SUMMARY  

• The efficacy and safety of the use of ERLEADA without androgen deprivation therapy (ADT) has not been established.
• Evidence-based guidelines recommend using ADT to maintain castrate levels of serum testosterone (<50 ng/dL) even in patients with castration-resistant prostate cancer.¹
• In the phase 3 TITAN and SPARTAN studies that evaluated the efficacy and safety of ERLEADA 240 mg orally once daily compared to placebo in patients with metastatic castration-sensitive prostate cancer (mCSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC), respectively, all patients received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy.^2-5
• Results from a phase 2 study evaluating ADT plus abiraterone acetate with prednisone (AAP), ERLEADA, and ERLEADA plus AAP in patients with multiple clinical states of prostate cancer, including newly diagnosed metastatic prostate cancer, have been reported (N=128).⁶
  • Primary and secondary endpoint results at week 25 are described below. With a median follow-up of 14 months, prostate-specific antigen (PSA) ≤0.2 ng/mL was achieved by 75.6% (95% confidence interval [CI], 59.7-87.6) of patients in the ADT plus AAP arm, 60.0% (95% CI, 43.3-75.1) of patients in the ERLEADA arm, and 79.5% (95% CI, 63.5-90.7) of patients in the ERLEADA plus AAP arm.⁶
  • The estimated 2-year overall survival (OS) rate was 87.9% (95% CI, 77.9-97.8) with ERLEADA, 92.7% (95% CI, 84.8-100) with ERLEADA plus AAP, and 92.5% (95% CI, 84.3-100) with AAP plus ADT (P=0.5926).⁷
  • Grade 3-4 adverse events (AEs) occurred in 31.0%, 21.4% and 36.4% of patients in the ADT plus AAP, ERLEADA, and ERLEADA plus AAP arms, respectively (Table: Adverse Events). Treatment-related adverse events (TRAEs) of all grades were observed in 71.4% of patients in the ADT plus AAP arm, 81.0% of patients in the ERLEADA arm, and 81.8% of patients in ERLEADA plus AAP arm.⁶
• No published literature was identified that evaluated the use of ERLEADA without ADT for the treatment of patients with nmCRPC.
• Results from phase 2 studies in other clinical states of prostate cancer have been reported.^8-11

Clinical Data

Phase 2 Study

Maluf et al (2021)⁶ reported results of a phase 2 study, LACOG-0415, that evaluated the efficacy and safety of ERLEADA, ERLEADA plus AAP, and AAP plus ADT in patients (N=128) with multiple clinical states of prostate cancer, including newly diagnosed metastatic prostate cancer (NCT02867020).

Study Design/Methods

• Phase 2, randomized, open-label, multicenter study
• Patients were randomized 1:1:1 to receive the following treatments:
  • ERLEADA 240 mg orally once daily alone
  • ERLEADA 240 mg orally once daily plus abiraterone acetate 1,000 mg orally once daily plus prednisone 5 mg orally twice daily
  • Abiraterone acetate 1,000 mg orally once daily plus prednisone 5 mg orally twice daily plus ADT (goserelin 10.8 mg subcutaneously every 12 weeks)
• Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs 2) and metastatic disease (yes vs no).
• Patients were treated until week 25, disease progression (radiographic per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 and/or symptomatic +/- biochemical progression according to the Prostate Cancer Working Group Criteria 3), unacceptable toxicity, or consent withdrawal.
• Select inclusion criteria: locally advanced prostate cancer with positive lymph nodes, not candidates to radical surgery or radiotherapy and PSA ≥2 ng/mL; high-risk biochemical recurrence defined as PSA of ≥4 ng/mL and PSA doubling-time <10 months, or PSA ≥20 ng/mL; or mCSPC and PSA of ≥2 ng/mL; testosterone levels ≥230 ng/dL.
• Select exclusion criteria: prior ADT (except in the context of local therapy with an ADT-free interval of ≥12 months prior to study entry); prostate adenocarcinoma with neuroendocrine differentiation or small cell histology; known or suspected brain or skull metastases, or leptomeningeal metastatic disease; prior hormonal therapy or chemotherapy, except if administered in the adjuvant/neoadjuvant setting for localized disease (must be completed ≥12 months before); prior radiation therapy for a primary tumor (within 3 months before study entry) or for metastases; active or asymptomatic viral hepatitis or chronic liver disease, or ascites or bleeding disorders secondary to hepatic dysfunction; surgical castration prior to study entry; impaired cardiac function; history of seizure or condition that may predispose to seizures¹²
• Primary endpoint: proportion of patients who achieved PSA ≤0.2 ng/mL at week 25
• Secondary endpoints: PSA decline of ≥50% and ≥80% at week 25; maximum PSA decline; overall PSA change from baseline up to week 25 and up to week 52; testosterone levels during treatment; radiographic progression-free survival (rPFS); health-related quality of life (HRQoL); PSA progression; and safety

