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Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel–prednisone in metastatic castration-resistant prostate cancer

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Summary

Background: Docetaxel–prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods: Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m2 every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. Results: In phase 1 (n = 6, orteronel 200 mg; n = 8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n = 23). After 4 cycles, 68, 59, and 23 % of patients achieved ≥30, ≥50, and ≥90 % PSA reductions, respectively; median best PSA response was −77 %. Seven of 10 (70 %) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78 %), alopecia (61 %), diarrhea (48 %), nausea (43 %), dysgeusia (39 %), and neutropenia (39 %). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. Conclusions: Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses.

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Acknowledgments

The authors would like to thank the patients who participated in this study and their families, as well as staff at all investigational sites. Stephen Mosley and Emma Landers of FireKite, part of the KnowledgePoint360 Group, an Ashfield Company, provided writing support during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc., and complied with Good Publication Practice 2 guidelines (Graf C, et al. BMJ 2009;339:b4330).

Disclosures

Employment: NK, SM, AS, MB (Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited).

Consultancy or membership on board of directors or advisory committee: DPP, DBA (Millennium Pharmaceuticals, Inc.), WKO (Bellicum).

Research funding: DPP, EH, WKO, WRC (Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), DPP (Sanofi-Aventis).

Honoraria: WKO (Janssen, Dendreon, Medivation, Sanofi, Astellas).

Conflicts of interest

None.

Disclosure of financial support

This research was funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

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Authors and Affiliations

  1. Department of Medicine, Smilow Cancer Center, Yale University Medical Center, 333 Cedar Street, PO Box 208032, New Haven, CT, 06520, USA

    Daniel P. Petrylak

  2. Associates in Oncology and Hematology, Chatanooga, TN, USA

    Jitendra G. Gandhi

  3. Alaska Clinical Research Center, Anchorage, AK, USA

    William R. Clark

  4. Department of Oncology, Karmanos Cancer Institute, Detroit, MI, USA

    Elisabeth Heath

  5. Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA

    Jianqing Lin

  6. Division of Hematology and Medical Oncology, Mount Sinai Hospital, New York, NY, USA

    William K. Oh

  7. Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

    David B. Agus

  8. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Bradley Carthon

  9. Oncology Clinical Research, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA

    Susan Moran

  10. Biostatistics, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA

    Ning Kong

  11. Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA

    Ajit Suri & Michael Bargfrede

  12. Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    Glenn Liu

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  1. Daniel P. Petrylak
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Correspondence to Daniel P. Petrylak.

Electronic supplementary material

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Supplementary Table 1

Summary of PK parameters for orteronel and docetaxel alone, and in combination (DOC 78 kb)

Supplementary Table 2

Statistical analysis of plasma pharmacokinetics parameters for orteronel and docetaxel, alone and in combination (DOC 81 kb)

Supplementary Fig. 1

Change from baseline in median serum levels of (a) DHEA-S and (b) testosterone. DHEA-S, dehydroepiandrosterone-sulfate (GIF 32 kb)

High resolution image (EPS 1103 kb)

Supplementary Fig. 2

Mean (±SD) plasma concentration-time profiles for (a) orteronel ± docetaxel and (b) docetaxel ± orteronel. SD, standard deviation (GIF 68 kb)

High resolution image (EPS 1127 kb)

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Petrylak, D.P., Gandhi, J.G., Clark, W.R. et al. Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel–prednisone in metastatic castration-resistant prostate cancer. Invest New Drugs 33, 397–408 (2015). https://doi.org/10.1007/s10637-014-0199-x

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