Name: Neeti Trivedi

Company/Organization: Johnson & Johnson                                                                                                        

Address: 800 Ridgeview Drive, Horsham, PA 19044

E‐mail: [email protected]

Date of Request: July 16,2025

PathwaysPanel: Prostate Cancer

Dear Cigna Advisory Panel,

On behalf of Janssen Biotech, Inc., a Johnson and Johnson company, we are submitting this information for the Prostate Medical Oncology Pathways panel to review. This submission is based on clinical effectiveness, overall survival and HRU cost in the real world for patients with mCSPC initiating androgen receptor pathway inhibitor (ARPI).

Two similarly designed real-world, retrospective, longitudinal, head-to-head, casual analyses compared overall survival (OS) by 24 months in ARPI-naïve patients with metastatic castration-sensitive prostate cancer (mCSPC) who were newly initiated on apalutamide (n=1879) or abiraterone acetate (n=2073), and apalutamide (n=1810) or enzalutamide (n=1909). Patients initiated on apalutamide had a statistically significant 26% reduction in the risk of death by 24 months when compared with patients initiated on abiraterone acetate (HR, 0.74; 95% CI, 0.59-0.93; P=0.010). Additionally, patients initiated on apalutamide had a statistically significant 23% reduction in the risk of death by 24 months when compared with patients initiated on enzalutamide (HR, 0.77; 95% CI, 0.62-0.96; P=0.019).^2,3

FDA Clearance: ERLEADA is an androgen receptor inhibitor indicated for the treatment of patients with (1) metastatic castration-sensitive prostate cancer (mCSPC) and (2) non-metastatic castration-resistant prostate cancer. Patients taking ERLEADA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Please refer to the enclosed product prescribing information for the full FDA-approved indications and safety information.¹ 

