Background Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. Objective To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). Design, setting, and participants We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo). Intervention Patients received 240 mg/d apalutamide while continuing on androgen-deprivation therapy. Outcome measurements and statistical analysis Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS). Results and limitations A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo–not reached [NR]); median MFS was NR (95% CI, 33.4 mo–NR). Most of the patients discontinued study treatment (n = 33) due to disease progression (n = 11 [22%]) or adverse events (AEs) (n = 9 [18%]). The most common AE was fatigue (any grade, n = 31 [61%]) although grade ≥3 fatigue was uncommon (n = 2 [4%]). These represent the first apalutamide nmCRPC patient clinical data. Conclusions In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control. Patient summary Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting. Trial registration ClinicalTrials.gov identifier NCT01171898
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Financial disclosures: Matthew R. Smith certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Matthew R. Smith has served as a consultant to Janssen Research & Development. Emmanuel S. Antonarakis has served as a consultant/adviser to Janssen Biotech, Astellas, Medivation, ESSA, Sanofi, and Dendreon; he has received research funding from Aragon Pharmaceuticals, Johnson & Johnson, Janssen Biotech, Astellas, Tokai, Sanofi, Dendreon, Exelixis, Novartis, and Genentech. Charles J. Ryan has received honoraria from Janssen Research & Development. William R. Berry has received research grants from AHRQ. Neal D. Shore is a consultant/adviser to Algeta, Amgen, Bayer, BNI, Dendreon, Ferring, Janssen, Millennium, and Sanofi. Glenn Liu has nothing to report. Joshi J. Alumkal has received research funding from Aragon Pharmaceuticals. Celestia S. Higano received consulting fees or honoraria from AbbVie, Algeta, Astellas, Bayer, Dendreon, Genentech, Johnson & Johnson, Medivation, Novartis, Pfizer, and Veridex; grants or research support from Amgen, Aragon Pharmaceuticals, AstraZeneca, Bayer, Dendreon, Exelixis, Genentech, Johnson & Johnson, Medivation, Millennium, Novartis, OncoGenex, Sanofi-Aventis US, Taxynergy, and Teva; and other financial benefits from Cell Therapeutics. Edna Chow Maneval was an employee at Aragon Pharmaceuticals. Rajesh Bandekar is an employee of Janssen Research & Development and holds stock and stock options in Johnson & Johnson. Carla J. de Boer is an employee of Janssen Biologics and holds stock and stock options in Johnson & Johnson. Margaret K. Yu is an employee of Janssen Research & Development and holds stock and stock options in Johnson & Johnson. Dana E. Rathkopf has served as a consultant/adviser to and has received research funding from Janssen Research & Development, AstraZeneca, Celgene, Ferring, Medivation, Millennium/Takeda, and Novartis.
Funding/Support and role of the sponsor: This study was funded by Aragon Pharmaceuticals, Inc. and supported by Janssen Research & Development. The sponsors were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Janssen Research & Development, LLC, is performing work on behalf of Aragon. Writing assistance was funded by Janssen Global Services, LLC.
- Antitumor activity
- Castration-resistant prostate cancer