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XTANDI inhibits multiple steps of the androgen receptor (AR) signaling pathway

In preclinical studies, XTANDI induced tumor cell death by inhibiting AR signaling at multiple steps within the prostate cell.*1-3
Watch the video to learn about the mechanism of action (MOA) of XTANDI.

  • 1

    Introduction

    Introduction

  • 2

    Inhibition of Multiple Steps

    Inhibition of Multiple Steps

  • 3

    Cell Death

    Cell Death

  • 4

    Rational Design

    Rational Design

  • 5

    Conclusion

    Conclusion

XTANDI was rationally designed to address AR overexpression and the potential agonist properties of first-generation AR inhibitors (ARI)2,3

XTANDI results in preclinical studies

*Clinical significance is unknown.
†In vitro.

 
 

Based on current understanding, the MOA does not involve suppression of the corticosteroid synthesis pathways1,3,4

NO detrimental effect on mineralocorticoid balance3,4

NO difference in testosterone levels between patients treated with XTANDI and patients receiving placebo in the AFFIRM study3

Indication

XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety Information

Contraindications  XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions  In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Adverse Reactions  The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1-­4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-­4) and in 6% of patients on placebo (no grade 3-­4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI

patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event.

Drug Interactions: Effect of Other Drugs on XTANDI  Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Effect of XTANDI on Other Drugs  XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see Full Prescribing Information for complete safety information.

References

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