Benjamin H. Lowentritt, MD, FACS1; Ibrahim Khilfeh, PharmD2; Dominic Pilon, MA3; Shawn Du, PhD2; Carmine Rossi, PhD3; Frederic Kinkead, MA3; Lilian Diaz, MSc3; Gordon Brown, DO4
1Chesapeake Urology, Towson, Maryland, USA
2Johnson & Johnson, Horsham, Pennsylvania, USA
3Analysis Group, Inc, Montréal, QC, Canada
4New Jersey Urology, Cherry Hill, New Jersey, USA
KEYWORDS:
Neoplasm metastasis; prostate-specific antigen; prostatic neoplasms; treatment outcome
Abstract
Background: Given the limited real-world evidence regarding prostate-specific antigen (PSA) responses to androgen receptor pathway inhibitor treatment among patients with de novo metastatic castration-sensitive prostate cancer (mCSPC), also known as metastatic hormone-sensitive prostate cancer, this study compared PSA90 responses (ie, ≥90% reduction in PSA from pretreatment levels) between patients with de novo mCSPC treated with either apalutamide or enzalutamide.
Methods: PPS Analytics Population Health Management Platform (PPS Analytics) electronic health record data were linked to Komodo Research Database claims for patients with de novo mCSPC. Apalutamide and enzalutamide cohorts were balanced using inverse probability of treatment weighting. Weighted Kaplan-Meier curves and hazard ratios were used to compare the PSA90 response rates between treatment cohorts.
Results: A total of 986 patients with de novo mCSPC were included (apalutamide: n = 503, enzalutamide: n = 483). Within 6 months of treatment initiation, patients treated with apalutamide vs enzalutamide were more likely to achieve a PSA90 response (hazard ratio, 1.32 [95% CI, 1.08-1.60]; P < .001). The median time to PSA90 response was earlier with apalutamide than with enzalutamide treatment (apalutamide, 3.7 months; enzalutamide, 5.9 months).
Conclusions: Because a deep and early PSA response is a prognostic indicator of improved long-term clinical outcomes, this study provides real-world evidence supporting apalutamide vs enzalutamide treatment among patients with de novo mCSPC.
It was estimated that there would be 299 000 new cases of prostate cancer in the United States in 2024 and more than 35 000 prostate cancer– related deaths, making prostate cancer the most frequently diagnosed cancer among men.1 The majority of patients are diagnosed while their cancer is in the localized stage—that is, confined to the prostate—and these cases often progress to metastatic disease following diagnosis.1,2 An estimated 5% of men have metastatic castration-sensitive prostate cancer (mCSPC), also known as metastatic hormone-sensitive prostate cancer, at the time of diagnosis (ie, de novo mCSPC) and are more likely to experience worse survival outcomes. De novo mCSPC accounts for 45% of all metastatic prostate cancer cases.3,4
The recommended treatment for high-volume de novo mCSPC currently involves the use of androgen-deprivation therapy (ADT) or chemotherapy in combination with androgen receptor pathway inhibitors (ARPIs), which have recently been shown to improve survival outcomes in this population.5-10 The second-generation ARPIs apalutamide and enzalutamide both received US Food and Drug Administration (FDA) approval in 2019 for use in patients with mCSPC based on results of the TITAN (apalutamide) and ARCHES (enzalutamide) trials.11-14 These phase 3 randomized, placebo-controlled, double-blind trials both demonstrated improvements to radiographic progression-free survival in patients with mCSPC following treatment with ADT plus either apalutamide or enzalutamide.
Prostate-specific antigen (PSA) levels are frequently evaluated as a marker of prostate cancer treatment response, with earlier and deeper PSA reductions associated with superior long-term outcomes.15,16 Although existing real-world studies have evaluated PSA responses to ARPI treatment in patients with mCSPC,17,18 no previous real-world studies have evaluated PSA responses among patients with de novo mCSPC following ARPI treatment or compared PSA responses between ARPIs.
Given the poor survival outcomes among patients with de novo mCSPC,3 greater understanding of real-world responses to ARPI treatment in this subpopulation is vital to optimize treatment for patients with mCSPC. This study therefore aimed to compare real-world PSA responses between patients with de novo mCSPC treated with either apalutamide or enzalutamide.
