Benjamin L. Maughan, MD1 ; Yanfang Liu, MD2; Suneel Mundle, PhD3; Xiayi Wang, PhD4; Lawrence I. Karsh, MD5
1Huntsman Cancer Institute, University of Utah, Salt Lake City
2Department of Global Real-World Evidence, Janssen Pharmaceuticals LLC, Raritan, New Jersey
3Global Medical Affairs, Janssen Research & Development, Raritan, New Jersey
4Department of Data Science, Janssen Pharmaceuticals LLC, Titusville, New Jersey
5AdventHealth Medical Group Urology Denver, Denver, Colorado
KEYWORDS:
Apalutamide; kinetics; prostatic neoplasms; prostate-specific antigen; survival
Abstract
Background: Apalutamide plus androgen-deprivation therapy (ADT) is an effective, life-prolonging treatment for metastatic hormone-sensitive prostate cancer (mHSPC). We evaluated correlations between prostate-specific antigen (PSA) response kinetics and overall survival (OS) in patients with mHSPC in real-world practice in the United States.
Methods: This retrospective, observational cohort study used electronic health records from the ConcertAI RWD360 prostate cancer dataset. All patients with newly diagnosed mHSPC who initiated apalutamide and ADT were enrolled. Correlations between PSA responses within the first 3 months (50% and 90% declines in PSA and undetectable PSA [≤0.2 ng/mL]) and 24-month OS were evaluated. Adjusted hazard ratios were estimated using multivariate Cox proportional hazard models.
Results: A total of 183 patients were included of mean (SD) age 73 (8) years. Their median (IQR) duration of follow-up was 16.4 (10.0-23.1) months. Overall survival was higher when patients achieved undetectable PSA, 50%, and 90% declines in PSA within 3 months (24-month OS, 87%, 80%, and 84%, respectively) compared with patients who did not reach these levels (57%, 54%, 65%, respectively). The adjusted hazard ratio for death was 0.15 (95% CI, 0.05-0.47; P = .001) when undetectable PSA was reached within 3 months and 0.27 (95% CI, 0.12-0.65; P = .003) when undetectable PSA was reached after 3 months vs not reached during the study period.
Conclusions: This real-world study confirms clinical trial findings. Rapid and deep decreases in PSA levels were strongly associated with OS in patients with mHSPC who initiated apalutamide and ADT. The faster and deeper the response, the better the survival rate.
Notable advances have been made in the treatment of metastatic prostate cancer over the past 10 to 15 years. Androgen-deprivation therapy (ADT) alone was previously the standard of care but has been superseded by combination treatments that include ADT plus an androgen receptor pathway inhibitor (ARPI) or docetaxel.1,2 Clinical trial data and real-world evidence have shown improved overall survival (OS) when these combinations are used for the upfront treatment of patients with metastatic disease compared with ADT alone.3,4 Despite these gains, the prognosis for patients with metastatic prostate cancer remains poor. Between 2014 and 2020, the 5-year relative survival rate for patients in the United States with distant metastases at diagnosis was 36.6%.5
Early and deep reductions in prostate-specific antigen (PSA) levels are response indicators in metastatic castration-resistant prostate cancer associated with improved clinical outcomes in patients initiated on an ARPI and ADT.6,7 In metastatic hormone-sensitive prostate cancer (mHSPC), post hoc analyses of clinical trial data have also found correlations between PSA response dynamics and clinical outcome. In the LATITUDE study of abiraterone acetate plus prednisone and ADT in patients with mHSPC, declines in PSA levels to 50% of baseline (PSA50), 90% of baseline (PSA90), or to undetectable levels (PSA <0.2 ng/mL) at any time during the study positively correlated with radiographic progressionfree survival (PFS) and survival.8 A post hoc analysis of the TITAN study of apalutamide and ADT in patients with mHSPC showed that deep and rapid PSA decline was strongly associated with a 65% reduced risk of death and a 62% reduced risk of castration resistance compared with patients with no PSA decline.9 In a real-world study in the United States, patients who did not reach undetectable PSA levels (≤0.2 ng/mL) on treatment with docetaxel and ADT or on ARPIs and ADT had substantially poorer outcomes in terms of PFS and OS than did patients who reached undetectable PSA levels.10
Apalutamide with ADT is an effective, well-tolerated, life-prolonging treatment option for patients with mHSPC.11 Real-world data show that apalutamide plus ADT induces early and deep PSA responses and rates of OS that are consistent with clinical trial findings, with a significant association between the PSA response and improved radiographic PFS.12,13 We sought to further confirm clinical trial findings by evaluating correlations between PSA response kinetics and OS in adults with mHSPC treated with upfront apalutamide plus ADT in real-world practice in the United States.