• Rationale^2,3
• These studies were designed with methodological considerations for designing real-world evidence studies required by Duke-Margolis’s framework and FDA guidance issued for the development of real word evidence for regulatory decision making.
• In two similarly designed real-world, retrospective, longitudinal, head-to-head, casual analyses, OS by 24 months was evaluated in ARPI-naïve patients with mCSPC after newly initiating treatment with either
• (1) apalutamide ([APA], n=1879) or abiraterone acetate ([ABI], n=2073)² or
• (2) APA (n=1810) or enzalutamide ([ENZ], n=1909).³
• Patients in the two studies were assigned to mutually exclusive treatment cohorts based on the first dispensation or paid pharmacy claim (index date) for APA or ABI or ENZ.
• The baseline period was defined as 12 months before the index date and the observation period spanned from the index date to the latter end of clinical or claims activity but no later than 12/31/2023.
• Data Source^2,3
• The clinical data supporting both studies were retrieved from Precision Point Specialty (PPS) Analytics, as part of routine clinical care from community-based urology practices in the US and were linked with administrative claims data from the Komodo Research Database (KRD) meeting fit-for-purpose dataset requirement.
• Statistical Analysis^2,3
• In both studies, a power calculation was conducted to ensure that the sample size was sufficient to detect statistically significant differences in OS between all cohorts.    
• Inverse probability of treatment weighting (IPTW) based on propensity score was used to account for differences in baseline sociodemographic and clinical characteristics between the APA and ABI and APA and ENZ cohorts.
  • Each patient was attributed an inverse probability of treatment weight, defined as 1/(propensity score) for the APA cohort and 1/(1-propensity score) for the ABI or ENZ cohorts.
• Weighted Kaplan-Meier analyses were used to assess the proportion of patients surviving by up to 48 months post-index, and weighted Cox proportional hazards models were used to compare the OS between the cohorts at 24 months (primary outcome) and 48 months (exploratory outcome).
• Overall survival in patients with mCSPC treated with Apalutamide versus Abiraterone Acetate- Results:²
• Patient Characteristics
• Pre-index baseline characteristics were well balanced between the APA and ABI cohorts, using inverse-probability of treatment-weighting with standardized differences approximately <10%.
  • The mean age was 72 years; ~62% were White; 19% were Black or African American; ~66% had bone metastasis, ~53% had nodal metastasis, ~22% had visceral metastasis, and ~75% used ADT at time of index.  
• Overall Survival
• 24 Months Post-index
  • By 24 months post-index, patients initiated on APA had a statistically significant 26% reduction in the risk of death vs ABI (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.59-0.93; P=0.010).
  • The proportion of patients surviving at 24 months post-index was 88.7% in the APA cohort and 85.8% in the ABI cohort.
• 48 Months Post-index
  • When evaluating OS using all available follow-up at 48 months post-index, results remained consistent with OS at 24 months post-index favoring APA vs ABI (HR, 0.72; 95% CI, 0.59-0.88; nominal P<0.001). This endpoint was not adjusted for multiple comparisons. Therefore, the p-value displayed is nominal, and statistical significance has not been established.
  • The proportion of patients surviving at 48 months post-index was 77.3% in the APA cohort and 69.4% in the ABI cohort.
• Overall survival in patients with mCSPC treated with Apalutamide versus Enzalutamide- Results:³
• Patient Characteristics
• Pre-index baseline characteristics were well balanced between the APA and ENZ cohorts, using inverse-probability of treatment-weighting with standardized differences approximately <10%.
  • The mean age was 73 years; ~60% were White; 23% were Black or African American; ~72% had bone metastasis, ~49% had nodal metastasis, ~20% had visceral metastasis, and ~79% used ADT at time of index.  
• Overall Survival
• 24 Months Post-index
  • By 24 months post-index, patients initiated on APA had a statistically significant 23% reduction in the risk of death vs ENZ (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.62-0.96; P=0.019)
  • The proportion of patients surviving at 24 months post-index was 87.6% in the APA cohort and 84.6% in the ENZ cohort.
• 48 Months Post-index
  • When evaluating OS using all available follow-up at 48 months post-index, results remained consistent with OS at 24 months post-index favoring APA vs ENZ (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 proportion of patients surviving at 48 months post-index was 75.6% in the APA cohort and 68.1% in the ENZ cohort.
• Comparison of HRU and Costs among patients with mCSPC Prostate Cancer Treated with APA or ENZ:⁴
• In a real-world, retrospective study healthcare resource utilization (HRU), and medical and pharmacy costs were evaluated among patients with mCSPC who initiated APA, n=486 or  ENZ, n=601 and had 6 months of continuous closed medical and pharmacy insurance eligibility prior to and on the index date (index date=the first dispensation or paid pharmacy claim for APA or ENZ). Linked clinical data from Precision Point Specialty (PPS) Analytics, were collected as part of routine clinical care from community-based urology practices in the US, the clinical data were linked with administrative claims data from the Komodo Research Database (KRD) obtained from January 2016 to December 2023. Patients with mCSPC were identified based on diagnosis code or clinical indicator for bone, nodal, or visceral metastasis without evidence of castration resistance. Inverse probability treatment weighting (IPTW) was used to balance differences in key sociodemographic and clinical baseline characteristics, all-cause HRU and cost outcomes (2024 US dollars), measured per-patient-per-month (PPPM) were described and compared between the APA and ENZ cohorts during the observation period using rate ratios (RR) and mean cost differences (MCD).
  • Pre-index baseline characteristics were well balanced between the APA and ENZ cohorts. Median age: 70 years, ~53% White, ~25% Black, 8% Hispanic or Latino, ~58% Medicare-insured, in both cohorts
  • Patients in the APA cohort had a 42% significantly lower rate of all-cause inpatient admissions during the observation period compared with those in the ENZ cohort (RR: 0.58; 95% [CI]: 0.37, 0.86; P=0.012). This trend was also significant/consistent in PC-related inpatient admissions (RR: 0.58, 95% CI (0.37, 0.86); P= 0.012)    
  • Patients in the APA cohort experienced a 62% significant reduction in the number of all-cause inpatient days compared with the ENZ cohort (RR: 0.38; 95% CI: 0.19, 0.70; p=0.004). This trend was also significant/consistent in PC-related inpatient days (RR:0.38 95% CI (0.19, 0.70); P=0.004)  
  • Mean all-cause medical costs were also significantly lower in the apalutamide cohort than the enzalutamide cohort (MCD: -$1,845 PPPM; 95% CI: -52, -4,908; P=0.044); the mean difference in outpatient costs between the APA and ENZ cohorts (-$1,605; 95% CI: 124, -4,699; P=0.104) accounted for 87% of the medical cost savings in the APA cohort.

