SUMMARY  

• Falls and fractures occurred in patients who received ERLEADA. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.¹ Please refer to local labeling for additional considerations and data.
• In SPARTAN, the phase 3 study in patients with non-metastatic castration-resistant prostate cancer (nmCRPC; N=1207), at the final analysis of overall survival (OS), which occurred after a median follow-up of 52 months, adverse events (AEs) of falls were reported in 22%, 9.5%, and 11% of patients in the ERLEADA, placebo, and crossover groups, respectively. Grade 3-4 falls occurred in 2.7%, 0.8%, and 2.6% of patients in the ERLEADA, placebo, and crossover groups, respectively. Fractures were reported in 18%, 7.5%, and 9.2% of patients in the ERLEADA, placebo, and crossover groups, respectively. Grade 3-4 fractures occurred in 4.9%, 1.0%, and 5.3% of patients in the ERLEADA, placebo, and crossover groups, respectively.^2,3 Safety results, including falls and fractures, were also previously reported in the second interim analysis for OS.⁴
  • A multivariate analysis of select patient baseline and post-baseline characteristics identified age ≥75 years, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 1, history of neuropathy, and use of alpha-blockers as independent baseline predictors of time to fall (all P<0.05), while age ≥75 years and lower serum albumin were identified as independent baseline predictors of time to fracture (all P<0.05). During treatment with ERLEADA, patients who experienced treatment-emergent adverse events (TEAEs) of neuropathy, arthralgia, and decreased weight were at increased risk of experiencing a fall (all P<0.05), while patients who experienced TEAEs of fall or neuropathy were at increased risk of experiencing a fracture (all P<0.05).^5-7
• In TITAN, the phase 3 study in patients with metastatic castration-sensitive prostate cancer (mCSPC; N=1052), at the final analysis of OS, which occurred after a median follow-up of 44.0 months, AEs of falls were reported in 9.4%, 7.0%, and 3.8% of patients in the ERLEADA, placebo, and crossover groups, respectively. Grade ≥3 falls occurred in 1.3%, 0.9%, and 0 patients in the ERLEADA, placebo, and crossover groups, respectively. Fractures were reported in 10.3%, 4.9%, and 2.4% of patients in the ERLEADA, placebo, and crossover groups, respectively. Grade ≥3 fractures occurred in 3.4%, 0.8%, and 0 patients in the ERLEADA, placebo, and crossover groups, respectively. The incidence of fall with event rate per 100 patient-years of exposure were 4.6, 6.8, and 5.7 in the ERLEADA, placebo, and crossover groups, respectively. The incidence of fracture with event rate per 100 patient-years of exposure were 6.1, 4.2, and 2.1 in the ERLEADA, placebo, and crossover groups, respectively.^8,9

CLINICAL DATA

Phase 3 Study in Patients with nmCRPC (SPARTAN)

The SPARTAN study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC (N=1207).¹⁰ Patients were required to have a prostate-specific antigen doubling time of ≤10 months and confirmation of non-metastatic disease by blinded independent central review. Patients were randomized 2:1 to receive either ERLEADA orally at a dose of 240 mg once daily (n=806) or placebo once daily (n=401). All patients received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median treatment duration at primary analysis was 16.9 months in the ERLEADA group and 11.2 months in the placebo group.¹¹ After unblinding of the study, 76 (19%) patients in the placebo group received therapy with ERLEADA plus androgen deprivation therapy (crossover group). At the final analysis for OS, after a median follow-up of 52 months, 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 crossover group.²

The incidences of falls and fractures reported at the SPARTAN primary analysis and the final analysis for OS are shown in Table: Falls and Fractures in Phase 3 SPARTAN Study. In the ERLEADA group, the rates of falls and fractures by group term (event rate/100 patient-years) did not change substantially after the first and second interim analyses.³ AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.¹⁰

In the SPARTAN primary analysis, the most frequent serious AE (>2%) was fracture (3.4%) in the ERLEADA group.¹¹ A prior fall (within 7 days) preceding fracture was common for both treatment groups (40% in the ERLEADA group and 50% in the placebo group).¹¹

Bone-targeted agents (at the dose approved for use in the treatment of osteoporosis) were permitted concomitant medications during the study.¹¹ If a patient was taking a bone-targeted agent prior to enrollment in the study, the patient was required to maintain a stable dose. The percentage of patients receiving bone-targeted agents for osteoporosis or osteopenia at study entry was low (ERLEADA, 10.2%; placebo, 9.7%).^10,11

In the SPARTAN primary analysis, the incidence of fracture for patients who were not receiving concomitant bone-targeted therapy at study entry was 82/722 patients (11%) in the ERLEADA group compared with 22/359 patients (6.1%) in the placebo group.¹¹ Among patients who were receiving concomitant bone-targeted therapy at study entry, fracture occurred in 12/81 patients (15%) in the ERLEADA group and 4/39 patients (10%) in the placebo group.

