SUMMARY

• No prospective, randomized trials have been conducted to evaluate sequencing of ERLEADA and enzalutamide.
• In SPARTAN, patients in both the ERLEADA and placebo groups who progressed to metastatic castration-resistant prostate cancer (mCRPC) during the study were eligible to receive subsequent approved therapy for mCRPC, including enzalutamide.^1-3 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, 8.3% (32 out of 386) of patients in the ERLEADA group and 13% (38 out of 285) of patients in the placebo group received enzalutamide as the first subsequent therapy.^4,5 Subsequent therapy results, including number of patients treated with enzalutamide, were also previously reported in the primary analysis and in the second interim analysis for OS.^1,3,6,7
  • A post hoc analysis evaluated efficacy outcomes in patients receiving first subsequent therapy, including enzalutamide, following progression to mCRPC after initial treatment with ERLEADA. Results are summarized in Table: Efficacy Outcomes of Subsequent Treatment in 1L mCRPC After Progression on ERLEADA.⁸
• In TITAN, patients in both the ERLEADA and placebo groups who progressed during the study were eligible to receive subsequent systemic therapy for prostate cancer, including enzalutamide.^9-11 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, 3.6% (9 out of 247) of patients in the ERLEADA group and 7.0% (24 out of 345) of patients in the placebo group received enzalutamide as the first subsequent systemic therapy.^12,13 Subsequent therapy results, including number of patients treated with enzalutamide, were also previously reported in the primary analysis for OS.^9,11
  • 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.^14,15
• A phase 1b study evaluated the use of ERLEADA in combination with abiraterone acetate plus prednisone in patients with mCRPC who previously received enzalutamide, abiraterone acetate plus prednisone, docetaxel, and/or cabazitaxel (N=57). Of the 13, 19, 10, and 15 patients who received prior therapy with enzalutamide, abiraterone acetate plus prednisone, enzalutamide and abiraterone acetate plus prednisone, or who did not receive prior therapy with either, 15%, 21%, 0%, and 80% of patients had a ≥50% reduction in prostate-specific antigen (PSA) from baseline, and 0%, 0%, 0%, and 40% of patients had a ≥90% reduction in PSA from baseline, respectively. The most commonly reported (≥40%) adverse events (AEs) were fatigue (56.1%), nausea (40.4%), and vomiting (40.4%).^16,17

CLINICAL DATA

No prospective, randomized trials have been conducted to evaluate sequencing of ERLEADA and enzalutamide. However, information on subsequent therapy reported in the phase 3 SPARTAN study (NCT01946204) conducted in patients with non-metastatic castrationresistant prostate cancer (nmCRPC) and in the 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 PSA doubling time ≤10 months), patients were excluded if they had received prior therapy with a second-generation antiandrogen (eg, enzalutamide). 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.⁴ 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 mCRPC was at the discretion of the treating physician.¹

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, 8.3% (32 out of 386) of patients in the ERLEADA group and 13% (38 out of 285) of patients in the placebo group received enzalutamide as the first subsequent therapy.⁵

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.^1,2,4

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).

A post hoc analysis of patients in the ERLEADA group evaluated the relative efficacy outcomes of subsequent therapies in patients who progressed to mCRPC. At SPARTAN study completion, 237 patients remained on ERLEADA without progression, while 311 progressed following initial treatment with ERLEADA plus ADT and received subsequent treatment with abiraterone acetate, docetaxel, enzalutamide, or other. Compared to the ERLEADA intent to treat (ITT) population (N=806), the subsequent first mCRPC treatment cohort had a higher PSA value at baseline and proportion of patients with PSA doubling time ≤6 months at the point of randomization, experienced poorer deep PSA response to ERLEADA in terms of undetectable PSA and PSA90, and had poorer median metastasis-free survival (MFS; 25.8 months vs 40.5 months) and OS (52.8 months vs 73.9 months) from randomization.⁸ A summary of the efficacy outcomes in patients who received subsequent therapy after progression on ERLEADA are outlined in Table: Efficacy Outcomes of Subsequent Treatment in 1L mCRPC After Progression on ERLEADA.

Phase 3 TITAN Study

In TITAN, the phase 3, randomized, double-blind, placebo-controlled, multicenter study (N=1052) conducted in patients with mCSPC, patients were excluded if they had received prior therapy with a second-generation antiandrogen (eg, enzalutamide). 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.^9-11 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.¹²

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.¹² 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. Of the patients who were alive at treatment discontinuation, 3.6% (9 out of 247) of patients in the ERLEADA group and 7.0% (24 out of 345) of patients in the placebo group received enzalutamide as the first subsequent systemic therapy. Enzalutamide was the third most common first subsequent hormonal therapy received by patients in both treatment groups, after abiraterone acetate plus prednisone and bicalutamide.¹³ There were 138 patients in the ERLEADA group and 261 patients in the placebo group who discontinued treatment for progressive disease and remained alive, of whom 9 (6.5%) and 20 (7.7%) received enzalutamide as first life-prolonging subsequent therapy for prostate cancer, respectively.¹²

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.^9,10,12

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 21 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, as well as a phase 1b study in patients with mCRPC.