Results

Patient Characteristics

• A total of 128 patients were randomized and 120 of these patients were evaluable for the primary endpoint.
• The baseline demographics and disease characteristics were well balanced (Table: Select Patient Baseline Characteristics).
• A total of 74.2%, 17.2%, and 8.6% of patients had metastatic disease, high-risk biochemical recurrence disease, and locally advanced disease, respectively.

Efficacy

• With a median follow-up of 14 months, PSA ≤0.2 ng/mL was achieved in 75.6% (95% CI, 59.7-87.6) in the ADT plus AAP arm, 60.0% (95% CI, 43.3-75.1) in the ERLEADA arm, and 79.5% (95% CI, 63.5-90.7) in the ERLEADA plus AAP arm at week 25.
• Primary and secondary endpoint results are described in the table below.
• A total of 92.3%, 80.0%, and 87.5% of patients without metastatic disease achieved PSA ≤0.2 ng/mL in the ADT plus AAP, ERLEADA, and ERLEADA plus AAP arms, respectively.
• PSA progression at week 25 was observed in 3 patients in the ERLEADA arm, all of whom had metastatic disease at baseline.

2-year OS and TTF Analysis

• An additional analysis was conducted that evaluated the 2-year OS and time-to-treatment failure (TTF) outcomes from the LACOG 0415 study.⁷
  • A total of 110 patients continued treatment after week 25.
  • At the 2-year visit, 80 (62.5%) patients remained on the study treatment.
  • The estimated 2-year OS rate was 87.9% (95% CI, 77.9-97.8) with ERLEADA, 92.7% (95% CI, 84.8-100) with ERLEADA plus AAP, and 92.5% (95% CI, 84.3-100) with AAP plus ADT (P=0.5926).
  • At week 25, the 2-year OS rate was 92.9% (95% CI, 85.3-96.2) in patients with PSA ≤0.2 ng/mL and 85.0% (95% CI, 72.9-97.1) in patients with PSA >0.2 ng/mL (P=0.1250).
  • Median TTF was 24.0 months (95% CI, not estimated [NE]) with ERLEADA, 24.0 months (95% CI, 13.0-24.0) with ERLEADA plus AAP, and 24.0 months (95% CI, 23.3-24.0) with AAP plus ADT.

Patient-Reported HRQoL

• In an analysis evaluating patient-reported outcomes (PROs) of HRQoL, there were no clinically significant changes in Functional Assessment of Cancer Therapy-Prostate (FACT-P) total and subscales scores from baseline to week 25 in the 3 treatment groups and no statistically significant difference between the groups in the time to FACT-P deterioration (P=0.3371).¹³

Safety

• A summary of AEs in shown in Table: Adverse Events.
• Grade 3-4 AEs occurred in 31.0%, 21.4% and 36.4% of patients in the ADT plus AAP, ERLEADA, and ERLEADA plus AAP arm, respectively.
• TRAEs of all grades were observed in 71.4% of patients in the ADT plus AAP arm, 81.0% of patients in the ERLEADA arm, and 81.8% of patients in ERLEADA plus AAP arm.
• Treatment interruptions due to toxicity occurred in 4.8%, 9.5% and 18.2% of patients in the ADT plus AAP, ERLEADA, and ERLEADA plus AAP arms, respectively.
• A total of 9 patients discontinued therapy before week 25, of which 6 due to toxicity (ADT plus AAP arm: stroke [n=1]; ERLEADA arm: grade 3 rash [n=1]; ERLEADA plus AAP: grade 3 rash and acute renal failure [n=1], grade 3 hypertension, grade 3 rash/pruritus, grade 3 pruritus [n=1 each]).
• In the additional analysis that evaluated the 2-year OS and TTF, the reasons for treatment discontinuation included disease progression (n=8 [6.3%]), toxicity (n=10 [7.8%]), death (n=6 [4.7%]), withdrawal (n=4 [3.1%]), and other (n=19 [14.8%]).⁷

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 08 April 2024.