SUMMARY

• No prospective, randomized trials have been conducted to evaluate sequencing of ERLEADA and cabazitaxel.
• 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 cabazitaxel.^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, 6.2% (24 of 386) of patients in the ERLEADA group and 4.2% (12 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; cabazitaxel was among these other agents, however specific usage was not delineated.^4,5 Subsequent therapy results, including number of patients treated with cabazitaxel, were previously reported in the primary analysis.^1,3 Subsequent therapy results that combined data for various therapies including cabazitaxel (specific usage not delineated), were also previously reported in the second interim analysis for OS.⁶
• 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 cabazitaxel.^7-9 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, 0.8% (2 of 247) of patients in the ERLEADA group and 1.4% (5  of 345) of patients in the placebo group received cabazitaxel as the first subsequent systemic therapy.^10,11 Subsequent therapy results, including number of patients treated with cabazitaxel, were also previously reported in the primary analysis for OS.^7,9
  • 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 low-risk disease. PFS2 results were reported in aggregate for the ERLEADA and placebo groups and were not stratified by first subsequent therapy received.^12,13

CLINICAL DATA

No prospective, randomized trials have been conducted to evaluate sequencing of ERLEADA and cabazitaxel. However, information on subsequent therapy reported in the phase 3 SPARTAN study (NCT01946204) conducted in patients with nonmetastatic castration-resistant 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 prostate-specific antigen [PSA] doubling time ≤10 months), patients who received prior chemotherapy could be included if they received treatment ≥4 weeks prior to randomization and in the adjuvant/neoadjuvant setting (eg, clinical trial). 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 of 803) of patients in the ERLEADA group, 100% (322 of 322) of patients in the placebo group, and 39% (30 of 76) of patients in the crossover group had discontinued study treatment. A total of 48% (386 of 806) and 71% (285 of 401) of patients in the ERLEADA and placebo groups, respectively, received first subsequent systemic therapy for prostate cancer. Of patients who discontinued study treatment and received first subsequent therapy for prostate cancer, 6.2% (24 of 386) of patients in the ERLEADA group and 4.2% (12 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; cabazitaxel was among these other agents, however specific usage was not delineated.⁵

Results for the secondary endpoint, time to initiation of cytotoxic chemotherapy (defined as time from randomization to initiation of a new cytotoxic chemotherapy), were reported in aggregate for the ERLEADA and placebo groups and not stratified by individual therapies. Additionally, results for the exploratory endpoint, PFS2 (defined as 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), were reported in aggregate for the ERLEADA and placebo groups and were not stratified by individual therapies 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).

Phase 3 TITAN Study

In TITAN, the phase 3, randomized, double-blind, placebo-controlled, multicenter study (N=1052) conducted in patients with mCSPC, prior therapy with cabazitaxel was not permitted. 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 bilateral orchiectomy.^7-9 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.¹⁰

In the final OS analysis, which occurred at a median follow-up of 44.0 months, 49.0% (257 of 525) of patients in the ERLEADA group and 67.9% (358 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.¹⁰ A total of 48.6% (120 of 247) of patients in the ERLEADA group and 64.1% (221 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, 0.8% (2 of 247) of patients in the ERLEADA group and 1.4% (5  of 345) of patients in the placebo group received cabazitaxel as the first subsequent systemic therapy.¹¹ 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 2 (1.4%) and 4 (1.5%) received cabazitaxel as first life-prolonging subsequent therapy for prostate cancer, respectively.¹⁰

Results for the secondary endpoint, time to initiation of cytotoxic chemotherapy (defined as time from randomization to initiation of cytotoxic chemotherapy), were reported in aggregate for the ERLEADA and placebo groups and not stratified by individual therapies. Additionally, results for the exploratory endpoint of PFS2, which was defined as time from randomization to the first occurrence of investigator-assessed 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, were reported in aggregate for the ERLEADA and placebo groups and were not stratified by individual therapies received.^7,8,10

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.