SUMMARY

• Apalutamide is an androgen receptor (AR) inhibitor that is structurally distinct from the AR inhibitor enzalutamide.^1,2
• Prospective, Randomized, Head-to-Head Studies
  • No studies comparing the efficacy and safety of ERLEADA with enzalutamide have been conducted.
• Real-World, Retrospective Studies (Metastatic Castration-Sensitive Prostate Cancer [mCSPC]) - Survival
  • Head-to-head, longitudinal study: compared overall survival (OS) at 24 months for patients who newly initiated ERLEADA (n=1810) vs enzalutamide (n=1909). Patients in the ERLEADA vs enzalutamide weighted cohort had a 23% reduction in the risk of death (87.6% vs 84.6%; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.62-0.96; P=0.019).³
  • ROME study: unadjusted real-world survival rates were as follows for the ERLEADA (n=234) and enzalutamide (n=527) cohorts, respectively: 91.5% vs 90.4% by 12 months, 87.9% vs 80.3% by 18 months, and 85.4% vs 73.9% by 24 months. By 24 months postindex, patients in the ERLEADA cohort had a 41% lower mortality rate relative to patients initiated on enzalutamide (unadjusted HR, 0.59; 95% CI, 0.37-0.95; P=0.030).⁴
  • OASIS study: starting with ERLEADA plus androgen deprivation therapy (ADT) compared with enzalutamide plus ADT was associated with a statistically significant lower risk of death (adjusted HR, 0.5; 95% CI, 0.28-0.92; P<0.05).⁵
• Real-World, Retrospective Studies/Analyses (mCSPC) – PSA & Other Results
  • PROMPT-1 study: patients in the ERLEADA weighted cohort were 21% more likely to achieve ≥90% prostate-specific antigen (PSA) reduction from baseline (PSA90) response compared with the enzalutamide weighted cohort (HR, 1.21; 95% CI, 1.05-1.40; P=0.008) by 6 months postindex. The median time to PSA90 was 3.7 months vs 5.1 months, respectively.⁶
  • De novo study: 62.8% vs 49.6% of patients with de novo mCSPC in the ERLEADA and enzalutamide groups, respectively, achieved PSA90 at 6 months (HR, 1.39; 95% CI, 1.11-1.74; P=0.004). The median time to PSA90 was 3.5 months vs 6.1 months, respectively.⁷
  • Summary of descriptive analyses for the rates of PSA90, undetectable PSA (≤0.2 ng/mL), progression to castration resistance (CR), castration resistance-free survival (CRFS), and/or OS in patients initiated on ERLEADA or enzalutamide are summarized in Tables: Clinical Outcome Results and Clinical Outcomes.^8,9
  • Summary of PSA90 response was compared between patients initiated on ERLEADA or enzalutamide. Results are summarized in Table: PSA90 Response Results in ERLEADA vs Enzalutamide Groups.¹⁰ Additionally, PSA90 was assessed as well as undetectable PSA among patients initiated on ERLEADA or enzalutamide; results are summarized in Table: PSA Response Results in the ERLEADA and Enzalutamide Groups.¹¹
• Real-World, Retrospective Studies (Non-Metastatic Castration-Resistant Prostate Cancer [nmCRPC])  – Safety and Utilization: analyses describing the incidence and/or management of adverse events (AEs) in patients who received treatment with ERLEADA or enzalutamide,^12,13 assessing the prevalence of potential drug-drug interactions (pDDIs),¹⁴ and comparing utilization of ERLEADA and enzalutamide ^15,16 have been reported.
• Matching-Adjusted Indirect Comparison (MAIC) Studies (nmCRPC): utilized data from the phase 3 registrational studies, SPARTAN (ERLEADA plus ADT vs placebo plus ADT) and PROSPER (ERLEADA plus ADT vs placebo plus ADT), have been reported.^17-19

CLINICAL DATA

No prospective, randomized, head-to-head clinical trials comparing the efficacy and safety of ERLEADA with enzalutamide have been conducted.