Patient demographics and clinical variables were obtained from the PPS Analytics Population Health Management Platform (PPS Analytics) database, which consists of routinely collected electronic health record (EHR) data from US community-based urology practices. Data from February 1, 2017, to December 31, 2023, were used. Available PPS Analytics clinical data comprised laboratory test results; second-generation ARPI dispensing information; prostate cancer–related medication and procedure details; and International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision, Clinical Modification, diagnostic codes, creating a robust dataset of information specific to prostate cancer not typically available from traditional insurance claims data sources.
The PPS Analytics dataset was linked to the Komodo Research Database (KRD), which contains insurance claims 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 KRD included both open and closed claims with information about inpatient and outpatient procedures, prescription fills, and billing and reimbursement. The 2 databases 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 unlinked and linked data were deidentified and Health Insurance Portability and Accountability Act compliant; therefore, approval by an institutional review board was not required.
A retrospective longitudinal cohort study was used to perform this causal analysis. Guidance from the FDA regarding the use of noninterventional studies to generate real-world evidence was incorporated into the study protocol.19 The index date was defined as the date of the first record for apalutamide or enzalutamide—determined by the earliest of either the first paid pharmacy claim in the KRD or the first in-office dispensing in PPS Analytics on or after December 16, 2019 (date of apalutamide and enzalutamide’s FDA approval for mCSPC11,12 )—and was used to assign patients into mutually exclusive apalutamide or enzalutamide treatment cohorts (Supplementary Figure 1). The baseline period included the 12 months before the index date, with the observation period consisting of the index date until the earliest of 6 months, index treatment discontinuation (defined by a 90-day treatment gap), initiation of a new ARPI (ie, treatment switch, excluding first-generation ARPIs), initiation of radiopharmaceutical therapy, the latter of the end of open insurance claim activity in the KRD or clinical activity in PPS Analytics, or the end of data availability (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 were required to have at least 1 pharmacy claim or dispensation for apalutamide or enzalutamide, 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. In addition, patients were required to meet the de novo mCPSC inclusion criteria, defined by the earliest observed prostate cancer diagnosis within 180 days of metastasis. Patients who initiated an index ARPI before December 16, 2019; had no prescription for any 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 had received treatment with radiopharmaceuticals before or on the index date were excluded from this study. Algorithms based on diagnosis codes and clinical indicators were used to assess metastatic disease and castration resistance, as described previously.17 Concurrent ADT use was not required for inclusion in this study.
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 [ie, bone, nodal, or visceral]; prior ADT use [ie, preindex record of ADT and concurrent use with the index ARPI]; prior chemotherapy use; prior first-generation ARPI use; baseline PSA level; baseline testosterone level; and initial Gleason score) were described.
The proportion of patients who achieved at least a 90% reduction in PSA from the most recent baseline PSA observed within the 13 weeks before and including the index date (ie, PSA90 response) within 6 months of the index date was measured as the primary outcome. The proportion of patients with a PSA90 response within the entire observation period (ie, not restricted to the first 6 months after the index date) as well as the median time to first PSA90 response were evaluated as exploratory outcomes. During the observation period, postindex PSA measurement patterns were also evaluated.
The null hypothesis was that there would be no difference in PSA90 response rates by 6 months after the index date between patients treated with apalutamide andn patients treated with enzalutamide. The alternative hypothesis was that there was a difference in PSA90 response rates by 6 months after the index date between patients treated with apalutamide or enzalutamide. Inverse probability of treatment weighting was used to balance potential confounding variables between patients who received treatment with apalutamide and patients who received treatment with enzalutamide. Propensity scores were generated using probability estimates from logistic regression models in which the dependent variable was apalutamide initiation. These estimates were the result of a logistic regression model including the following independent variables: age, race, geographic region, payer type, index year, time between metastasis and the index date, time between initial prostate cancer diagnosis and the index date (because we used real-world data, it is possible that patients’ dates of initial prostate cancer diagnosis and metastasis differed), metastasis type, prior ADT use, prior first-generation antiandrogen use, prior chemotherapy use, most recent baseline PSA level, most recent baseline testosterone level, and earliest Gleason score. Patients treated with apalutamide were attributed a weight of 1/propensity score and patients treated with enzalutamide were attributed a weight of 1/(1 – propensity score), with weights normalized using the mean weight of each respective cohort.20 Weights were truncated at the 95th percentile to reduce the impact of extreme weights. No patients were removed from the study analyses as a result of inverse probability of treatment weighting. Baseline characteristics with standardized differences less than 10% between the apalutamide and enzalutamide cohorts after inverse probability of treatment weighting were considered balanced.21
Weighted Kaplan-Meier analyses were used to describe the proportion of patients treated with either apalutamide or enzalutamide 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 ARPI 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 503 patients with de novo mCSPC treated with apalutamide and 483 patients with de novo mCSPC treated with enzalutamide were included (Figure 1).