ConcertAI (SymphonyAI) captures data from the electronic health records of more than 4 million oncology patients through a network of more than 900 oncology clinic sites across the United States. It receives structured and unstructured inpatient and outpatient health care data, including results from laboratory and imaging investigations, physician and surgical notes, and other documents collected as part of routine care. Disease staging, PSA results, and castration resistance status are captured in the ConcertAI RWD360 research-grade data source. ConcertAI RWD360 includes data from approximately 5% of patients with prostate cancer in the United States, of whom approximately 95% are treated by medical oncologists and 5% by urologists. A high percentage of patients in the database undergo regular PSA testing.
This retrospective observational cohort study evaluated correlations between the depth and speed of the PSA response and OS in adult patients with mHSPC initiated on apalutamide plus ADT. Patients aged at least 18 years with a diagnosis of mHSPC in the database who initiated treatment with apalutamide plus ADT from January 1, 2018, until September 30, 2022, were included. Criteria used to determine hormone sensitivity status are provided in Box 1.
The index date was the date of the first prescription for apalutamide plus ADT for the treatment of mHSPC during the study period. Patients with any other malignancy (other than nonmelanoma skin cancer or bladder cancer treated by transurethral resection alone) before the diagnosis of prostate cancer were excluded. Only patients with monthly PSA results available were included in the analysis. Follow-up was conducted until patient death, loss to follow-up, or the date of March 31, 2023, whichever occurred first.
This study used deidentified patient data. Therefore, ethical review and patient consent were not required. The study was conducted according to all applicable guidelines and regulations.
Prostate-specific antigen outcomes of interest were time to PSA50, time to PSA90, and time to undetectable PSA (≤0.2 ng/mL). The baseline PSA value was no earlier than 13 weeks before the index date and no later than 30 days after the index date. Overall survival was defined as the time from the index date until death from any cause. Comorbidities were identified using International Classification of Disease, Tenth Revision, Clinical Modification codes and assessed using the Charlson Comorbidity Index (CCI).
Hormone-sensitive prostate cancer was confirmed if at least 1 of the following conditions was met:
At least 1 International Classification of Disease, Tenth Revision, Clinical Modification diagnosis code of Z19.1 (hormone-sensitive malignancy status) within 12 months before the index date or on the index date.
Hormone naive was defined as having no diagnosis of castration resistance at any time before the index date and no claims for ADT for 18 months (12 months if patients had 12-18 months of continuous enrollment) before the index date.
Evidence of surgical castration at any time before the index date and at least 2 PSA test results (including 1 nadir and 1 after nadir) after surgical castration and within 12 months of or on the index date. Patients should have no evidence of biomedical progression, defined as a PSA level ≥2 ng/mL and a PSA level increase ≥25% from nadir.
Evidence of medical castration (at least 1 episode of 90 days or more of continuous ADT) before the index date and at least 2 PSA test results (including 1 nadir and 1 after nadir) within the same ≥90 days of continuous ADT and within 12 months of or on the index date. Patients should have no evidence of biomedical progression, defined as a PSA level ≥2 ng/mL and a PSA level increase of ≥25% from nadir.
Demographic features and disease characteristics were summarized for all patients. Categorical variables were presented as counts and percentages and continuous variables as median (IQR) values.
Patients were stratified according to whether they did or did not reach the specified PSA response after apalutamide plus ADT treatment initiation. Patients who achieved the PSA end point were further stratified by time to response (<3 months or ≥3 months). The rate of PSA decline was indicated as the percentage of patients who achieved PSA50, PSA90, or undetectable PSA levels within 3 months of treatment initiation or at any time during the study.
Kaplan-Meier methods were used to estimate time to PSA50, PSA90, and undetectable PSA and median survival times with 2-sided 95% CIs. A multivariate Cox proportional hazards regression model assessed the hazard ratio (HR) for death after adjusting for baseline demographic and clinical characteristics identified during the bivariate analyses and based on expert input: age, CCI, and baseline PSA. Inverse probability of treatment weighting was used to adjust differences in baseline covariates between the PSA response groups.14 Adjusted HRs were presented with 2-sided 95% CIs. Missing categorical data were reported separately. Missing continuous data were not included in the analysis. No imputations for missing data were performed. All statistical tests were 2 sided, and P < .05 was defined as statistically significant. Data extraction was performed using Structured Query Language software, and analyses were conducted using Python (Python Software Foundation) and R, version 4.3.1, statistical software (R Foundation for Statistical Computing).
The database contained 9136 patients with mHSPC, of whom 315 initiated treatment with apalutamide plus ADT during the study period. Of these patients, 183 had PSA test results available for analysis. The mean (SD) age of patients analyzed was 72.55 (8.44) years, 79.3% of these patients were aged 65 years or older, and 12.6% of patients had a CCI of at least 2 (Table 1); 120 patients (66%) presented with de novo metastases. The study included 44 patients (24.0%) who were aged 80 years or older. The median (IQR) baseline PSA was 4.8 (0.8-20.7) ng/mL. The total median (IQR) length of follow-up was 16.4 (10.0-23.1) months.