Additional DATA

Retrospective Real-World Studies in Patients with mCSPC

Bilen et al (2024)³ conducted a head-to-head, real-world, retrospective, longitudinal study to evaluate OS at 24 months among US-based patients with mCSPC who initiated ERLEADA (n=1810) or enzalutamide (n=1909) using clinical data from Precision Point Specialty (PPS) Analytics linked with claims data from Komodo Research Database from December 2018 to December 2023. This analysis utilized propensity score-weighted cohorts of androgen receptor pathway inhibitors (ARPIs)-naïve patients newly initiated on ERLEADA or enzalutamide and followed an intent-to-treat design. The analysis used weighted Cox proportional hazards models to evaluate the causal relationship between index treatment and OS, weighted Kaplan-Meier analysis to assess the portion of patients surviving by 24 months post-index, and inverse probability of treatment weighting (IPTW) based on the propensity score to account for differences in baseline characteristics between both cohorts. Concurrent use of ADT was not required; 79.2% vs 77.8% patients were receiving ADT at baseline in the ERLEADA vs enzalutamide weighted cohorts, respectively.

Patients in the ERLEADA cohort had a 23% reduction in the risk of death compared with enzalutamide (87.6% vs 84.6%; HR, 0.77; 95% CI, 0.62-0.96; P=0.019). When evaluating OS using all available follow-up at 48 months postindex, results were 75.6% vs 68.1% in the ERLEADA vs enzalutamide weighted cohorts, respectively (HR, 0.77; 95% CI, 0.64-0.93; nominal P=0.008); this endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established. The mean (median) follow-up period was 17.2 (20.1) months vs 17.2 (20.1) months and duration of continuous index ARPI use was 9.6 (6.9) months vs 8.6 (6.4) months in patients who initiated ERLEADA vs enzalutamide, respectively.

Bilen et al (2024)⁴ conducted a real-world, retrospective, longitudinal cohort study to evaluate survival among US-based patients with mCSPC who initiated ERLEADA (n=234) or enzalutamide (n=527) using electronic health record data from the Flatiron Metastatic Prostate Cancer Core Registry from January 2013 to May 2023 (ROME study). Concurrent use of ADT was not required for inclusion however most patients (>84%) had prior use of ADT before treatment initiation. The median time between metastasis and index treatment initiation was 2.3 months in the ERLEADA cohort and 2.8 months in the enzalutamide cohort.

Using Kaplan-Meier analysis, unadjusted real-world survival rates were as follows for the ERLEADA and enzalutamide cohorts, respectively: 91.5% vs 90.4% by 12 months, 87.9% vs 80.3% by 18 months, and 85.4% vs 73.9% by 24 months. By 24 months postindex, patients in the ERLEADA cohort had a 41% lower mortality rate relative to patients initiated on enzalutamide (unadjusted HR, 0.59; 95% CI, 0.37-0.95; P=0.030). The median time on treatment and observation period was 10.9 months and 13.3 months in the ERLEADA cohort and 11.1 months and 14.8 months in the enzalutamide cohort.

Maughan et al (2024)⁵ conducted a real-world, retrospective, observational cohort study to evaluate the impact of first-line treatment in US-based patients with mCSPC (OASIS study). Patients with a mCSPC diagnosis from January 2018 to September 2022 in the ConcertAI database that started treatment with any androgen receptor signaling inhibitor (ARSI), docetaxel, or ADT alone were included. Enrollment included 4626 patients that started treatment with ERLEADA plus ADT (n=165), enzalutamide plus ADT (n=643), abiraterone acetate with prednisone plus ADT (n=1064), docetaxel plus ADT (n=293), and ADT alone (n=543).

Using multivariate Cox regression with IPTW method of risk of death, starting with ERLEADA plus ADT compared with enzalutamide plus ADT was associated with a statistically significant lower risk of death (adjusted HR, 0.5; 95% CI, 0.28-0.92; P<0.05). Results for ERLEADA plus ADT and enzalutamide plus ADT compared with ADT alone for OS, time to CR, and time to undetectable PSA outcomes are shown in Table: Adjusted HRs by Initial Treatment Compared to ADT Alone.

Lowentritt et al (2024)⁶ conducted a real-world, retrospective, longitudinal propensity score-weighted cohort study to evaluate PSA90 response by 6 months in patients with mCSPC newly initiated on ERLEADA (n=862) or enzalutamide (n=871) using data from the Komodo Health Solutions Research Database from December 16, 2018, to September 30, 2022 (PROMPT-1). Concurrent use of ADT was not required for inclusion however most patients (>86%) in the IPTW population had prior use of ADT before treatment initiation. Mean baseline PSA was 22.7 ng/mL and 23.3 ng/mL in the ERLEADA and enzalutamide weighted cohorts, respectively.

