed objective response (29.9% versus 22.2%) and clinical benefit (89.3% versus 81.3%) rates were significantly improved with the addition of palbociclib.10002
The most common adverse event in the palbociclib arm was grade 3 neutropenia (63.2% versus 4.4%).10002 In addition, grade 2 and 3 fatigue, stomatitis, and diarrhea occurred more frequently in the palbociclib arm.10002 The incidence of grade ≥4 adverse events was similar across study groups (12.3% versus 8.9% for palbociclib versus control).10002 Discontinuation of therapy due to adverse events was reported by 14 patients in the palbociclib arm.10002 No treatment-related deaths were reported in the study.10002
Based on current evidence, palbociclib in combination with trastuzumab +/- pertuzumab and endocrine therapy for the treatment of patients with HR+/HER2+ metastatic breast cancer has Level 1 (high strength/quality) evidence supporting its use.10002 The addition of palbociclib to standard therapy in the first line metastatic setting significantly improved PFS with a manageable toxicity profile.10002
Guidelines from the American Society of Clinical Oncology (ASCO) provide recommendations for treatment of hormone receptor-positive, HER2-negative, metastatic breast cancer.26, 27 For patients with hormone receptor-positive, HER2-negative, metastatic breast cancer who have not received any prior treatment, received treatment with tamoxifen only, or who have not recently (within 1 year) been treated with an aromatase inhibitor (i.e., anastrozole, exemestane, letrozole), first-line treatment should be initiated with an aromatase inhibitor plus a CDK4/6 inhibitor.26, 27 For patients recently exposed to aromatase inhibitor therapy or who experienced recurrence during treatment with an aromatase inhibitor, first-line treatment should be initiated with fulvestrant plus a CDK4/6 inhibitor.26, 27
Guidelines from the European Society of Medical Oncology (ESMO) recommend combination therapy with fulvestrant, palbociclib, and inavolisib as a first-line treatment option for patients with hormone receptor-positive, HER2-negative metastatic breast cancer and a PIK3CA mutation who have experienced disease recurrence while on adjuvant endocrine therapy or ≤12 months after completion of such adjuvant endocrine therapy.29
Palbociclib is administered orally (as capsules or tablets) once daily.1, 21 The capsules should be administered with food while the tablets may be administered without regard to food at approximately the same time each day.1, 21 The capsules and tablets should be swallowed intact and should not be chewed, crushed, or opened/split.1, 21
If a dose of palbociclib is missed or vomited, patients should not double the dose or take extra doses.1, 21 The next dose should be taken at the regularly scheduled time.1, 21
Store palbociclib capsules and tablets at 20-25ºC; excursions permitted between 15-30ºC.1, 21 Store tablets in their original blister pack.21
Initial Therapy for Advanced Breast Cancer
For the initial treatment of hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer, the recommended adult dosage of palbociclib is 125 mg once daily on days 1-21 of each 28-day cycle in combination with an aromatase inhibitor.1, 21 In the PALOMA-2 study, therapy was continued until disease progression or unacceptable toxicity occurred.1, 21
Clinicians should consult the respective manufacturers' labelings for the recommended dosage of the aromatase inhibitor used in combination with palbociclib.1, 21
Premenopausal or perimenopausal women receiving combination therapy with palbociclib and an aromatase inhibitor should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current standards of care.1, 21 Men receiving combination therapy with palbociclib and an aromatase inhibitor should consider treatment with an LHRH agonist according to current standards of care.1, 21
Previously Treated Advanced Breast Cancer
For the treatment of hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer in patients with disease progression following endocrine therapy, the recommended adult dosage of palbociclib is 125 mg once daily on days 1-21 of each 28-day cycle in combination with fulvestrant 500 mg IM on days 1 and 15 during cycle 1, and then on day 1 of each 28-day cycle thereafter.1, 21 In the PALOMA-3 study, therapy was continued until disease progression or unacceptable toxicity occurred.1, 15, 21