Baseline characteristics were well balanced between the apalutamide and enzalutamide cohorts after inverse probability of treatment weighting (Table 1). Patients treated with either apalutamide or enzalutamide had a similar mean age of 74.0 years (SD, 9.2 for apalutaide and 9.1 for enzalutamide). Most patients were White (apalutamide, 63.2%; enzalutamide, 62.7%), from the US South (apalutamide, 53.1%; enzalutamide, 51.9%), and insured with Medicare (apalutamide, 81.4%; enzalutamide, 81.1%). Patients treated with apalutamide had a median time of 3.2 months between metastasis diagnosis and index ARPI initiation compared with a median time of 4.2 months for patients treated with enzalutamide. The mean (SD) baseline PSA level was similar between treatment cohorts (apalutamide, 27.3 [60.0] μg/L; enzalutamide, 26.0 [56.8] μg/L).
The mean (SD) on-treatment observation period was 334.6 (319.1 [median, 235.0]) days for patients who received treatment with apalutamide and 294.0 (280.6 [median, 206.0]) days for patients who received treatment with enzalutamide. A PSA90 response by 6 months was achieved by 59.8% of patients who received treatment with apalutamide vs 50.6% of patients who received treatment with enzalutamide (Figure 2). Patients treated with apalutamide were 32% more likely to attain a PSA90 response by 6 months after the index date than were patients treated with enzalutamide (hazard ratio, 1.32 [95% CI: 1.08-1.60]; P < .001). The median time to first PSA90 response was 3.7 months following treatment with apalutamide compared with 5.9 months following treatment with enzalutamide.
A total of 83.2% of patients who received treatment with apalutamide and 76.8% of patients who received treatment with enzalutamide had at least 1 PSA measurement during the observation period (Supplementary Table 1). Similarly, 80.9% of patients who received treatment with apalutamide and 75.6% of patients who received treatment with enzalutamide had at least 1 PSA measurement within 6 months of index ARPI treatment initiation. The mean (SD) number of PSA tests administered per year was 4.3 (3.5 [median, 3.8]) for patients who received treatment with apalutamide and 3.9 (3.6 [median, 3.6]) for patients who received treatment with enzalutamide.
This real-world study is the first to compare PSA responses following treatment with either apalutamide or enzalutamide among patients with de novo mCSPC. Patients treated with apalutamide were statistically significantly more likely to achieve a PSA90 response compared with patients treated with enzalutamide by 6 months following treatment initiation. A PSA90 response was further achieved a median of 2 months earlier among patients treated with apalutamide compared with patients treated with enzalutamide. This study benefited from the inclusion of linked PPS Analytics EHR data and KRD insurance claims data, allowing for the identification of characteristics related to prostate cancer not commonly available in large commercial databases while also providing complementary medical and pharmacy information for care received outside of PPS Analytics urology practices.
