SUMMARY

• In SPARTAN, the phase 3 study in patients with non-metastatic castrationresistant 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 fatigue were reported in 33% of patients in the ERLEADA group, 21% of patients in the placebo group, and 16% of patients in the crossover group. Grade 3-4 fatigue was reported in 0.9%, 0.3%, and 1.3% of patients in the ERLEADA, placebo, and crossover groups, respectively.¹ Safety results, including fatigue, were also previously reported in the second interim analysis for OS.²
  • Patient-reported outcomes (PROs), assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and the 3-level version of the European Quality of Life-5 Dimensions (EQ-5D-3L) questionnaire, were a prespecified exploratory endpoint. At final analysis, responses to question GP1 (“I have a lack of energy”) and GP5 (“I am bothered by side effects of treatment”) of the FACT-P questionnaire suggested that fatigue in both groups was similar over time, patients were “not at all bothered” by side effects, and bother did not increase over time.³
• In TITAN, the phase 3 study in patients with metastatic castrationsensitive prostate cancer (mCSPC; N=1052), at the final analysis of OS, which occurred after a median follow-up of 44.0 months, treatment-emergent adverse events (TEAEs) of fatigue were reported in 20.4% of patients in the ERLEADA group, 16.9% of patients in the placebo group, and 7.2% of patients in the crossover group. Treatment-related TEAEs of fatigue were reported in 13.5%, 8.7%, and 6.7% of patients in the ERLEADA, placebo, and crossover groups, respectively.^4,5
  • PROs were a prespecified exploratory endpoint and the Brief Fatigue Inventory (BFI) was one instrument used for assessment. BFI results indicated that patient experience of fatigue (both intensity and interference) were not different between groups for the duration of treatment.⁶ In a post-hoc analysis, the likelihood for fatigue or worsening fatigue was similar between groups.⁷
  • At final analysis, >78% of patients in the ERLEADA group and >71% of patients in the placebo group had energy levels that were stable or improved relative to baseline levels at each cycle per responses to question GP1 of the FACT-P questionnaire.⁸ In a post-hoc analysis, PSA decline (≤0.2 ng/mL) correlated with health-related quality of life (HRQoL) measures (e.g., time to decline in FACT-P total score, time to decline in BFI worst fatigue) at month 3 and month 6 following treatment with ERLEADA.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.¹

The incidences of fatigue reported at the SPARTAN primary analysis and the final analysis for OS are shown in Table: Fatigue in Phase 3 SPARTAN Study. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.¹⁰

In the SPARTAN primary analysis, among patients with fatigue, dose reduction occurred in 14 (1.7%) patients in the ERLEADA group and in 0 patients in the placebo group, while dose interruption occurred in 18 (2.2%) patients in the ERLEADA group and in 2 (0.5%) patients in the placebo group. Fatigue led to treatment discontinuation in 8 (1.0%) patients in the ERLEADA group and in 1 (0.3%) patient in the placebo group.¹² At the final analysis for OS, fatigue led to treatment discontinuation in 1.1% of patients in the ERLEADA group.¹³

Patient-Reported Outcomes

PROs were a prespecified exploratory endpoint and the FACT-P was one instrument used for assessment of HRQoL. PRO questionnaires were completed and collected during the treatment phase at baseline, day 1 of cycle 1 (before dose), day 1 of cycles 2-6, day 1 of every 2 cycles starting at cycle 7-13, then day 1 of every 4 cycles unless otherwise specified.¹⁴

Results

Primary Analysis

• The following was reported within the FACT-G physical well-being domain, "I have lack of energy" during the treatment phase:¹⁴
  • The proportion of patients who reported that they “very much” or “quite a bit” had lack of energy ranged from 9% of patients at cycle 29 to 17% of patients at cycle 3 in the ERLEADA group and from 7% of patients at cycle 11 to 13% of patients at cycle 25 in the placebo group.