Premenopausal or perimenopausal patients receiving combination therapy with palbociclib and fulvestrant should be treated with a LHRH agonist according to current standards of care.1, 21
Previously Treated or Following Recurrence of Advanced Breast Cancer
For the treatment of endocrine-resistant, PIK3CA -mutated hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer following recurrence on or after completing adjuvant endocrine therapy, the recommended adult dosage of palbociclib is 125 mg once daily on days 1-21 of each 28-day cycle in combination with fulvestrant and inavolisib.1, 21
Clinicians should consult the respective manufacturers' labelings for the recommended dosage of fulvestrant and inavolisib used in combination with palbociclib.1, 21
Premenopausal or perimenopausal women receiving combination therapy with palbociclib, fulvestrant, and inavolisib should be treated with a LHRH agonist according to current standards of care.1, 21 Men receiving combination therapy with palbociclib, fulvestrant, and inavolisib should consider treatment with an LHRH agonist according to current standards of care.1, 21
Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer†
For the first line treatment of HR+/HER2+ metastatic breast cancer in patients without disease progression following induction therapy, the recommended adult dosage of palbociclib is 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment.10002 Palbociclib is administered in combination with anti-HER2 and endocrine therapy (e.g., fulvestrant or an aromatase inhibitor).10002
Dosage Modification for Toxicity
Management of some adverse effects may require temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of palbociclib therapy.1, 21 Dosage adjustment of palbociclib is recommended based on individual safety and tolerability.1, 21 Up to 2 dosage reductions for toxicity may be made.1, 21 If dosage modification is necessary, an initial dosage reduction to 100 mg once daily is recommended.1, 21 If further dosage reduction is necessary, the dosage should be reduced to 75 mg once daily.1, 21 Dosages less than 75 mg once daily are not recommended.1, 21
For grade 3 febrile neutropenia (absolute neutrophil count [ANC] 500 to less than 1000/mm3 associated with fever of 38.5°C or more and/or infection), palbociclib therapy should be interrupted until ANC reaches or exceeds 1000/mm3.1, 21 Upon resumption of therapy, the dosage of palbociclib should be reduced.1, 21
If grade 1 or 2 hematologic toxicity occurs, palbociclib may be continued at the same dosage.1
If grade 1 or 2 neutropenia occurs during cycle 1-6, monitoring of CBCs should be repeated every 3 months, prior to subsequent cycles, and as clinically indicated.1, 21
If grade 3 hematologic toxicity is reported after CBC monitoring on day 1 of any cycle, therapy with palbociclib should be interrupted; monitoring of CBCs should be repeated within 1 week.1, 21 The next cycle should be delayed until the toxicity resolves to grade 2 or less; therapy with palbociclib may be continued at the same dosage.1, 21
If grade 3 hematologic toxicity is reported after CBC monitoring on day 15 of cycle 1 or 2, palbociclib may be continued at the same dosa monitoring of CBCs should be repeated on day 22.1, 21 If grade 4 hematologic toxicity is reported after repeat CBC monitoring on day 22 of the cycle, therapy with palbociclib should be interrupted; therapy may be resumed at a reduced dosage when the toxicity resolves to grade 2 or less.1, 21
If prolonged (i.e., lasting longer than 7 days) recovery from grade 3 neutropenia occurs or grade 3 neutropenia recurs on day 1 of subsequent cycles, resumption of therapy at a reduced dosage may then be considered.1, 21
For grade 4 hematologic toxicity, therapy with palbociclib should be interrupted; therapy may be resumed at a reduced dosage when the toxicity resolves to grade 2 or less.1, 21
An exception is made for patients with grade 3 or 4 lymphopenia presenting without an associated clinical event such as an opportunistic infection; no dosage modification is required in such patients.1, 21
Interstitial Lung Disease/Pneumonitis
For severe interstitial lung disease (ILD)/pneumonitis, palbociclib therapy should be permanently discontinued.1, 21
If persistent grade 3 or greater nonhematologic toxicity occurs despite appropriate medical management, palbociclib therapy should be withheld until the toxicity resolves to grade 1 or less, or to grade 2 or less if the toxicity is not considered a safety risk for the patient.1, 21 Upon resumption of therapy, the palbociclib dosage should be reduced.1, 21