There were 81.4% of patients in the ERLEADA weighted cohort vs 77.5% of patients in the enzalutamide weighted cohort with a postindex PSA measurement. By 6 months postindex, patients in the ERLEADA weighted cohort were 21% more likely to achieve PSA90 response compared with the enzalutamide weighted cohort (HR, 1.21; 95% CI, 1.05-1.40; P=0.008). The same trend was observed over the entire observation period (P=0.008). At 6 months, 62.5% vs 53.8% of patients achieved PSA90 in the ERLEADA vs enzalutamide cohorts, with a median time to PSA90 of 3.7 months vs 5.1 months, respectively.

Lowentritt et al (2024)⁷ conducted retrospective real-world analyses to evaluate PSA90 response at 6 months in next-generation ARSI-naïve patients with de novo mCSPC initiating ERLEADA (n=332) or enzalutamide (n=383) using data from the Komodo Health Solutions Research Database from December 16, 2019, to September 30, 2022.

A weighted Kaplan-Meier analysis was used to assess the proportion of patients who achieved a PSA90 response. A weighted Cox proportional hazards model was used to assess the time to PSA90 response. Patients were required to have the first ERLEADA or enzalutamide dispensation or pharmacy claim on or after the index date, de novo mCSPC (metastatic diagnosis observed ≤180 days after the initial prostate cancer diagnosis), ≥12 months of preindex clinical activity, and ≥1 PSA measurement within 13 weeks before the index date.

The mean preindex PSA level was 32.7 vs 32.6 ng/mL in the ERLEADA and enzalutamide groups, respectively. By 6 months postindex, 81.0% of patients in the ERLEADA group and 75.2% of patients in the enzalutamide group had ≥1 PSA test. At 6 months, 62.8% vs 49.6% of patients achieved PSA90 in the ERLEADA vs enzalutamide group (HR, 1.39; 95% CI, 1.11-1.74; P=0.004), with a median time to PSA90 of 3.5 vs 6.1 months, respectively.

Lowentritt et al (2023)⁸ conducted a real-world, retrospective, longitudinal cohort study to evaluate PSA outcomes and disease progression in patients with mCSPC that were initiated on ERLEADA (n=589) or enzalutamide (n=597). The study also included data for patients who initiated treatment with abiraterone acetate; however, the results for this cohort are not summarized below.

Kaplan-Meier analyses were used to assess the rates of PSA90, PSA 0.2, progression to CR, and CRFS separately for each cohort. All analyses were descriptive and were not adjusted for potential baseline confounders. Patients were required to have ≥12 months of clinical activity prior to the index date. Concurrent use of ADT was not required for inclusion in either cohort. Among the exclusion criteria were prior use of an ARSI before the index date or the use of ≥2 ARSIs on the index date and prior use of any radiopharmaceuticals.

Most patients had prior use of ADT and concurrent use of ADT in the ERLEADA (90.5%, 96.3%) and enzalutamide (89.8%, 94.5%) cohorts, respectively. Median baseline PSA was 19.2 ng/mL and 18.8 ng/mL in the ERLEADA and enzalutamide cohorts, respectively. The descriptive analyses are summarized in Table: Clinical Outcome Results.

Lowentritt et al (2023)⁹ conducted retrospective real-world analyses to describe clinical outcomes in patients with mCSPC that were initiated on ERLEADA (n=155) or enzalutamide (n=385) using electronic medical record (EMR) data from the Flatiron Metastatic Prostate Cancer Core Registry. The study also included data for patients who initiated treatment with abiraterone acetate; however, the results for this cohort are not summarized below.

Kaplan-Meier analyses were used to assess the rates of progression to CR, OS, and CRFS separately for each cohort. All analyses were descriptive and were not adjusted for potential baseline confounders. Patients were required to have ≥12 months of clinical activity prior to the index date. Concurrent use of ADT was not required for inclusion in either cohort. Among the exclusion criteria were prior use of an ARSI before the index date or the use of ≥2 ARSIs on the index date, and prior use of any advanced therapy for prostate cancer (ie, chemotherapy, immunotherapy, radiopharmaceuticals, estrogens, or PARP inhibitors).

Most patients had prior use of ADT before initiation of ERLEADA (83.2%) and enzalutamide (83.9%). The mean observation period was 12.7 months and 13.2 months in the ERLEADA and enzalutamide cohorts, respectively. The descriptive analyses are summarized in Table: Clinical Outcomes.

Lowentritt et al (2023)¹⁰ conducted a real-world analysis to retrospectively compare the proportion of patients with a PSA90 by 6 months postindex and time to PSA90 response from the date of index treatment initiation in patients with mCSPC that were initiated on ERLEADA or enzalutamide.

