SUMMARY

• No prospective, randomized trials have been conducted to evaluate sequencing of ERLEADA and bicalutamide.
• In SPARTAN, patients that received prior therapy with a first-generation antiandrogen (eg, bicalutamide, flutamide, or nilutamide) were eligible for inclusion.^1,2 However, results were not delineated for patients who received prior treatment with bicalutamide. In the final analysis for overall survival (OS), which occurred after a median follow-up of 52 months, of patients who received first subsequent systemic therapy for prostate cancer, 6.2% (24 out of 386) of patients in the ERLEADA group and 4.2% (12 out of 285) of patients in the placebo group received agents other than abiraterone acetate plus prednisone, enzalutamide, docetaxel, carboplatin, radium-223, or sipuleucel-T as the first subsequent therapy; bicalutamide was among these other agents, however specific usage was not delineated.^3,4 Subsequent therapy results that combined data for various therapies including bicalutamide (specific usage not delineated) were also previously reported in the second interim analysis for OS.⁵
• In TITAN, patients that received prior therapy with a first-generation antiandrogen (eg, bicalutamide, flutamide, or nilutamide) were eligible for inclusion.⁶ Patients in both the ERLEADA and placebo groups who progressed during the study were eligible to receive subsequent systemic therapy for prostate cancer, including bicalutamide. In the final analysis for OS, which occurred after a median follow-up of 44.0 months, of the patients who were alive at treatment discontinuation, 6.5% (16 out of 247) of patients in the ERLEADA group and 8.7% (30 out of 345) of patients in the placebo group received bicalutamide.^7,8 Subsequent therapy results, including number of patients treated with bicalutamide, were also previously reported in the primary analysis for OS.^6,9
  • Two post-hoc analyses evaluated second progression-free survival (PFS2) by first subsequent therapy (specifically hormonal compared to taxane therapy) following discontinuation of study treatment as well as in patients with baseline high- and lowrisk disease. PFS2 results were reported in aggregate for the ERLEADA and placebo groups and were not stratified by first subsequent therapy received.^10,11

CLINICAL DATA

No prospective, randomized trials have been conducted to evaluate sequencing of ERLEADA and bicalutamide. However, information on previous and/or subsequent therapy reported in the phase 3 SPARTAN study (NCT01946204) conducted in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and phase 3 TITAN study (NCT02489318) conducted in patients with metastatic castration-sensitive prostate cancer (mCSPC) is summarized in this section.

Phase 3 SPARTAN Study

In SPARTAN, the phase 3, randomized, double-blind, placebo-controlled, multicenter study (N=1207) conducted in patients with high-risk nmCRPC (defined as prostate-specific antigen [PSA] doubling time ≤10 months), patients who received a first-generation antiandrogen (eg, bicalutamide, flutamide, or nilutamide) were eligible for inclusion in the study if the therapy was a part of an initial combined androgen blockade or a second-line hormonal therapy while demonstrating continuing PSA progression off the antiandrogen for ≥4 weeks prior to randomization. A total of 806 patients were randomized to receive ERLEADA 240 mg orally once daily and 401 patients received placebo. All patients in the study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy.^1,2 The final OS analysis included 1201 patients: 803 patients in the ERLEADA group and 398 patients in the placebo group. The median treatment duration was 32.9 months in the ERLEADA group, 11.5 months in the placebo group, and 26.1 months in the placebo to ERLEADA crossover group.³ Following detection of distant metastasis, patients were eligible to receive treatment with sponsor-provided abiraterone acetate plus prednisone. After study drug discontinuation, the administration of abiraterone acetate plus prednisone or any other treatment for metastatic castration-resistant prostate cancer (mCRPC) was at the discretion of the treating physician.¹

A total of 73% of patients received prior treatment with an antiandrogen; 69% of patients received bicalutamide and 10% of patients received flutamide.¹² Results were not delineated for patients who received prior treatment with bicalutamide.