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of palbociclib with drugs that are strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided; an alternative drug with no or minimal CYP3A inhibition potential should be considered.1, 21 If concomitant use of a strong CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of palbociclib to 75 mg once daily.1, 21 If concomitant use of the strong CYP3A inhibitor is discontinued, the palbociclib dosage should be returned (after 3-5 terminal half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the strong CYP3A inhibitor.1, 21
For patients with severe hepatic impairment (Child-Pugh class C), the manufacturer recommends reducing the initial dosage of palbociclib to 75 mg once daily on days 1-21 of each 28-day cycle.1, 21 No dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1, 21
No dosage adjustment is necessary in patients with creatinine clearance >15 mL/minute.1, 21 Palbociclib has not been studied in patients requiring dialysis.1, 21
The manufacturer makes no specific dosage recommendations for geriatric patients.1, 21
Neutropenia is the most commonly occurring adverse reaction in studies of patients receiving palbociclib.1, 21 In the principal efficacy studies, grade 3 or greater neutropenia occurred in 66% of patients receiving palbociclib in combination with letrozole and those receiving palbociclib in combination with fulvestrant.1, 21 The median time to occurrence of neutropenia was 15 days.1, 21 The median duration of grade 3 or greater neutropenia was 7 days.1, 21 Febrile neutropenia has been observed in 1.8% of patients receiving palbociclib.1, 21 In the PALOMA-3 study, fatal neutropenic sepsis occurred in one patient.1, 21
Monitor complete blood counts (CBC) at baseline, prior to initiation of each cycle, and as clinically indicated; additional monitoring of CBC should be obtained on day 15 of cycles 1 and 2.1, 21 More frequent monitoring may be necessary in patients who develop hematologic toxicity during therapy.1, 21, 21 Temporary interruption, dosage reduction, or treatment delay may be necessary if neutropenia occurs during therapy with the drug.1, 21
Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis has occurred in patients receiving cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) inhibitors, including palbociclib in combination with endocrine therapy.1, 21 In the PALOMA-3, PALOMA-2, and PALOMA-1 studies, ILD or pneumonitis occurred in 1% of palbociclib-treated patients, and grade 3 or 4 ILD or pneumonitis occurred in 0.1% of patients receiving the drug.1, 21 No fatal cases of ILD or pneumonitis were reported in these studies; however, additional cases of ILD or pneumonitis, including fatal cases, have been reported during postmarketing experience in patients receiving palbociclib.1, 21
Patients receiving palbociclib should be monitored for symptoms of ILD and pneumonitis.1, 21 If manifestations suggestive of ILD or pneumonitis (e.g., hypoxia, cough, dyspnea, interstitial infiltrates) occur, palbociclib therapy should be temporarily interrupted and other etiologies (e.g., infection, neoplasm) should be excluded.1, 21 If severe ILD or pneumonitis occurs, therapy with palbociclib should be permanently discontinued.1, 21
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of palbociclib in pregnant women; however, based on its mechanism of action and animal findings, palbociclib may cause fetal harm.1, 21 Embryofetal toxicity (i.e., decreased fetal weight) and teratogenicity (i.e., skeletal alterations) have been demonstrated in rats and rabbits receiving palbociclib at exposure levels of approximately 4 and 9 times the human exposure at the recommended dosage, respectively;1, 21 however, embryofetal toxicity was not observed in the offspring of female rats receiving the drug from 15 days prior to breeding through day 7 of gestation at exposure levels of approximately 4 times the human exposure at the recommended dosage.1, 21
Pregnancy should be avoided during palbociclib therapy.1, 21 The manufacturer recommends confirmation of pregnancy status prior to initiation of palbociclib, and women of childbearing potential should be advised to use an effective method of contraception while receiving palbociclib and for at least 3 weeks after discontinuance of therapy.1, 21 Male patients should be advised to use an effective method of contraception while receiving palbociclib and for 3 months after discontinuance of therapy each time they have sexual contact with women of childbearing potential.1, 21 Patients should be apprised of the potential hazard to the fetus if used during pregnancy.1, 21
