How does Carbozatinib (Cabozantinib) affect fertility in patients with medullary thyroid cancer?

Cabozantinib's Impact on Fertility in Medullary Thyroid Cancer Patients

Based on nonclinical findings, cabozantinib significantly impairs both male and female fertility, with evidence showing decreased sperm counts, reduced reproductive organ weights, and decreased embryo viability in animal studies. 1

Effects on Male Fertility

Cabozantinib has demonstrated significant negative impacts on male fertility in preclinical studies:

• In fertility studies with rats, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately 13-fold of human AUC at the recommended dose), with documented:

  • Decrease in sperm counts
  • Reduction in reproductive organ weights 1

• In 6-month toxicology studies in dogs, hypospermia was observed at plasma exposures approximately 0.5-fold of those expected in humans at the recommended dose 1

Effects on Female Fertility

The impact on female fertility is equally concerning:

• Female fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (5-fold of human AUC at the recommended dose) with:

  • Significant decrease in the number of live embryos
  • Significant increase in pre- and post-implantation losses 1

• Female rats administered 5 mg/kg/day for 14 days (approximately 9-fold of human AUC at the recommended dose) exhibited ovarian necrosis 1

• In 6-month toxicology studies in dogs, absence of corpora lutea was observed at plasma exposures <0.1-fold of those expected in humans at the recommended dose 1

Clinical Implications for MTC Patients

Fertility Preservation Considerations

For patients with medullary thyroid cancer who need cabozantinib treatment but are concerned about fertility:

1. Pre-treatment fertility preservation is critical:

   • ASCO guidelines recommend discussing fertility preservation options before starting treatment 2
   • Expeditious referrals to reproductive specialists are essential as some preservation methods require timing with menstrual cycles 2

2. For male patients:

   • Sperm banking is the most established and successful option 2
   • Should be completed before initiating cabozantinib therapy 2

3. For female patients:

   • Embryo and egg freezing are the most established options 2
   • These procedures typically take 2-4 weeks and must be completed before starting treatment 2

Treatment Considerations

When treating MTC with cabozantinib, clinicians should consider:

• Cabozantinib is effective for progressive metastatic MTC, with studies showing improved progression-free survival compared to placebo (11.2 months vs 4.0 months) 3

• The standard dose for MTC is 140 mg/day in capsules, though a tablet formulation at 60 mg/day is used for other cancers 4

• Common adverse events include diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue 3

Patient Counseling Points

When discussing cabozantinib with MTC patients of reproductive age:

1. Inform patients about fertility risks before initiating treatment 2

2. Discuss fertility preservation options and provide referrals to reproductive specialists 2

3. Consider psychological support for patients experiencing distress about potential infertility 2

4. Emphasize time sensitivity of fertility preservation procedures, which must be completed before starting cabozantinib 2

5. Address insurance coverage concerns and connect patients with advocacy organizations that may provide cost-saving programs 2

Key Pitfalls to Avoid

• Delaying fertility discussions: Fertility preservation options should be discussed at the earliest opportunity, ideally at diagnosis or before treatment planning 2

• Overlooking psychological impact: Fertility concerns can cause significant distress; referral for psychological counseling should be offered 2

• Assuming reversibility: Unlike some cancer treatments where fertility effects may be temporary, preclinical data suggests cabozantinib's effects on fertility may be significant 1

• Neglecting to discuss with male patients: While female fertility is often the focus, male patients should also be counseled about fertility preservation options 2