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 240mg/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.

Keywords: Antitumor activity; Apalutamide; Castration-resistant prostate cancer; Safety.

Fig. 1

Study design. Progression-free survival not analyzed for the nonmetastatic castration-resistant prostate cancer (nmCRPC) cohort and for four patients with metastatic disease not included in the nmCRPC efficacy analysis. AA = abiraterone acetate; CRPC = castration-resistant prostate cancer; mCRPC = metastatic castration-resistant prostate cancer; PSA = prostate-specific antigen.

Fig. 2

Patient disposition. PSA = prostate-specific antigen. ^*Patients may have discontinued due to more than one type of progression.

Fig. 3

Waterfall plot for (A) 12-wk prostate-specific antigen (PSA) response and (B) maximal PSA response at any time.

Fig. 4

Secondary end points: (A) Time to prostate-specific antigen progression (PSA); (B) metastasis-free survival. CI = confidence interval; NR = not reached.