Palbociclib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1, 21 Pregnancy should be avoided during palbociclib therapy.1, 21 The manufacturer recommends confirmation of pregnancy status prior to initiation of palbociclib, and women of childbearing potential should be advised to use an effective method of contraception while receiving palbociclib and for at least 3 weeks after discontinuance of therapy.1, 21
It is not known whether palbociclib is distributed into human milk.1, 21 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to palbociclib in nursing infants, women should be advised to discontinue nursing during therapy and for 3 weeks after discontinuance of the drug.1, 21 The effects of the drug on nursing infants or on milk production are unknown.1, 21
Females and Males of Reproductive Potential
Results of animal studies suggest that palbociclib may impair male fertility.1, 21 Adverse effects on male reproductive organs and sperm (i.e., decreased organ weight, atrophy or degeneration, intratubular cellular debris, hypospermia, low sperm motility and density, decreased secretion) were observed in rats and dogs receiving palbociclib at exposure levels of approximately 10 or more and 0.1 times the human exposure at the recommended dosage, respectively, in a repeat-dose toxicity study; effects on male reproductive organs were partially reversible following a 4- and 12-week nondosing period in rats and dogs, respectively.1, 21 Decreased fertility also was observed in male rats receiving palbociclib at exposure levels 20 times the human exposure at the recommended dosage.1, 21
The manufacturer states that men should consider sperm preservation prior to initiating palbociclib therapy.1, 21
Pregnancy should be avoided during palbociclib therapy.1, 21 The manufacturer recommends confirmation of pregnancy status prior to initiation of palbociclib, and women of childbearing potential should be advised to use an effective method of contraception while receiving palbociclib and for at least 3 weeks after discontinuance of therapy.1, 21 Male patients should be advised to use an effective method of contraception while receiving palbociclib and for 3 months after discontinuance of therapy each time they have sexual contact with women of childbearing potential.1, 21 Patients should be apprised of the potential hazard to the fetus if used during pregnancy.1, 21
Safety and efficacy of palbociclib have not been established in pediatric patients younger than 18 years of age.1, 21 Safety and efficacy were assessed ( not established ) in 3 open-label trials including 140 pediatric patients (<17 years of age); no new safety signals occurred and palbociclib exposure in patients administered the drug as monotherapy or in combination were within range of those seen in adults administered a similar dosed based on body surface area.1, 21
Altered glucose metabolism associated with pancreatic islet cell vacuolation, cataracts, ocular lens degeneration, renal tubule vacuolation, chronic progressive nephropathy, and atrophy of adipose tissue have been observed in immature animals receiving palbociclib for 27 weeks (at exposure levels approximately 11 times the AUC in humans at the recommended dosage); tooth abnormalities (i.e., discoloration, ameloblast degeneration or necrosis, mononuclear cell infiltrate) also have been observed in animals receiving palbociclib at exposure levels approximately 15 times the AUC in humans at the recommended dosage.1, 21
In the PALOMA-2 study, 41% of palbociclib-treated patients were ≥65 years of age and 11% were ≥75 years of age.1, 21 In the PALOMA-3 study, 25% of palbociclib-treated patients were ≥65 years of age and 8% were ≥75 years of age.1, 21 No overall differences in safety and efficacy were observed between geriatric and younger patients.1, 21
In individuals with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment, AUC of the unbound fraction of palbociclib was increased by 34 or 77%, respectively, compared with individuals with normal hepatic function.1, 21 Peak plasma concentrations of the unbound fraction of palbociclib also were increased by 38 or 72% in individuals with moderate or severe hepatic impairment, respectively, compared with individuals with normal hepatic function.1, 21
