Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort

Matthew R. Smith, Emmanuel S. Antonarakis, Charles J. Ryan, William R. Berry, Neal D. Shore, Glenn Liu, Joshi Alumkal, Celestia S. Higano, Edna Chow Maneval, Rajesh Bandekar, Carla J. de Boer, Margaret K. Yu, Dana E. Rathkopf

    Research output: Contribution to journalArticle

    49 Citations (Scopus)

    Abstract

    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 The androgen receptor antagonist apalutamide was safe in patients with high-risk nonmetastatic castration-resistant prostate cancer and, based on durable prostate-specific antigen responses and disease control, exhibited robust activity. These results support continued clinical development of apalutamide in future efficacy and safety studies.

    Original languageEnglish (US)
    JournalEuropean Urology
    DOIs
    StateAccepted/In press - 2016

    Fingerprint

    Androgen Receptor Antagonists
    Castration
    Prostatic Neoplasms
    Prostate-Specific Antigen
    Safety
    Androgen Receptors
    ARN-509
    Fatigue
    Confidence Intervals
    Neoplasm Metastasis
    Neoplasm Grading

    Keywords

    • Antitumor activity
    • Apalutamide
    • Castration-resistant prostate cancer
    • Safety

    ASJC Scopus subject areas

    • Urology

    Cite this

    Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. / Smith, Matthew R.; Antonarakis, Emmanuel S.; Ryan, Charles J.; Berry, William R.; Shore, Neal D.; Liu, Glenn; Alumkal, Joshi; Higano, Celestia S.; Chow Maneval, Edna; Bandekar, Rajesh; de Boer, Carla J.; Yu, Margaret K.; Rathkopf, Dana E.

    In: European Urology, 2016.

    Research output: Contribution to journalArticle

    Smith, Matthew R. ; Antonarakis, Emmanuel S. ; Ryan, Charles J. ; Berry, William R. ; Shore, Neal D. ; Liu, Glenn ; Alumkal, Joshi ; Higano, Celestia S. ; Chow Maneval, Edna ; Bandekar, Rajesh ; de Boer, Carla J. ; Yu, Margaret K. ; Rathkopf, Dana E. / Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. In: European Urology. 2016.
    @article{a076172c158741809819bfdeb3b2f840,
    title = "Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort",
    abstract = "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 The androgen receptor antagonist apalutamide was safe in patients with high-risk nonmetastatic castration-resistant prostate cancer and, based on durable prostate-specific antigen responses and disease control, exhibited robust activity. These results support continued clinical development of apalutamide in future efficacy and safety studies.",
    keywords = "Antitumor activity, Apalutamide, Castration-resistant prostate cancer, Safety",
    author = "Smith, {Matthew R.} and Antonarakis, {Emmanuel S.} and Ryan, {Charles J.} and Berry, {William R.} and Shore, {Neal D.} and Glenn Liu and Joshi Alumkal and Higano, {Celestia S.} and {Chow Maneval}, Edna and Rajesh Bandekar and {de Boer}, {Carla J.} and Yu, {Margaret K.} and Rathkopf, {Dana E.}",
    year = "2016",
    doi = "10.1016/j.eururo.2016.04.023",
    language = "English (US)",
    journal = "European Urology",
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    TY - JOUR

    T1 - Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort

    AU - Smith, Matthew R.

    AU - Antonarakis, Emmanuel S.

    AU - Ryan, Charles J.

    AU - Berry, William R.

    AU - Shore, Neal D.

    AU - Liu, Glenn

    AU - Alumkal, Joshi

    AU - Higano, Celestia S.

    AU - Chow Maneval, Edna

    AU - Bandekar, Rajesh

    AU - de Boer, Carla J.

    AU - Yu, Margaret K.

    AU - Rathkopf, Dana E.

    PY - 2016

    Y1 - 2016

    N2 - 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 The androgen receptor antagonist apalutamide was safe in patients with high-risk nonmetastatic castration-resistant prostate cancer and, based on durable prostate-specific antigen responses and disease control, exhibited robust activity. These results support continued clinical development of apalutamide in future efficacy and safety studies.

    AB - 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 The androgen receptor antagonist apalutamide was safe in patients with high-risk nonmetastatic castration-resistant prostate cancer and, based on durable prostate-specific antigen responses and disease control, exhibited robust activity. These results support continued clinical development of apalutamide in future efficacy and safety studies.

    KW - Antitumor activity

    KW - Apalutamide

    KW - Castration-resistant prostate cancer

    KW - Safety

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