Multivariate Analysis of Patient Characteristic Predictors of Falls and Fractures

A post-hoc analysis was performed to identify predictors of falls and fractures for patients in the ERLEADA group (n=806) of the SPARTAN study.^5-7 A univariate Cox proportional hazards model was utilized to assess the association of approximately 50 patient baseline characteristics, including demographics, comorbidities, and concomitant medications (eg, bone-targeted agents), and post-baseline covariates, including development of clinically relevant TEAEs and initiation of clinically relevant drug classes ≤1 month prior to a fall or fracture, with time to fall or time to fracture during the study. The baseline covariates identified as significant on univariate analysis (P<0.10) were included in a multivariate model along with any post-baseline covariates identified as significant (P<0.10) on univariate analysis (when treated as time-dependent covariates). The final multivariate model was used to identify significant baseline and post-baseline covariates (P<0.05) as independent predictors of time to fall and time to fracture.⁶

In the ERLEADA group, median time to first fall among patients who experienced treatment-emergent fall was 9.2 months, and median time to first fracture among patients who experienced treatment-emergent fracture was 10.3 months. A total of 20 patients (2.5%) had ≥1 treatment-emergent fall, and 24 patients (3.0%) had ≥1 treatment-emergent fracture. The final multivariate model identified age ≥75 years, ECOG-PS of 1, history of neuropathy, and use of alpha-blockers as independent baseline predictors of time to fall (all P<0.05), while age ≥75 years and lower serum albumin were identified as independent baseline predictors of time to fracture (all P<0.05). During treatment with ERLEADA, patients who experienced TEAEs of neuropathy, arthralgia, and decreased weight were at increased risk of experiencing a fall (all P<0.05), while patients who experienced TEAEs of fall or neuropathy were at increased risk of experiencing a fracture (all P<0.05).^6,7 Among the 125 patients who experienced a fall during treatment, 39.2% had a fracture after fall and 4% had a fracture before fall. Among patients who did not have a treatment-related fall, 5.9% had a treatment-related fracture.⁷

Refer to Table: Independent Baseline and After-baseline Characteristics Significantly Associated with Time to Fall in the ERLEADA Group of the SPARTAN Study and Table: Independent Baseline and Post-baseline Predictors of Time to Fracture in the ERLEADA Group of the SPARTAN Study for the results of the multivariate analysis.

Additional Information

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 Study in Patients with mCSPC (TITAN)

The TITAN study evaluated the efficacy and safety of ERLEADA in patients with mCSPC (N=1052). Patients were randomized 1:1 to receive either ERLEADA orally at a dose of 240 mg once daily (n=525) or placebo once daily (n=527).¹² All patients received a concomitant GnRH analog or had a bilateral orchiectomy.¹³ Patient baseline demographic and disease characteristics were well balanced, and there were no substantial differences between groups. The median treatment duration at primary analysis was 20.5 months in the ERLEADA group and 18.3 months in the placebo group.¹² After unblinding of the study, 208 (39.5%) patients in the placebo group received therapy with ERLEADA plus androgen deprivation therapy (crossover group). At the final analysis for OS, after a median follow-up of 44.0 months, 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 crossover group.⁸

The incidence of falls and fractures reported at the TITAN primary analysis and the final analysis for OS are shown in Table: Falls and Fractures in Phase 3 TITAN Study. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.3.¹²

In the TITAN primary analysis, no treatment discontinuations due to falls or fractures were reported.¹⁴ One patient in each group had a dose interruption due to a grade ≥3 fall. Dose interruptions were reported for one patient in the ERLEADA group due to grade ≥3 hip fracture and one patient in the placebo group due to grade ≥3 pathological fracture. A prior fall (within 7 days) preceding fracture was common for both treatment groups (52% in the ERLEADA group and 42% in the placebo group).¹⁵

Bone-targeted agents for the management of bone-related metastasis (at the dose approved for use in the treatment of osteoporosis) were permitted concomitant medications during the study.¹³ Patients were required to be on a stable dose ≥28 days prior to randomization or could initiate therapy upon documented radiographic progression. The percentage of patients receiving a bone-targeted agent was 17% in the ERLEADA group and 24% in the placebo group.¹⁵ The incidence of fracture was not delineated for patients who did or did not receive a bone-targeted agent.

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 24 October 2024. Summarized in this response are relevant data limited to the phase 3 SPARTAN and TITAN studies in patients with nmCRPC and mCSPC, respectively.