SUMMARY

• No prospective, randomized trials have been conducted to evaluate sequencing of ERLEADA and docetaxel.
• 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 docetaxel.^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, 8.5% (33 of 386) of patients in the ERLEADA group and 7.0% (20 of 285) of patients in the placebo group received docetaxel as the first subsequent therapy.^4,5 Subsequent therapy results, including number of patients treated with docetaxel, were also previously reported in the primary analysis and second interim analysis for OS.^1,3,6,7
  • A post hoc analysis evaluated efficacy outcomes in patients receiving first subsequent therapy, including docetaxel, 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 who received prior therapy with docetaxel for metastatic castrationsensitive prostate cancer (mCSPC) were eligible for inclusion. Patients in both the ERLEADA and placebo groups who progressed during the study were eligible to receive subsequent systemic therapy for prostate cancer, including docetaxel.^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, 17.0% (42 of 247) of patients in the ERLEADA group and 22.6% (78 of 345) of patients in the placebo group received first subsequent systemic therapy with docetaxel, which was the most common first subsequent chemotherapy received by patients in both groups.^12,13 Subsequent therapy results, including number of patients treated with docetaxel, were also previously reported in the primary analysis for OS.^9,10
  • Two post hoc analyses evaluated second progression-free survival (PFS2) by first subsequent therapy (specifically hormonal compared with 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 post hoc analysis of patients in the ERLEADA group showed that radiographic progressionfree survival (rPFS), OS, time to prostate-specific antigen (PSA) progression, and ≤0.2 ng/mL PSA response were similar among patients who received and those who did not receive prior docetaxel. Results are summarized in Table: Post-hoc Analysis Results of Patients With or Without Prior Docetaxel Use in the ERLEADA Group.¹⁶

CLINICAL DATA

No prospective, randomized trials have been conducted to evaluate sequencing of ERLEADA and docetaxel. 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 in the phase 3 TITAN study (NCT02489318) conducted in patients with 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 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 received first subsequent therapy for prostate cancer, 8.5% (33 of 386) of patients in the ERLEADA group and 7.0% (20 of 285) of patients in the placebo group received docetaxel as the first subsequent therapy.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.^1,2,5

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 who received prior docetaxel for a maximum of 6 cycles for mCSPC (with last dose administered ≤2 months prior to randomization) with no evidence of progression during treatment or before randomization were eligible for inclusion and stratified accordingly. 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

Primary Analysis

The median treatment duration was 20.5 months with ERLEADA and 18.3 months with placebo.⁹

A total of 10.7% (113 of 1052 [ERLEADA group: n=58, placebo group: n=55]) of patients enrolled in the study received prior treatment with docetaxel for a median of 6 cycles. The subgroup analysis results for the dual primary endpoints, rPFS and OS, are summarized in Table: Subgroup Analysis Results of Patients With Prior Docetaxel Use – Primary Analysis.^9,10

Among patients who discontinued treatment during the study, 51.2% (87 of 170) of patients in the ERLEADA group and 70.1% (190 of 271) of patients in the placebo group were receiving subsequent systemic therapy for prostate cancer at data cutoff. Of these patients, 33.3% (29 of 87) of patients in the ERLEADA group and 35.3% (67 of 190) of patients in the placebo group received first subsequent therapy with docetaxel. Docetaxel was the most common first subsequent chemotherapy received by patients in both the groups.^9,10

Final OS Analysis

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 subgroup analysis of patients with prior docetaxel use, there were a total of 21 events among 58 patients in the ERLEADA group and 17 events among 55 patients in the placebo group. Median OS was not reached in either subgroup of patients (hazard ratio, 1.12; 95% confidence interval, 0.59-2.12).¹²

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.¹² 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, 17.0% (42 of 247) of patients in the ERLEADA group and 22.6% (78 of 345) of patients in the placebo group received first subsequent systemic therapy with docetaxel, which was the most common first subsequent chemotherapy received by patients in both groups.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 37 (26.8%) and 71 (27.2%) received docetaxel as first life-prolonging subsequent therapy for prostate cancer, respectively.¹²

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.^9,11,12

A post hoc analysis of patients in the ERLEADA group was conducted to compare the outcomes in patients who did or did not receive prior docetaxel. Before randomization to ERLEADA, 58 patients received docetaxel and 467 patients did not. Results of the compared outcomes are summarized in Table: Post Hoc Analysis Results of Patients With or Without Prior Docetaxel Use in the ERLEADA Group. Results were also reported for patients with high- vs low-volume disease and the overall case-matched population.¹⁶

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 20 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.