Gordon Brown, DO1; Ibrahim Khilfeh, PharmD2; Carmine Rossi, PhD3; Shawn Du, PhD2; Frederic Kinkead, MA3; Lilian Diaz, MSc3; Dominic Pilon, MA3; Benjamin H. Lowentritt, MD, FACS4
1New Jersey Urology, Cherry Hill, New Jersey, USA
2 Johnson & Johnson, Horsham, Pennsylvania, USA
3 Analysis Group, Inc, Montréal, QC, Canada
4 Chesapeake Urology, Towson, Maryland, USA
KEYWORDS:
Neoplasm metastasis; prostate-specific antigen; prostatic neoplasms; treatment outcome
Abstract
Background: Deep prostate-specific antigen (PSA) responses are associated with improved clinical outcomes among patients with metastatic castration-sensitive prostate cancer (mCSPC), also known as metastatic hormone-sensitive prostate cancer. This study compared real-world PSA90 responses (ie, ≥90% reduction in PSA from pretreatment levels) among patients with de novo mCSPC treated with apalutamide vs abiraterone acetate.
Methods: PPS Analytics Population Health Management Platform (PPS Analytics) electronic health record data were linked to Komodo Research Database claims. Patients with de novo mCSPC who initiated apalutamide or abiraterone acetate were included. Patient characteristics were balanced between treatment cohorts using inverse probability of treatment weighting. Weighted Kaplan-Meier curves and hazard ratios were used to compare PSA90 response between treatment cohorts.
Results: A total of 1028 patients with de novo mCSPC were included (apalutamide: n = 521; abiraterone acetate: n = 507). Patients treated with apalutamide were more likely to achieve a PSA90 response within 6 months of treatment initiation relative to patients treated with abiraterone acetate (hazard ratio, 1.37 [95% CI, 1.12-1.67]; P = .002). The median time to PSA90 response was earlier with apalutamide compared with abiraterone acetate treatment (apalutamide, 3.6 months; abiraterone acetate, 8.1 months).
Conclusions: Patients with de novo mCSPC experienced statistically significantly higher PSA90 response rates when treated with apalutamide vs abiraterone acetate. Additional research is warranted to assess the impact of early, deep PSA response on real-world clinical outcomes.
Prostate cancer is the leading type of cancer among men, accounting for an estimated 299 000 new cases and 35 250 deaths in the United States in 2024.1 The majority of prostate cancer cases are diagnosed while still localized to the primary site, with many cases eventually progressing to metastatic disease.2,3 In some patients, however, metastatic prostate cancer is present at initial diagnosis, while the patient is castration sensitive (ie, de novo metastatic castration-sensitive prostate cancer [mCSPC], also known as de novo metastatic hormone-sensitive prostate cancer), representing 5% of prostate cancer cases at diagnosis and approximately 45% of all cases of metastatic prostate cancer.4,5
Despite being responsive to androgen-deprivation therapy (ADT), high-volume de novo mCSPC is associated with poor long-term clinical outcomes and is often first treated with chemotherapy, though positive results have been identified with androgen receptor pathway inhibitor (ARPI) treatment in this subpopulation.2,3,5-7 The phase 3 randomized, placebo-controlled TITAN and LATITUDE trials demonstrated greater radiographic progression-free survival among patients with mCSPC treated with either ADT plus apalutamide (TITAN) or abiraterone acetate (LATITUDE) compared with patients treated with ADT and placebo.8,9 The US Food and Drug Administration (FDA) subsequently approved apalutamide in September 2019 for patients with mCSPC and abiraterone acetate in February 2018 for patients with high-risk mCSPC (ie, with at least 2 of the following 3 factors: Gleason score ≥8, ≥3 bone lesions, and the presence of measurable fisceral metastasis) based on the results of these trials.9-11
Prostate-specific antigen (PSA) levels are an important indicator of prostate cancer treatment response, with earlier and deeper PSA responses associated with superior long-term outcomes.12,13 Despite the need for effective therapies in this patient subgroup, no previous real-world studies have evaluated PSA responses with ARPI treatment among patients with de novo mCSPC or compared PSA responses following treatment with apalutamide or abiraterone acetate. The aim of this real-world study was therefore to compare PSA90 responses (ie, ≥90% reduction of PSA from pretreatment levels) among patients with de novo mCSPC treated with either apalutamide or abiraterone acetate in US clinical practice.