IPTW based on propensity score was used to account for differences in baseline characteristics and balancing of baseline characteristics after weighting was confirmed between both cohorts. The observation period spanned from the index date to either index treatment discontinuation, initiation of a different next-generation ARSI or the use of radiopharmaceuticals, end of clinical activity (eg, death), or end of data availability, whichever occurred first.

Patients were required to have ≥12 months of clinical activity prior to the index date and ≥1 PSA test during the 13 weeks prior to and including index date. Among the exclusion criteria were prior use of a next-generation ARSI before the index date or the use of ≥2 next-generation ARSIs on the index date and evidence of CR prior to or on the index date. Concomitant use of ADT was not required for inclusion.

Before applying IPTW, a total of 186 patients treated with ERLEADA and 165 patients treated with enzalutamide were identified and after applying IPTW, the reweighted cohort sizes were 174 patients and 177 patients, respectively. The mean baseline PSA level was 18.4 ng/mL vs 18.3 ng/mL in the ERLEADA weighted cohort vs the enzalutamide weighted cohort, respectively.

In the IPTW population, 73.6% of patients treated with ERLEADA and 70.5% of patients treated with enzalutamide had ≥1 PSA test during the observation period, with nearly all (100% vs 98.7%, respectively) having their first PSA test within 6 months following treatment initiation. The PSA90 response and median time to PSA90 response results were significant in the ERLEADA vs enzalutamide cohorts at 6 months and beyond (Table: PSA90 Response Results in ERLEADA vs Enzalutamide Groups). No safety data were reported.

Pilon et al (2021)¹¹ conducted a real-world analysis to retrospectively describe PSA responses (PSA90 and undetectable PSA [PSA <0.2 ng/mL]) among patients with mCSPC who initiated treatment with ERLEADA or enzalutamide. The study also included data for patients who initiated treatment with abiraterone acetate; however, the results for this cohort are not summarized below.

The observation period spanned from the index date to index treatment discontinuation, initiation of a different next-generation androgen signaling inhibitor (ASI) or the use of radiopharmaceuticals, end of clinical activity (eg, death), or end of data availability, whichever occurred first. KaplanMeier analysis was used to assess the proportion of patients who achieved each PSA response outcome at 3, 6, 9, and 12 months postindex, as well as the median time to PSA response.

Patients were required to have ≥12 months of clinical activity prior to the index date and ≥1 medication dispensation of ERLEADA, enzalutamide, or abiraterone acetate. Select exclusion criteria were prior use of a next-generation ASI before the index date or the use of >1 ASI on the index date and evidence of CR prior to or on the index date. PSA responses were assessed for patients who had ≥1 PSA measurement during the 13 weeks before the index date.

Overall, 45.0% and 70.0% of patients treated with ERLEADA, respectively, and 33.0% and 58.3% of patients treated with enzalutamide, respectively, had a PSA test on average every 3 and 6 months. Patients achieving PSA90 and undetectable PSA responses were observed by 3 months, with the proportion increasing at 6 months postindex (Table: PSA Response Results in the ERLEADA and Enzalutamide Groups). No safety data were reported.

Retrospective Real-World Studies in Patients with nmCRPC

Appukkuttan et al (2024)¹² evaluated the incidence of non-central nervous system (CNS)-related AEs and CNS-related AEs and healthcare resource utilization among US-based patients with nmCRPC treated with ERLEADA (n=156) or enzalutamide (n=449) in a retrospective, real-world, observational cohort study using Optum Clinformatics Data Mart claims data. The median time from treatment initiation to non-CNS-related AE and CNS-related AE was 116 days and 337 days in the ERLEADA group and 117 days and 250 days for the enzalutamide group, respectively. The mean per patient per year AE count estimates for the ERLEADA group vs enzalutamide group were 19.7 vs 19.8 for non-CNS-related AEs and 4.9 vs 5.7 for CNS-related AEs, respectively.

Hussain et al (2022)¹³ conducted a real-world analysis to retrospectively describe the incidence and management of AEs in patients with nmCRPC who received treatment with ERLEADA or enzalutamide. Patients were followed for a median of 1.1 years (ERLEADA, 1.2 years; enzalutamide, 1.0 years). Of these, 525 (75.1%) patients experienced ≥1 AE (ERLEADA, 72.0%; enzalutamide, 78.7%). The most commonly reported AEs and AEs of special interest are described in Table: Summary of AEs.