In individuals with mild hepatic impairment (Child-Pugh class A), AUC of the unbound fraction of palbociclib was decreased by 17% and peak plasma concentrations of the unbound fraction of palbociclib were increased by 7% compared with individuals with normal hepatic function.1, 21 In a population pharmacokinetic analysis, no clinically important differences in systemic exposure of palbociclib were observed between patients with mild hepatic impairment (total bilirubin concentration not exceeding the upper limit of normal [ULN] with AST concentration exceeding the ULN, or total bilirubin concentration exceeding 1 to 1.5 times the ULN with any AST concentration) and those with normal hepatic function.1, 21
In vivo, the mean unbound fraction of palbociclib increased incrementally with worsening hepatic function.1, 21
The AUC of palbociclib was increased by 39, 42, or 31% in individuals with mild (creatinine clearance of 60 to less than 90 mL/minute), moderate (creatinine clearance of 30 to less than 60 mL/minute), or severe (creatinine clearance less than 30 mL/minute) renal impairment, respectively, compared with individuals with normal renal function.1, 21 Peak plasma concentrations of palbociclib were increased by 17, 12, or 15% in individuals with mild, moderate, or severe renal impairment, respectively, compared with individuals with normal renal function.1, 21 In a population pharmacokinetic analysis, no clinically important differences in systemic exposure of palbociclib were observed between patients with mild or moderate renal impairment and those with normal renal function.1, 21
In vivo, renal impairment does not appear to affect the mean unbound fraction of palbociclib.1, 21
Formal pharmacokinetic studies have not been conducted in patients requiring dialysis.1, 21
The most common adverse effects (≥20%) of palbociclib in combination with either letrozole or fulvestrant included decreased white blood cell count, decreased neutrophils, increased creatinine, decreased hemoglobin, decreased platelets, infections, increased AST and ALT, fatigue, nausea, stomatitis, diarrhea, and alopecia.1, 21
The most common adverse effects (≥20%) of palbociclib in combination with inavolisib and fulvestrant included decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.1, 21
Palbociclib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A and sulfotransferase (SULT) 2A1.1, 21 In vitro studies indicate that palbociclib does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 or induce CYP isoenzymes 1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations; however, in vivo studies indicate that the drug is a weak time-dependent inhibitor of CYP3A.1, 21
In vitro studies indicate that palbociclib has a low potential for inhibition of organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, OAT 3, organic anion transport protein (OATP) 1B1 and OATP1B3 at clinically relevant concentrations.1, 21 In vitro studies also indicate that palbociclib has potential to inhibit P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) at clinically relevant concentrations.1, 21
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of palbociclib with strong inhibitors of CYP3A may result in increased peak plasma concentrations and systemic exposure (AUC) of palbociclib.1, 21 When the strong CYP3A inhibitor itraconazole (200 mg daily) was administered concomitantly with palbociclib (single 125-mg dose) in healthy individuals, the peak plasma concentrations and AUC of palbociclib were increased by 34 and 87%, respectively.1, 21
Concomitant use of palbociclib with strong inhibitors of CYP3A (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir-boosted lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, verapamil, voriconazole) should be avoided, and selection of an alternative drug with no or minimal CYP3A inhibition potential should be considered.1, 21 If concomitant use of a strong CYP3A inhibitor cannot be avoided, the manufacturer recommends dosage reduction of palbociclib to 75 mg once daily.1, 21 If concomitant use of the strong CYP3A inhibitor is discontinued, the palbociclib dosage should be returned (after 3-5 terminal half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the strong CYP3A4 inhibitor.1, 21
Grapefruit products are CYP3A inhibitors and should be avoided because of the potential for increased plasma palbociclib concentrations during concurrent use.1, 21