Data were obtained from the PPS Analytics Population Health Management Platform (PPS Analytics) database, which consists of routinely collected electronic health record (EHR) data from multiple US community urology practices. Data from February 1, 2017, to December 31, 2023, were used. The PPS Analytics EHR data are robust and include demographic variables, clinical variables, and variables specific to prostate cancer that capture information about sites of metastases, castration resistance progression, laboratory test values (eg, PSA testing, testosterone, Gleason score), and dispensing information for ARPIs (eg, fill dates, amount dispensed, dosage).
The PPS Analytics dataset was linked to Komodo Research Database (KRD) insurance claims. The Komodo database contains both inpatient and outpatient diagnosis and procedure information, prescription fills, and billing and reimbursement data for more than 330 million patients in the United States covered by commercial insurance, Medicaid, or Medicare. These data were collected between January 1, 2016, and December 31, 2023. The PPS Analytics and KRD data were linked by Datavant, using its patentpending deidentification technology, whereby patient information is supplemented with an encrypted token that cannot be reversed to reveal the original information. All data were Health Insurance Portability and Accountability Act compliant; therefore, approval by an institutional review board was not required.
This causal analysis used a retrospective longitudinal cohort design, with the study protocol incorporating guidance from the FDA regarding noninterventional studies for drugs and biological products.14 The date of the first record for apalutamide or abiraterone acetate, identified as the earlier of the first paid pharmacy claim in the KRD or the first in-office dispensing in PPS Analytics, on or after September 17, 2019 (ie, latter date of FDA approval for apalutamide or abiraterone acetate for mCSPC10,11 ), defined the index date and was used to assign patients into mutually exclusive treatment cohorts (Supplementary Figure 1). The baseline period was the 12 months before the index date, while the observation period spanned from the index date until the earliest of (1) 6 months, (2) index treatment discontinuation (ie, a 90-day treatment gap), (3) the initiation of a new ARPI (ie, treatment switch, excluding first-generation ARPIs), (4) initiation of radiopharmaceutical therapy, or (5) the latter of the end of open insurance claim activity in Komodo or clinical activity in PPS Analytics (ie, December 31, 2023).
The study was considered exempt research under 45 CFR §46.104(d)(4) because it involved only the secondary use of data that were deidentified in compliance with the Health Insurance Portability and Accountability Act—specifically, 45 CFR §164.514.
Adult patients with at least 1 paid pharmacy claim or dispensation for apalutamide or abiraterone acetate, at least 1 PSA measurement within the 13 weeks up to and including the index date, confirmed metastasis before or on the index date, and at least 12 months of clinical activity noted in PPS Analytics before the index date were included in this analysis. In addition, patients were required to meet the de novo mCSPC inclusion criteria, defined by the earliest observed diagnosis of prostate cancer within 180 days of metastasis. Patients who initiated an index ARPI before September 17, 2019; had no prescription for a second-generation ARPI apart from the index ARPI before or on the index date; had evidence of castration resistance before or on the index date; or used radiopharmaceuticals before or on the index date were excluded from this study. Algorithms based on clinical indicators were used to assess metastatic disease and castration resistance, as described previously.15 Concurrent ADT use was not required for inclusion in this study. Concurrent prednisone use was not required for inclusion in the abiraterone acetate cohort.