In other real-world studies evaluating PSA90 responses following apalutamide or enzalutamide treatment among the overall population of patients with mCSPC, patients treated with apalutamide were 21% to 56% more likely to attain a PSA90 response within 6 months of treatment initiation compared with patients who received treatment with enzalutamide.17,22 In addition, the PSA90 response was achieved a median of approximately 1.5 to 2.0 months earlier among the apalutamide cohort.17,22
Evaluating treatment outcomes among the de novo mCSPC population is essential given the poor prognosis associated with this disease subgroup.23 No previous real-world studies, however, have evaluated PSA90 responses following ARPI treatment in patients with de novo mCSPC. A subgroup analysis of the pivotal apalutamide TITAN trial evaluated the PSA90 response among patients with de novo mCSPC and treated with apalutamide (411/525 [78%] patients enrolled), determining that 70% of patients with synchronous, high-volume mCSPC and 83% of patients with synchronous, low-volume mCSPC achieved a PSA90 response following treatment.6 Because this subgroup analysis considered PSA90 responses within the entire 44-month study follow-up period, these findings are comparable with the proportion of patients with de novo mCSPC in the current analysis who achieved a PSA90 response within 12 months of apalutamide treatment initiation (70%).6 Although no analysis has been completed to evaluate the PSA90 response to treatment among patients with de novo mCSPC in the ARCHES trial, undetectable PSA rates (<0.2 µg/L) among patients in the ARCHES trial treated with enzalutamide were found to be numerically higher in the patients diagnosed with de novo mCSPC than in patients who progressed to mCSPC following initial diagnosis.8
Relative to the previously noted real-world studies evaluating PSA responses following apalutamide or enzalutamide treatment among all patients with mCSPC,17,22 patients with de novo mCSPC were similarly more likely to attain a PSA90 response after receiving treatment with apalutamide vs enzalutamide (32% increased likelihood with apalutamide), and they attained this response a median of approximately 2 months sooner. The comparability of these results suggests that, despite an association of de novo mCSPC with poor treatment outcomes,3 the subgroup of patients with de novo mCSPC may respond to ARPI therapy to a similar extent as the overall mCSPC population. Further investigation regarding the association between PSA responses to ARPI treatment and subsequent survival outcomes within the de novo mCSPC population is therefore warranted.
This study was subject to several limitations. First, as with all EHR and administrative claims databases, inaccuracies or omissions within the data are possible and may have affected the identification of patients with mCSPC or the detection of PSA testing patterns and responses. Although the links between PPS Analytics and the KRD were comprehensive, there was no information on volume of metastasis, and erroneous links may have led to misclassification or information bias. Second, surveillance bias may have been possible if more frequent PSA testing was performed for 1 ARPI relative to the other. The mean number of follow-up PSA tests per year, however, was similar between patients who received treatment with apalutamide and patients who received treatment with enzalutamide (apalutamide mean, 4.3 tests; enzalutamide mean, 3.9 tests). Patients without a follow-up PSA test were furthermore assumed to not have achieved a PSA90 response, though this may not have always been the case. Finally, because all PSA data were sourced from the PPS Analytics urology network, any PSA testing conducted outside of this network would not be captured. Because most patients received care, including medication dispensing, through PPS Analytics, however, this was not expected to substantially affect data availability.
Patients with de novo mCSPC were significantly more likely to achieve a PSA90 response following treatment with apalutamide than with enzalutamide as early as 6 months after treatment initiation. The PSA90 response was achieved over 2 months sooner following treatment with apalutamide compared with treatment with enzalutamide. Given that a deep and early PSA response is associated with better longterm clinical outcomes, apalutamide treatment may be a better option than enzalutamide treatment in patients with de novo mCSPC.
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Published: June 23, 2025.
Conflict of Interest Disclosures: B. Lowentritt is an employee of Chesapeake Urology Associates and has received consulting fees from Johnson & Johnson. I. Khilfeh and S. Du are employees and stockholders of Johnson & Johnson. D. Pilon, C. Rossi, F. Kinkead, and L. Diaz are employees of Analysis Group, Inc, a consulting company that has provided paid consulting services to Johnson & Johnson. G. Brown is an employee of New Jersey Urology 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: Lowentritt BH, Khilfeh I, Pilon D, et al. Comparison of deep prostate-specific antigen response in patients with de novo metastatic castration-sensitive prostate cancer initiated on apalutamide vs enzalutamide. Rev Urol. 2025;24(2):e69-e80.
Corresponding author: Carmine Rossi, PhD, Manager, Analysis Group, Inc, 1190 avenue des Canadiens-de-Montreal, Tour Deloitte, Suite 1500, Montreal, QC H3B 0G7 Canada (carmine.rossi@analysisgroup.com)