Concomitant use of palbociclib with CYP3A inducers may result in decreased peak plasma concentrations and AUC of palbociclib.1, 21 When the strong CYP3A inducer rifampin (600 mg daily) was administered concomitantly with palbociclib (single 125-mg dose) in healthy individuals, the peak plasma concentrations and AUC of palbociclib were decreased by 70 and 85%, respectively.1, 21 When the moderate CYP3A inducer modafinil (400 mg daily) was administered concomitantly with palbociclib (single 125-mg dose) in healthy individuals, peak plasma concentrations and AUC of palbociclib were decreased by 11 and 32%, respectively.1, 21
Concomitant use of palbociclib with strong inducers of CYP3A (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) should be avoided.1, 21
Drugs Metabolized by Hepatic Microsomal Enzymes
When the CYP3A substrate midazolam was administered concomitantly with palbociclib in healthy individuals, peak plasma concentrations and AUC of midazolam were increased by 37 and 61%, respectively.1, 21 If concomitant use of palbociclib with CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) cannot be avoided, a dosage reduction of the CYP3A substrate should be considered.1, 21
Drugs Affecting Gastric Acidity
When multiple doses of the proton-pump inhibitor rabeprazole were administered concomitantly with palbociclib (single 125-mg dose) in healthy individuals, peak plasma concentrations and AUC of palbociclib were decreased by 41 and 13%, respectively, under fed conditions and by 80 and 62%, respectively, under fasting conditions.1, 21 Because effects on gastric pH are less marked with histamine H2-receptor antagonists or antacids compared with proton-pump inhibitors, decreases in palbociclib exposure are expected to be minimal when H2-receptor antagonists or antacids are used concomitantly with palbociclib under fed conditions.1, 21 Clinically important effects on palbociclib exposure were not observed when antacids, histamine H2-receptor antagonists, or proton-pump inhibitors were used concomitantly with palbociclib under fed conditions.1
Concomitant use of palbociclib and anastrozole is not expected to have a clinically important effect on the pharmacokinetics of either drug.1, 21
Concomitant use of palbociclib and exemestane is not expected to have a clinically important effect on the pharmacokinetics of either drug.1, 21
Concomitant administration of palbociclib and fulvestrant did not affect the pharmacokinetics of either drug.1, 21
Concomitant administration of palbociclib and goserelin did not affect the pharmacokinetics of either drug.1, 21
Concomitant administration of palbociclib and letrozole did not affect the pharmacokinetics of either drug.1, 21
Palbociclib, a reversible and selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, is an antineoplastic agent.1, 21 Several mechanisms contribute to the dysregulation of the cell cycle during the G1 into S phase, including amplification or overexpression of the cyclin D oncogene or the loss of intrinsic CDK inhibitors (i.e., p16, p15, p18, p19, p21, p27, p57)6, 9, 11, 13 in breast cancer.3, 5, 7, 8, 9, 11, 12, 13 Palbociclib specifically inhibits CDK4 and 6 and blocks the interaction of CDK4 and 6 with cyclin D, resulting in inhibition of phosphorylation of the tumor suppressor protein retinoblastoma and inhibition of progression of the cell cycle from the G1 into S phase.8 In vitro, palbociclib has demonstrated reduced cellular proliferation of estrogen receptor-positive breast cancer cell lines by inhibiting the G1 into S phase of the cell cycle.1, 21 Decreased phosphorylation of retinoblastoma protein resulting in reduced E2F expression and signaling and increased cell growth arrest have been reported in breast cancer cell lines treated with palbociclib and antiestrogens compared with either drug alone.1, 21 In vitro, the combination of palbociclib with antiestrogens increased cell senescence for up to 6 days following discontinuance of therapy in estrogen receptor-positive breast cancer cell lines.1, 21 The combination of palbociclib and letrozole also has demonstrated increased inhibition of retinoblastoma protein phosphorylation, downstream signaling, and tumor growth compared with either drug alone in patient-derived estrogen receptor-positive breast tumor xenografts.1, 21 In vitro, human bone marrow mononuclear cells treated with palbociclib with or without an antiestrogen did not become senescent and cell proliferation resumed following discontinuance of exposure.1, 21