Baseline demographic characteristics (ie, age, race, geographic region, payer type, index year) and clinical characteristics (ie, times between initial metastasis diagnosis, initial prostate cancer diagnosis, and index date; metastasis type; prior ADT use [ie, preindex record of ADT and concurrent use with the index ARPI]; prior chemotherapy use; prior first-generation antiandrogen use; baseline PSA level; baseline testosterone level; and initial Gleason score) were described.
The primary study outcome was the proportion of patients with de novo mCSPC who attained a PSA90 response—relative to the most recent baseline PSA value within the 13 weeks up to and including the index date—within 6 months of the index date. Exploratory outcomes, including the proportion of patients who achieved a PSA90 response within the entire observation period and the median time to first PSA90 response, were also evaluated. During the observation period, postindex PSA measurement patterns were also evaluated.
The null hypothesis was that there would be no difference in rates of PSA90 response by 6 months after treatment initiation between ARPI-naive patients with de novo mCSPC treated with apalutamide vs abiraterone acetate. The alternate hypothesis was that there would be a difference in rates of PSA90 response by 6 months after treatment initiation between ARPI-naive patients with de novo mCSPC treated with apalutamide vs abiraterone acetate. Potential confounding factors between patients treated with either apalutamide or abiraterone acetate were balanced using inverse probability of treatment weighting. Propensity scores were generated using probability estimates from logistic regression models based on the binary dependent variable of apalutamide vs abiraterone acetate initiation. These estimates were the result of a logistic regression model that included the following independent variables: age, race, geographic region, payer type, index year, time between metastasis and the index date, metastasis type (ie, bone, nodal, or visceral), time between initial prostate cancer diagnosis and the index date (the dates associated with the initial prostate cancer diagnosis and metastasis could have differed in realworld data), prior ADT use, prior first-generation ARPI use, prior chemotherapy use, most recent baseline PSA level, most recent baseline testosterone level, and earliest Gleason score. A weight of 1/propensity score was attributed to patients in the apalutamide cohort and a weight of 1/(1 – propensity score) was attributed to patients in the abiraterone acetate cohort, with weights normalized using the mean weight of each respective cohort. Weights were truncated at the 95th percentile to reduce the impact of extreme weights. Baseline characteristics with standardized differences less than 10% between the apalutamide and abiraterone acetate cohorts after inverse probability of treatment weighting were considered balanced.
Weighted Kaplan-Meier analyses were used to describe the proportion of patients treated with either apalutamide or abiraterone acetate who achieved a PSA90 response by 6 months after the index date. Weighted Cox proportional hazards models were used to calculate hazard ratios and 95% CIs to assess the causal relationship between index treatment and PSA90 response by 6 months (primary outcome) and over the entire observation period (exploratory outcome). SAS Enterprise Guide, version 7.1, software (SAS Institute Inc) was used to perform all study analyses.
A total of 1028 patients with de novo mCSPC were included, of whom 521 patients received treatment with apalutamide and 507 received treatment with abiraterone acetate (Figure 1).
The baseline demographic and clinical characteristics of patients in the apalutamide and abiraterone acetate treatment cohorts were largely balanced after weighting. The mean (SD) age was 72.5 (9.3) years for patients who received treatment with apalutamide and 72.1 (9.2) years for patients who received treatment with abiraterone acetate (Table 1). In both treatment cohorts, most patients were White (apalutamide, 64.6%; abiraterone acetate, 64.2%), from the US South (apalutamide, 49.7%; abiraterone acetate, 47.2%), and insured with Medicare (apalutamide, 77.3%; abiraterone acetate, 76.1%). The median time between metastasis diagnosis and initiation of the index ARPI was similar between patients treated with apalutamide and abiraterone acetate (apalutamide, 3.1 months; abiraterone acetate, 3.7 months). The most recent mean (SD) baseline PSA level was 28.8 (63.4) μg/L for patients treated with apalutamide and 28.5 (59.9) μg/L for patients treated with abiraterone acetate.