The following publications are submitted for consideration: 

• • • Lowentritt B, Bilen MA, Khilfeh I, et al. Overall survival in patients with metastatic castration-sensitive prostate cancer treated with apalutamide versus abiraterone acetate: a head-to-head analysis of real-world patients in the USA. J Comp Eff Res. Published online May 9, 2025. doi:10.57264/cer-2025-0023
    • Bilen MA, Lowentritt B, Khilfeh I, et al. Overall Survival with Apalutamide vs Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer. Adv Ther. Published online May 29, 2025 doi: 10.1007/s12325-025-03207-6
    • Emmott N, Nafie M, Kim D, et al. Real-World Evidence to Support Causal Inference: Methodological Considerations for Non-Interventional Studies. Duke-Margolis Institute for Health Policy; 2024. Available at: https://healthpolicy.duke.edu/publications/real-world-evidence-support-causal-inference
    • U.S. Food and Drug Administration. Considerations for the use of real-world data and real-world evidence to support regulatory decision- making for drug and biological products. August 2023. FDA-2021-D-1214. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-real-world-data-and-real-world-evidence-support-regulatory-decision-making-drug 

The following references are of additional real-world studies that support these findings: 

• Maughan BL, Liu Y, Mundle S, et al. Survival outcomes of apalutamide as a starting treatment: impact in real-world patients with metastatic hormone sensitive prostate cancer (OASIS). Prostate Cancer Prostatic Dis. Published online December 20, 2024. doi:10.1038/s41391-024-00929-6   
• Shiota, M., Liu, Y., Mundle, S. et al. The impact of androgen receptor pathway inhibitors as starting treatment in metastatic castration-sensitive prostate cancer on patient outcomes (OASIS Japan). Sci Rep. 2025;15:13598. https://doi.org/10.1038/s41598-025-93136-9.

If you require further information, please contact me via the Medical Information Center at 1-800-526-7736. 

Sincerely, 

Neeti Trivedi, PharmD, MBA                                                                                                

Associate Director, Medical Information

Janssen Scientific Affairs, LLC

 Enclosures

• Please find the enclosed ERLEADA Full Prescribing Information and Patient Information.¹ 

REFERENCES

1. ERLEADA® (apalutamide) [Prescribing Information]. Horsham, PA: Janssen Products, LP. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/ERLEADA-pi.pdf
2. Lowentritt B, Bilen MA, Khilfeh I, et al. Overall survival in patients with metastatic castration-sensitive prostate cancer treated with apalutamide versus abiraterone acetate: a head-to-head analysis of real-world patients in the USA. J Comp Eff Res. Published online May 9, 2025. doi:10.57264/cer-2025-0023
3. Bilen MA, Lowentritt B, Khilfeh I, et al. Overall Survival with Apalutamide vs Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer. Adv Ther. Published online May 29, 2025 doi:10.1007/s12325-025-03207-6
4. Bilen MA, Lowentritt B, Burbage S, et al. Comparison of Healthcare Resource Utilization and Costs Among Patients with Metastatic Castration-Sensitive Prostate Cancer Treated with Apalutamide or Enzalutamide. Abstract for Poster Presentation at Academy Health Annual Research Meeting. June 7-10, 2025. Minneapolis, MN.