Following oral administration, the mean absolute bioavailability of palbociclib is 46%.1, 21 AUC and peak plasma concentrations of palbociclib are dose proportional over a dosage range of 25-225 mg.1, 21 Peak plasma concentrations of palbociclib are achieved about 6-12 hours following oral administration of the capsules.1 Peak plasma concentrations are attained 4-12 hours following oral administration of the tablets.21 Following repeated doses of palbociclib administered once daily, steady-state concentrations of the drug were achieved in 8 days and the median accumulation ratio for the drug was 2.4.1, 21
Absorption and systemic exposure to palbociclib capsules were decreased in approximately 13% of individuals receiving the drug in a fasting state; systemic exposure to palbociclib increased when the drug was administered with food in these individuals, but administration with food did not alter systemic exposure to a clinically important extent in other individuals.1 Administration of palbociclib with food reduces the interindividual variability in systemic exposure to palbociclib.1 Oral administration of palbociclib capsules with a low-fat, low-calorie (approximately 400-500 calories) or high-fat, high-calorie meal (approximately 800-1000 calories) resulted in increases in systemic exposure of 12 or 21%, respectively, and increases in peak plasma concentrations of 27 or 38%, respectively, compared with administration in the fasting state.1 When an oral dose of palbociclib capsules was administered between 2 moderate-fat, standard-calorie meals (approximately 500-700 calories per meal) (i.e., single dose administered 1 hour after the first meal and 2 hours before the second meal), systemic exposure and peak plasma concentrations of the drug were increased by 13 and 24%, respectively, compared with administration in the fasting state.1 Oral administration of palbociclib tablets with a high-fat, high-calorie meal (approximately 800-1000 calories per meal) or with a moderate-fat, standard-calorie meal (approximately 500-700 calories per meal) resulted in increases in systemic exposure of 22 or 9%, respectively, and increases in peak plasma concentrations of 26 or 10%, respectively, compared with administration of the tablets in the fasting state.21
Palbociclib is metabolized in the liver principally by cytochrome P-450 (CYP) isoenzyme 3A and sulfotransferase (SULT) 2A1.1, 21 In vitro, palbociclib is approximately 85% bound to plasma proteins.1, 21 Following oral administration of a single radiolabeled dose of palbociclib, 74.1% of the radioactivity was recovered in feces and 17.5% was recovered in urine; the majority of the dose was excreted as metabolites.1, 21 The mean plasma elimination half-life of the drug is 29 hours.1, 21
Population pharmacokinetic analyses indicate that age (22-89 years), sex, race (Asian versus non-Asian), and body weight do not have clinically important effects on the exposure of palbociclib.1, 21
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Palbociclib is obtained from specialty pharmacy providers.4 Contact manufacturer for additional information.4
1. Pfizer. Ibrance® (palbociclib) capsules prescribing information. New York, NY; 2025 Sept. [Web]
3. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med . 2014; 7:203-15. [PubMed 25206307]
4. Pfizer. Where can I get Ibrance?. From Ibrance® website. [Web]
5. Morikawa A, Henry NL. Palbociclib for the Treatment of Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Clin Cancer Res . 2015; 21:3591-6. [PubMed 26100274]
6. Rocca A, Farolfi A, Bravaccini S et al. Palbociclib (PD 0332991) : targeting the cell cycle machinery in breast cancer. Expert Opin Pharmacother . 2014; 15:407-20. [PubMed 24369047]
7. Murphy CG, Dickler MN. The Role of CDK4/6 Inhibition in Breast Cancer. Oncologist . 2015; 20:483-90. [PubMed 25876993]
8. Mangini NS, Wesolowski R, Ramaswamy B et al. Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer. Ann Pharmacother . 2015; 49:1252-60. [PubMed 26324355]
9. Vidula N, Rugo HS. Cyclin-Dependent Kinase 4/6 Inhibitors for the Treatment of Breast Cancer: A Review of Preclinical and Clinical Data. Clin Breast Cancer . 2016; 16:8-17. [PubMed 26303211]
10. Cadoo KA, Gucalp A, Traina TA. Palbociclib: an evidence-based review of its potential in the treatment of breast cancer. Breast Cancer (Dove Med Press) . 2014; 6:123-33. [PubMed 25177151]