The mean (SD) on-treatment observation period was 334.6 (325.2 [median, 225.0]) days for patients who received treatment with apalutamide and 280.4 (267.7 [median, 208.0]) days for patients who received treatment with abiraterone acetate. A total of 60.2% of patients treated with apalutamide and 47.0% of patients treated with abiraterone acetate achieved a PSA90 response within 6 months of ARPI initiation, with patients treated with apalutamide 37% more likely to achieve a PSA90 response by 6 months compared with patients treated with abiraterone acetate (hazard ratio, 1.37 [95% CI, 1.12-1.67]; P = .002) (Figure 2). In addition, PSA90 response was attained earlier in the apalutamide cohort (median time to PSA90 response, 3.6 months) compared with the abiraterone acetate cohort (median time to PSA90 response, 8.1 months).
Among patients treated with apalutamide, 83.0% had at least 1 PSA measurement during the observation period compared with 74.6% of patients treated with abiraterone acetate (Supplementary Table 1). Patients who received treatment with apalutamide had a mean (SD) 4.4 (3.5 [median, 3.8]) PSA tests administered per year compared with 5.1 (5.0 [median, 4.2]) PSA tests administered per year for patients who received treatment with abiraterone acetate.
In this real-world study evaluating PSA responses among patients with de novo mCSPC, patients on apalutamide attained deep and earlier PSA responses than did patients on abiraterone acetate. Specifically, patients who initiated apalutamide were 37% more likely to achieve a PSA90 response relative to patients who initiated abiraterone acetate. Furthermore, PSA90 responses were achieved approximately 4.5 months sooner among patients in the apalutamide cohort than patients in the abiraterone acetate cohort. A notable strength of the current analysis was the use of linked PPS Analytics and KRD, which allowed for the inclusion of characteristics related to prostate cancer identified within urology practice as well as the use of complementary insurance claims data for care received outside of the PPS Analytics network. To our knowledge, no previous study has compared PSA outcomes with apalutamide or abiraterone acetate treatment among patients with de novo mCSPC, particularly in a real-world US clinical setting.
Despite the lack of evidence within the de novo mCSPC subpopulation, 2 previous real-world studies have evaluated PSA90 responses with apalutamide vs abiraterone acetate treatment among populations that were largely representative of the overall population of US patients with mCSPC.15,16 Both studies evaluated real-world PPS Analytics EHR data, with 1 also linking the PPS Analytics database with the KRD insurance claims database.16 In these 2 analyses, patients treated with apalutamide were 53% and 68% more likely to achieve a PSA90 response within 6 months of treatment initiation compared with patients treated with abiraterone acetate. Apalutamide treatment resulted in patients attaining a PSA90 response after approximately 3.5 months in both real-world studies compared with approximately 10 months or not reaching PSA90 response with abiraterone acetate treatment. The greater reductions to PSA levels with apalutamide relative to abiraterone acetate are consistent with the observations among patients with de novo mCSPC in the current study. Although patients with de novo mCSPC were also more likely to achieve a PSA90 response within 6 months of apalutamide treatment initiation, the reduced likelihood (60.2%) compared with the representative mCSPC populations may be reflective of the unique physiology underlying this disease subtype.6
Despite increased prostate cancer mortality rates among patients with de novo mCSPC,5 there is no evidence regarding the real-world PSA responses to ARPI treatment among patients with de novo mCSPC. A subgroup analysis of the phase 3 apalutamide TITAN trial found that 70% of patients with high-volume de novo mCSPC—defined as either visceral metastases with at least 1 bone lesion or at least 4 bone lesions, including 1 outside of the vertebral column or pelvis (273/525 patients treated with apalutamide; 52%)—and 83% of patients with low-volume de novo mCSPC (138/525 patients treated with apalutamide; 26%) attained a PSA90 response with apalutamide treatment.7 No analyses among the subpopulation of patients with de novo mCSPC treated with abiraterone acetate in the LATITUDE trial have been conducted. The current study therefore provides essential real-world evidence regarding PSA responses among patients with de novo mCSPC following ARPI treatment, highlighting the earlier and deeper PSA90 response among patients who received treatment with apalutamide compared with patients treated with abiraterone acetate.