In the final OS analysis, which occurred at a median follow-up of 52 months, 70% (566 out of 803) of patients in the ERLEADA group, 100% (322 out of 322) of patients in the placebo group, and 39% (30 out of 76) of patients in the crossover group had discontinued study treatment. A total of 48% (386 out of 806) and 71% (285 out of 401) of patients in the ERLEADA and placebo groups, respectively, received first subsequent systemic therapy for prostate cancer. Of patients who received first subsequent therapy for prostate cancer, 6.2% (24 out of 386) of patients in the ERLEADA group and 4.2% (12 out of 285) of patients in the placebo group received agents other than abiraterone acetate plus prednisone, enzalutamide, docetaxel, carboplatin, radium-223, or sipuleucel-T as the first subsequent therapy; bicalutamide was among these other agents, however specific usage was not delineated.⁴

Results were reported for the exploratory endpoint of PFS2, which was defined as the time from randomization to investigator-assessed disease progression (PSA progression, detection of metastatic disease on imaging, symptomatic progression, or any combination) during the first subsequent treatment for mCRPC or death from any cause. However, PFS2 results were reported in aggregate for the ERLEADA and placebo groups and were not stratified by first subsequent therapy received.^1-3

Additional information regarding the SPARTAN study, including the clinical study report, protocol, and statistical analysis plan, can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm (scroll to the “Sponsor Clinical Study Reports ARN-509-003 SPARTAN NCT # 01946204” section at the bottom of the web page).

Phase 3 TITAN Study

In TITAN, the phase 3, randomized, double-blind, placebo-controlled, multicenter study (N=1052) conducted in patients with mCSPC, patients who started a GnRH agonist ≤28 days prior to randomization were required to take a first-generation antiandrogen (eg, bicalutamide, flutamide, or nilutamide) for ≥14 days prior to randomization, however the antiandrogen must have been discontinued prior to randomization. A total of 525 patients were randomized to receive ERLEADA 240 mg orally once daily and 527 patients received placebo. All patients in the study received a concomitant GnRH analog or had a prior bilateral orchiectomy.^6,9,13 The final OS analysis included 1052 patients: 525 patients in the ERLEADA group and 527 patients in the placebo group. The median treatment duration was 39.3 months in the ERLEADA group, 20.2 months in the placebo group, and 15.4 months in the placebo to ERLEADA crossover group.⁷

A total of 67% of patients in the ERLEADA group and 68.5% of patients in the placebo group received prior treatment with a first-generation antiandrogen.⁹ Results were not delineated for patients who received prior treatment with an antiandrogen.

In the final OS analysis, which occurred at a median follow-up of 44.0 months, 49.0% (257 out of 525) of patients in the ERLEADA group and 67.9% (358 out of 527) of patients in the placebo group had discontinued study treatment. At treatment discontinuation, 247 (47.0%) patients in the ERLEADA group and 345 (65.5%) patients in the placebo group were alive.⁷ A total of 48.6% (120 out of 247) of patients in the ERLEADA group and 64.1% (221 out of 345) of patients in the placebo group received first subsequent systemic therapy for prostate cancer. Abiraterone acetate was the most common first subsequent hormonal therapy received by patients, followed by bicalutamide. Of the patients who were alive at treatment discontinuation, 6.5% (16 out of 247) of patients in the ERLEADA group and 8.7% (30 out of 345) of patients in the placebo group received bicalutamide.^7,8

Results were reported for the exploratory endpoint of PFS2, which was defined as the time from randomization to the first occurrence of investigator-assessed disease progression (PSA progression, progression on imaging, or clinical progression) while the patient was receiving first subsequent therapy for prostate cancer or death due to any cause, whichever occurred first. However, PFS2 results were reported in aggregate for the ERLEADA and placebo groups and were not stratified by first subsequent therapy received.^6,7,13

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 25 November 2024. Summarized in this response are relevant data limited to the phase 3 SPARTAN study in patients with nmCRPC and phase 3 TITAN study in patients with mCSPC.