11. Finn RS, Dering J, Conklin D et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res . 2009; 11:R77.
12. Sutherland RL, Musgrove EA. CDK inhibitors as potential breast cancer therapeutics: new evidence for enhanced efficacy in ER+ disease. Breast Cancer Res . 2009; 11:112. [PubMed 20067604]
13. DeMichele A, Clark AS, Tan KS et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res . 2015; 21:995-1001. [PubMed 25501126]
15. 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. Lancet Oncol . 2016; :. [PubMed 26947331]
16. Turner NC, Slamon DJ, Ro J et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med . 2018; 379:1926-1936. [PubMed 30345905]
17. Food and Drug Administration. Drug safety communication: FDA warns about rare but severe lung inflammation with Ibrance®, Kisqali®, and Verzenio® for breast cancer. Silver Spring, MD; 2019 Sept 13. From FDA website. [Web]
18. Iwata H, Im SA, Masuda N et al. PALOMA-3: Phase III Trial of Fulvestrant With or Without Palbociclib in Premenopausal and Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That Progressed on Prior Endocrine Therapy-Safety and Efficacy in Asian Patients. J Glob Oncol . 2017; 3:289-303. [PubMed 28831437]
20. Diéras V, Harbeck N, Joy AA et al. Palbociclib with Letrozole in Postmenopausal Women with ER+/HER2- Advanced Breast Cancer: Hematologic Safety Analysis of the Randomized PALOMA-2 Trial. Oncologist . 2019; [PubMed 31217344]
21. Pfizer. Ibrance® (palbociclib) tablets prescribing information. New York, NY; 2025 Sept. [Web]
22. Finn R, Martin M, Rugo H, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med . 2016;375(20):1925-1936.
23. Rugo H, Finn R, Dieras V, et al. Palbociclib plus letrozole as first-line therapy in estrogen-receptor positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat . 2019;174(3):719-729.
24. Slamon D, Dieras V, Rugo H, et al. Overall survival with palbociclib plus letrozole in advanced breast cancer. J Clin Oncol . 2024;42:994-1000.
25. Cristofanilli M, Rugo H, Im S, et al. Overall survival with palbociclib and fulvestrant in women with HR+/HER2- ABC: updated exploratory analyses of PALOMA-3, a double-blind, phase III randomized study. Clin Cancer Res . 2022;28:3433-3442.
26. Burstein HJ, DeMichele A, Fallowfield L, et al. Endocrine and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer-capivasertib-fulvestrant: ASCO rapid recommendation update. J Clin Oncol . 2024;42(12):1450-1453.
27. Burstein HJ, Somerfield MR, Barton DL et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol . 2021; 39:3959-3977.
28. Jhaveri KL, Im SA, Saura C, et al. Overall survival with inavolisib in PIK3CA-mutated advanced breast cancer. N Engl J Med . 2025;393:151-61.
29. Trapani D, Martins-Branco D, Curigliano G, et al. on behalf of the ESMO guidelines committee. Updated treatment recommendations for systemic treatment: from the ESMO Metastatic Breast Cancer Living Guidelines. Ann Oncol . 2025;36(11):1414-18.
10001. Ran R, Ma Y, Wang H, Yang J, Yang J. Treatment strategies for hormone receptor-positive, human epidermal growth factor receptor-2 positive (HR+/HER2+) metastatic breast cancer: a review. Front Oncol. 2022;12:975463.
10002. Metzger O, Mandrekar S, DeMichele A, et al. AFT-38 PATINA: a randomized, open-label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy vs anti-HER2 therapy + endocrine therapy after induction treatment for hormone receptor positive (HR+)/HER2-positive metastatic breast cancer. San Antonio Breast Cancer Symposium. December 10-13, 2024.