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Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study

  • PHASE II STUDIES
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Summary

Introduction Ketoconazole is CYP-17 inhibitor with demonstrated activity in men with castration-resistant prostate cancer (CRPC). Lenalidomide is an antiangiogenic and immunomodulatory agent with broad antitumor activity. We hypothesized that the modulation of the cellular immune response to apoptosis caused by ketoconazole may be increased with the addition of lenalidomide. Methods This is an open-label, non-randomized, single-arm phase II study evaluating the efficacy and safety of the combination of ketoconazole and lenalidomide in patients with CRPC. Treatment schema included standard ketoconazole 400 mg orally three times daily plus hydrocortisone orally (20 mg in the morning and 10 mg at night) in combination with lenalidomide 25 mg orally daily for 21 days in a 28-day cycle and aspirin 75 mg daily. The primary endpoint of this study was response (either by ≥ 50% PSA decline or objective disease assessed by RECIST v1.0). Exploratory endpoints included changes in T cell, dendritic cell (DC) marker counts, and their correlation with PSA response to treatment. Results A total of 34 CRPC patients, median age 69 years, 76% ECOG 0 and 76% with metastases participated in the study. Patients received a median of 2 cycles (range 1–35); nine patients (26%) received >10 cycles of treatment. PSA responses were observed in 17 patients (50%) with 11 patients (32%) achieving a PSA decline of >90%. Among the 9 patients with measurable disease, 2 patients (22%) had PR and 2 other (22%) had SD as best response. Median time to failure (TTF) was 2.7 months (range 0.2–32.8); and 8 patients were treated for ≥ 15 months. Most common adverse events included fatigue (76%), skin reactions (62%), lymphopenia (44%) and anemia (44%). One possible treatment-related death was noted. For 16 patients with available serial correlative data, there was a significant increase in the dendritic cells subsets BDCA-1 (+146.7, −20.1 to +501.1%, p = 0.018) and BDCA-3 (39.8%, −100 to 282.6%, p = 0.001) after 8 weeks of treatment. No association between immune cell counts and PSA response at 8 weeks was observed. Conclusion The combination of ketoconazole and lenalidomide was well tolerated but did not meet the primary endpoint of response, despite durable responses were observed in a selected group of patients. Although ketoconazole has now been replaced with more active novel agents, the combination of novel CYP-17 inhibitors with agents capable of modulating the immune system warrants further prospective investigation. NCT00460031.

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Authors and Affiliations

  1. Case Comprehensive Cancer Center, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave/CA60, Cleveland, OH, 44195, USA

    Pedro C. Barata, Prateek Mendiratta, Allison Tyler & Jorge A. Garcia

  2. Case Comprehensive Cancer Center, University Hospitals Seidman Cancer Center, Cleveland, OH, USA

    Matthew Cooney

  3. Division Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA

    Robert Dreicer

  4. Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA

    Jorge A. Garcia

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Correspondence to Jorge A. Garcia.

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Conflicts of interest

Pedro Barata declares that he has no conflicts of interest. Matthew Cooney declares that he has no conflicts of interest. Prateek Mendiratta declares that he has no conflicts of interest. Allison Tyler declares that she has no conflicts of interest. Robert Dreicer declares that he has no conflicts of interest. Jorge A. Garcia declares that he has no conflicts of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Barata, P.C., Cooney, M., Mendiratta, P. et al. Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study. Invest New Drugs 36, 1085–1092 (2018). https://doi.org/10.1007/s10637-018-0660-3

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