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Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC)

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Abstract

Purpose

Recent data indicate that there is a significant cross-talk between the PI3K/Akt/mTOR and androgen receptor signaling pathways. We evaluated safety and tolerability as well as potential drug–drug interaction of ridaforolimus, a mammalian target of rapamycin (mTOR) inhibitor, when combined with the androgen receptor inhibitor bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer.

Patients and methods

Patients were treated with the combination of ridaforolimus 30 mg/day for 5 consecutive days each week and bicalutamide 50 mg/day. Ridaforolimus pharmacokinetics was assessed with and without bicalutamide.

Results

Twelve patients were enrolled including 1 screen failure. Dose reductions were required in 7 patients. Three of the 11 patients experienced a dose-limited toxicity, 1 with Grade 3 hyperglycemia and 2 with Grade 2 stomatitis leading to <75 % of planned ridaforolimus dose during the first 35 days of study treatment. The pharmacokinetic results showed no differences in exposures to ridaforolimus with and without concomitant bicalutamide administration.

Conclusions

Although there was no evidence of a clinically relevant pharmacological drug–drug interaction, the occurrence of dose-limiting toxicities in 3 of 11 evaluable patients at a reduced dose of ridaforolimus of 30 mg/day suggests that this combination may not be well suited for asymptomatic or minimally symptomatic prostate cancer patients.

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Acknowledgments

We thank Scott Vuocolo, PhD, of Merck for his critical review of the paper and editorial assistance. This work was supported by Merck, Whitehouse Station, USA. R. de Wit has received grant support and data management support from Merck.

Conflict of interest

The other authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3008 AE, Rotterdam, The Netherlands

    Hielke J. Meulenbeld & Ronald de Wit

  2. The Royal Marsden National Health Services Foundation Trust, Sutton, Surrey, UK

    Johann S. de Bono

  3. The Institute of Cancer Research, Sutton, Surrey, UK

    Johann S. de Bono

  4. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College of Cornell University, New York, NY, USA

    Scott T. Tagawa

  5. Division of Hematology-Oncology, Department of Medicine, Lineburger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Young E. Whang

  6. Merck Research Laboratories, North Wales, PA, USA

    Xiaoyun Li, Karl H. Heath, Anthe S. Zandvliet & Scot W. Ebbinghaus

  7. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

    Gary R. Hudes

Authors
  1. Hielke J. Meulenbeld
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  2. Johann S. de Bono
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  3. Scott T. Tagawa
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  4. Young E. Whang
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  5. Xiaoyun Li
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  8. Scot W. Ebbinghaus
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  9. Gary R. Hudes
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  10. Ronald de Wit
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Corresponding author

Correspondence to Hielke J. Meulenbeld.

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Meulenbeld, H.J., de Bono, J.S., Tagawa, S.T. et al. Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC). Cancer Chemother Pharmacol 72, 909–916 (2013). https://doi.org/10.1007/s00280-013-2250-6

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  • DOI: https://doi.org/10.1007/s00280-013-2250-6

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