Of the 525 patients with ≥1 AE, 250 were randomly selected for detailed data collection (ERLEADA, n=125; enzalutamide, n=125) and were followed for a median of 13 months from treatment initiation. In the ERLEADA and enzalutamide groups, respectively, the mean PSA level at nmCRPC diagnosis was 20.99 ng/mL and 25.35 ng/mL and the median therapy duration was 13.6 months and 12.8 months. A total of 444 AEs were reported in this subset. The most common AEs of any nature were fatigue/asthenia (50.8%), flush (20.8%), and arthralgia (18.8%). Grade 3-4 and grade 5 AEs occurred in 36 (14.4%) patients and 1 (0.4%) patient, respectively.

A total of 95 (38.0%) patients received treatment for an AE in the overall subset (ERLEADA, 36.8%; enzalutamide, 39.2%). More than half (51.6%) of the AEs resolved without a sequelae, while 41.4% did not resolve. In the overall subset, treatment discontinuation due to AE was reported in 10.4% of patients (ERLEADA, 8.0%; enzalutamide, 12.8%), and dose reduction due to AEs was reported in 7.6% of patients (ERLEADA, 7.2%; enzalutamide, 8.0%). A total of 12 (4.8%) patients were hospitalized due to AE (ERLEADA, 5.6%; enzalutamide, 4.0%), and the mean length of hospital stay was 4.58 days. AEs that led to hospitalizations included seizure, fracture, falls, hypertension, and other cardiovascular events. Treatment discontinuation due to any reason was reported in 26.8% of patients in the overall subset (ERLEADA, 28.0%; enzalutamide, 25.6%), and the most common reason was disease progression (53.7%). Physician-reported non-progression-related reasons for treatment discontinuation were unacceptable side effects/toxicity (overall subset, 38.8%; ERLEADA, 28.6%; enzalutamide, 50.0%), patient choice/preference/refusal (overall subset, 23.9%; ERLEADA, 20.0%; enzalutamide, 28.1%), death (overall subset, 4.5%; ERLEADA, 5.7%; enzalutamide, 3.1%), and other (overall subset, 1.5%; ERLEADA, 2.9%; enzalutamide, 0%).

Appukkuttan et al (2024)¹⁴ evaluated the prevalence of pDDIs in patients with nmCRPC (N=1515) treated with ERLEADA (n=340), enzalutamide (n=1063), or darolutamide (n=112) in a retrospective, real-world, observational cohort study using Optum Clinformatics Data Mart claims data from August 01, 2019, to March 31, 2021.

In total, 66% of patients received ≥5 concomitant medications at baseline. The most common therapeutic drug classes prescribed were cardiovascular (80%), CNS (52%), and anti-infective (50%). Of the 100 most prevalent comedications, pDDls reported were 30 for ERLEADA, 30 for enzalutamide, and 2 for darolutamide. At least 1 pDDI was identified in 58% (197/340) of patients receiving ERLEADA, 54% (577/1063) receiving enzalutamide, and 5% (6/112) receiving darolutamide. Four pDDls for ERLEADA were of grade X in severity (avoid combination; Table: Severity Levels of pDDls).

Appukkuttan et al (2021)¹⁵ conducted a real-world analysis to retrospectively compare the utilization of ERLEADA and enzalutamide among patients with nmCRPC from a urology EMR database. A total of 2636 patients were identified, 1023 (39%) patients treated with ERLEADA and 1613 (61%) patients treated with enzalutamide. In the ERLEADA and enzalutamide groups, the median baseline PSA level was 3.7 ng/dL and 4.1 ng/dL, median duration of follow-up was 18.7 months and 12.1 months, and median therapy duration was 12.9 months and 9.8 months, respectively.

Overall, 41.5% of patients discontinued use of initial medication, with another 9.4% switching therapy. In a patient subset randomly selected for chart review (ERLEADA group, n=455, enzalutamide group, n=522), AEs were the most common reason reported for drug discontinuation (ERLEADA group, 43.4%; enzalutamide group, 58.2%) and among the 5.6% of patients that had a dose reduction, 72.4% of patients in ERLEADA group and 73.1% of patients in the enzalutamide group reported AEs as the most common reason.

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
27 May 2024. Summarized in this response are relevant data limited to patients with mCSPC or nmCRPC. Due to methodological differences and other potential limitations including scope, timing, study designs and statistical approaches, network meta-analyses, and meta-analyses have been excluded in this response. Additional data beyond these parameters may be available in the literature.