Final Analysis

• Responses to question GP1 (“I have a lack of energy”) and GP5 (“I am bothered by side effects of treatment”) of the FACT-P questionnaire suggested that fatigue in both groups was similar over time, patients were “not at all bothered” by side effects, and bother did not increase. On average, patients receiving ERLEADA reported small changes in side-effect bother and on average, patient-reported side-effect bother increased by 0.61 points from baseline during the 30 days after TEAE observation (range, 0.16-1.01). For the TEAE observation of fatigue, 79.8% were followed by GP5 responses that were <2 points greater than at baseline.³

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).¹⁵ 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). All patients received a concomitant GnRH analog or had a prior bilateral orchiectomy.¹⁶ Patient baseline demographic and disease characteristics were well balanced, and there were no substantial differences between groups.¹⁵ The median treatment duration at primary analysis was 20.5 months in the ERLEADA group and 18.3 months in the placebo group. 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.⁴

The incidence of fatigue reported in the TITAN primary analysis and the final analysis for OS are shown in the Table: Fatigue in Phase 3 TITAN Study. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.3.¹⁵

In the TITAN primary analysis, among patients with fatigue, dose reduction occurred in 2 (0.4%) patients in the ERLEADA group and in 0 patients in the placebo group, while dose interruption occurred in 6 (1.1%) patients in the ERLEADA group and in 2 (0.4%) patients in the placebo group. Fatigue led to treatment discontinuation in 4 (0.8%) patients in the ERLEADA group and in 0 patients in the placebo group.¹⁷

Patient-Reported Outcomes

PROs were a prespecified exploratory endpoint and the BFI was one instrument used for assessment.⁶ The BFI assesses average and worst fatigue in the past 24 hours, fatigue at the time of the survey, and the extent to which fatigue interfered with daily activities. BFI was completed at baseline, averaged over 7 consecutive days (day -6 plus day 1 of each cycle visit) every 28 days, and at months 4, 8, and 12 during follow-up.⁷ Time to fatigue progression was defined as the time from randomization to the first date a patient had a worsening of fatigue scores by ≥2 points observed at two consecutive assessments ≥3 weeks apart.⁶

• Time to fatigue intensity progression was defined as the time from randomization to the first date with an increase of 2 points or more from baseline in the worst BFI intensity item (item 3) observed at two consecutive assessments ≥3 weeks apart.
• Time to fatigue interference progression was defined as an increase of at least 1.25 points from baseline in the average BFI interference score observed at two consecutive assessments ≥3 weeks apart.

Results

Primary Analysis

• At baseline, median worst fatigue score on the BFI (interquartile range) were well balanced between the treatment groups at baseline: ERLEADA group, 1.29 (0-3.29) and placebo group, 1.43 (0.14-3.14) and a total of 75% of patients reported no fatigue (score: 0) or mild fatigue (score: 1-3) as their worst fatigue experienced within the past 24 hours.⁶
• Median time to worst fatigue intensity and time to fatigue interference were similar between treatment groups (data reported below as ERLEADA vs placebo).⁶
  • Median time to worst fatigue intensity was not reached in either group; 25^th percentiles were 9.23 months vs 11.04 months (HR, 1.09; 95% CI, 0.88-1.35; P=0.44)
  • Median time to fatigue interference was not reached in either group; 25^th percentiles were 10.15 months vs 10.51 months (HR, 1.01; 95% CI, 0.81-1.26; P=0.93)
• Repeated-measures mixed-effects models showed that worst fatigue intensity and fatigue interference mean scores were similar between groups.⁶
• For most patients with no fatigue at baseline, fatigue remained stable and for most patients with mild fatigue at baseline, fatigue remained stable or improved, and most patients with moderate or severe fatigue at baseline improved ≥1 point.⁶
• A post-hoc analysis of change in fatigue from baseline showed no worsening over time in mean fatigue intensity and interference, except for fatigue intensity in the ERLEADA group in patients with severe baseline fatigue, and particularly those with no fatigue or moderate fatigue at baseline.⁶
• In a post-hoc analysis that included fatigue HRQoL assessments, the likelihood of patients being fatigued or experiencing increased fatigue was not different between treatment groups. There were no significant differences between groups on mean BFI domain scores or in time to deterioration (TTD) for any BFI items.⁷
  • Longer median TTD for “fatigue interfered with walking ability”, “fatigue interfered with mood”, and “fatigue interfered with relations” were observed in the ERLEADA group than in the placebo group; however, these differences were not statistically significant.

Final Analysis

• At each cycle, >78% of patients in the ERLEADA group and >71% of patients in the placebo group had energy levels that were stable or improved relative to baseline levels per responses to question GP1 (“I have a lack of energy”) of the FACT-P questionnaire.⁸
• In a post-hoc analysis, PSA decline (≤0.2 ng/mL) correlated with HRQoL measures (e.g., time to decline in FACT-P total score, time to decline in BFI worst fatigue) at month 3 and month 6 following treatment with ERLEADA (Table: HRQoL Measures of Patients with PSA Decline [≤0.2 ng/mL]).⁹

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 11 June 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.