Palbociclib
Overview
Palbociclib is an oral targeted anticancer therapy used in the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced or metastatic breast cancer. Classified as a cyclin-dependent kinase (CDK) 4/6 inhibitor, palbociclib works by blocking specific proteins involved in cell division, leading to the arrest of cancer cell growth. It is most often prescribed in combination with endocrine therapies such as aromatase inhibitors (e.g., letrozole) or selective estrogen receptor downregulators (e.g., fulvestrant). The medicine has been shown to significantly improve progression-free survival in its target patient group. Administered in cycles, palbociclib allows normal cells time to recover between dosing periods, helping to balance efficacy with tolerability.
Background and Date of Approval
Palbociclib was developed by Pfizer and represents one of the first CDK4/6 inhibitors approved for clinical use. It received accelerated approval from the United States Food and Drug Administration (FDA) in February 2015 for use in combination with letrozole in postmenopausal women with HR+/HER2– advanced breast cancer as initial endocrine-based therapy. This decision was based on the phase II PALOMA-1 trial, which demonstrated a substantial improvement in median progression-free survival compared to letrozole alone. Further evidence from the phase III PALOMA-2 trial confirmed these benefits, leading to full approval in 2017. Additional approval for use with fulvestrant in patients who experienced disease progression following prior endocrine therapy was granted after results from the phase III PALOMA-3 trial. Regulatory bodies including the European Medicines Agency (EMA) and the Drugs Controller General of India (DCGI) have also approved palbociclib for similar indications, expanding global access.
Uses
Palbociclib is indicated for the treatment of HR+/HER2– advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women and men. It is also indicated in combination with fulvestrant for patients with disease progression following endocrine therapy. While its primary use is in breast cancer, ongoing research is evaluating its potential role in other hormone-driven cancers, including certain subtypes of prostate and ovarian cancer, though these are not yet standard indications.
Administration
Palbociclib is taken orally at a recommended starting dose of 125 mg once daily for 21 consecutive days, followed by a 7-day treatment-free interval to complete a 28-day cycle. The capsules should be swallowed whole with food, and patients are advised to take the dose at the same time each day. Dose modifications to 100 mg or 75 mg daily may be required to manage side effects, particularly hematologic toxicities. Baseline and periodic complete blood counts are essential to monitor for treatment-related cytopenias.
Side Effects
Frequent side effects of palbociclib include neutropenia, leukopenia, fatigue, nausea, stomatitis, anemia, hair thinning, diarrhea, and upper respiratory tract infections. Neutropenia is the most common and typically occurs during the first two treatment cycles. Most cases are reversible with dose interruptions or reductions. Patients should be educated to report symptoms of infection promptly, particularly fever or sore throat.
Warnings
Serious adverse events can include febrile neutropenia, severe infections, and interstitial lung disease (ILD). Rare but potentially life-threatening ILD cases have been reported, requiring immediate discontinuation if suspected. Palbociclib is contraindicated in patients with hypersensitivity to the drug or any of its components. Caution is advised in patients with significant hepatic impairment, and the drug should be avoided during pregnancy due to potential harm to the fetus.
Precautions
Palbociclib is primarily metabolized by CYP3A enzymes. Strong CYP3A inhibitors such as ketoconazole and clarithromycin may increase palbociclib exposure and risk of toxicity, while strong CYP3A inducers such as rifampin and carbamazepine may reduce efficacy. Concomitant use of these drugs should be avoided where possible, or dosing adjustments considered. Grapefruit and grapefruit juice can also increase plasma concentrations and should be avoided. Effective contraception is recommended for patients of reproductive potential during treatment and for at least three weeks after the last dose.
Expert Tips
Prescribers should emphasize the importance of adherence to the 21-days-on, 7-days-off schedule and reinforce the need for routine blood count monitoring, particularly early in treatment. Pharmacists should counsel patients on recognizing infection signs and avoiding grapefruit products. Dose modifications should be guided by toxicity management protocols to maintain treatment continuity without compromising safety. Combination with endocrine therapy should be maintained as per indication unless disease progression or intolerance occurs.