Limitations associated with this study include those inherent to the analysis of retrospective EHR and administrative claims data. Study data may have contained inaccuracies or omissions to diagnosis dates, treatment start dates, or other variables, and erroneous links between datasets may have occurred. In addition, information on volume of metastasis was not available. Because PSA response data were obtained from the PPS Analytics EHR database, PSA testing and results performed outside of the network were not captured and may result in misclassification of the study outcome. This study furthermore may have been subject to surveillance bias if PSA testing was performed more frequently for 1 ARPI over the other. Previous studies have shown that the proportion of patients with PSA tests and levels of surveillance varies based on the setting in which patients are prescribed ARPI treatment.17 Patients treated with either apalutamide or abiraterone acetate nevertheless received a similar mean number of follow-up PSA tests per year (apalutamide, 4.4 tests; abiraterone acetate, 5.1 tests). In addition, although there are no estimates of the predictive value for the algorithm used to identify patients with castration sensitivity, this algorithm has been published and used previously.18,19
Among patients with de novo mCSPC, treatment with apalutamide was associated with a statistically significantly greater likelihood of attaining a PSA90 response within 6 months of treatment initiation as compared with treatment with abiraterone acetate. Patients with de novo mCSPC treated with apalutamide furthermore achieved a PSA90 response approximately 4.5 months earlier than patients treated with abiraterone acetate. Because an early and deep PSA90 response is a prognostic indicator of better long-term outcomes, this study provides valuable evidence regarding ARPI treatment among this understudied subpopulation.
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Published: June 23, 2025.
Conflict of Interest Disclosures: G. Brown is an employee of New Jersey Urology and has received consulting fees from Johnson & Johnson. I. Khilfeh and S. Du are employees and stockholders of Johnson & Johnson. C. Rossi, F. Kinkead, L. Diaz, and D. Pilon are employees of Analysis Group, Inc, a consulting company that has provided paid consulting services to Johnson & Johnson. B. Lowentritt is an employee of Chesapeake Urology Associates and has received consulting fees from Johnson & Johnson.
Funding/Support: This study was funded by Johnson & Johnson.
Author Contributions: All authors were involved in study conception and design, data analysis and interpretation, drafting the manuscript, and critically revising the manuscript for intellectual content. All authors approved the final version of the manuscript to be published and agree to be accountable for all aspects of the work.
Data Availability Statement: The data that support the findings of this study were used under license. These data cannot be shared as restrictions apply to their availability.
Acknowledgments: Medical writing assistance was provided by professional medical writer Molly Gingrich, MSc, an employee of Analysis Group, Inc, a consulting company that has provided paid consulting services to Johnson & Johnson, which funded the development and conduct of this study. The authors thank Kruti Joshi and Sabree Burbage, employees of Johnson & Johnson, for their contributions to this study. Part of the material in this manuscript was presented at the American Society of Clinical Oncology conference, held from May 30 to June 3, 2024, in Chicago, Illinois.
Supplementary Material: Supplementary material is available at Reviews in Urology online.
Citation: Brown G, Khilfeh I, Rossi C, et al. Comparison of prostate-specific antigen response among patients with de novo metastatic castrationsensitive prostate cancer initiated on apalutamide vs abiraterone acetate. Rev Urol. 2025;24(2):e57-e67.
Corresponding author: Carmine Rossi, PhD, Manager, Analysis Group, Inc, 1190 avenue des Canadiens-de-Montréal, Tour Deloitte, Ste 1500, Montréal, QC, H3B 0G7, Canada (carmine.rossi@analysisgroup.com)