Of the 183 patients enrolled in the study, 116 (63.4%) reached undetectable PSA during the study, 67 (36.6%) reached it within 3 months of initiating apalutamide plus ADT treatment, and 49 (26.8%) reached it 3 or more months after treatment initiation. Sixtyseven (36.6%) patients did not reach undetectable PSA at any time during the follow-up period. Patients who reached undetectable PSA levels within 3 months of treatment initiation tended to be younger (median age, 71.0 years) than patients who reached undetectable PSA levels later or not at all (median age, 75.0 years for both outcomes). Among patients who reached undetectable PSA levels within 3 months of treatment initiation, 10.4% were Black (vs 18.4% who reached undetectable PSA after >3 months and 20.9% who did not reach undetectable PSA), 82.1% were White (vs 73.5% and 64.2%), 41.9% were obese (vs 18.8% and 31.0%), and 91.0% had a CCI of 0 or 1 (vs 83.7% and 86.6%). Patients who reached undetectable PSA levels within 3 months of treatment initiation also had lower baseline PSA levels (median, 0.7 ng/mL vs 13.2 ng/mL and 10.4 ng/mL) (Table 1).
In total, 148 patients (80.9%) reached PSA50 during the study period, 124 patients (67.8%) reached PSA50 within 3 months of initiating apalutamide plus ADT treatment, and 24 patients (13.1%) reached PSA50 more than 3 months after treatment initiation. Thirty-five (19.1%) patients did not reach PSA50 at any time during the study period (Table 2). A decrease to PSA90 was reached by 104 (56.8%) patients during the study, by 69 (37.7%) patients within 3 months, and by 35 (19.1%) patients after 3 months; 79 (43.2%) patients did not reach PSA90 at any time during the study.
The rate of OS at 24 months was 87% in patients who reached undetectable PSA within 3 months of initiating treatment with apalutamide plus ADT, 80% in patients who reached undetectable PSA after 3 or more months, and 57% in patients who did not reach undetectable PSA during the observation period. The rate of 24-month OS was 80% for those patients who reached PSA50 within 3 months of starting treatment, 77% for patients who reached PSA50 after 3 months, and 54% for patients who did not reach PSA50 at all during the observation period. For PSA90, the rate of 24-month OS was 84%, 77%, and 65%, respectively, for these categories (Figure 1).
Overall survival at 24 months was statistically significantly longer in patients who achieved undetectable PSA, PSA50, or PSA90 at any time during the follow-up period compared with patients who did not reach these PSA levels. The adjusted HR was 0.22 (95% CI, 0.1-0.48) for undetectable PSA, 0.19 (95% CI, 0.077-0.45) for PSA50, and 0.16 (95% CI, 0.068-0.39) for PSA90 compared with patients who did not reach these PSA levels (Table 2).
There was a statistically significant decrease in the risk of death within 24 months when undetectable PSA, PSA50, or PSA90 was reached within 3 months after treatment initiation compared with when it was reached after 3 months or more (Table 2). The annual risk of death was 5% if undetectable PSA was reached within 3 months, 8% if PSA50 was reached within 3 months, and 6% when PSA90 was reached within 3 months vs 9% for undetectable PSA, 16% for PSA50, and 10% for PSA90 if the response was reached after more than 3 months. These results compared favorably with an annual risk of death of 23%, 22%, and 18% in patients who did not reach undetectable PSA, PSA50, or PSA90 at any time during the study.
Our study builds on the post hoc analysis of the TITAN study of patients with mHSPC treated with apalutamide plus ADT, which showed strong associations between the speed and depth of PSA response and clinical outcome.9 We showed that 24-month OS was statistically significantly greater in patients who reached undetectable PSA, PSA50, or PSA90 at any time during the follow-up period than it was for patients who did not reach these PSA levels. In addition, OS was higher when PSA50, PSA90, and undetectable PSA were reached quickly (within 3 months) after treatment initiation with apalutamide plus ADT.
To date, few real-world studies have explored the associations between PSA response kinetics and survival outcomes after ARPI and ADT are initiated in patients with mCSPC.10,13 Our results are aligned with a hospital-based study in Spain, which showed statistically significant associations between OS and radiographic PFS and PSA50 (achieved by 100% of patients), PSA90 (achieved by 88.0% of patients), and undetectable PSA (achieved by 82.4% of patients) within 12 months of initiation of apalutamide plus ADT.13 The proportion of patients who achieved undetectable PSA at 12 months in this study was lower in patients with high-volume vs low-volume disease (60% vs 92%) and in patients with de novo vs metachronous metastases (76% vs 87%).13
We recently showed that the percentage of patients reaching PSA50, PSA90, and undetectable PSA at 3 months was substantially higher in patients who initiated treatment with apalutamide plus ADT vs other treatments, including ARPIs.15 In view of the association between PSA response kinetics and survival, the more rapid PSA response induced by apalutamide plus ADT could explain its observed benefit over other ARPIs plus ADT.
In the TITAN post hoc analysis, the percentages of patients who achieved PSA50, PSA90, or undetectable PSA at any time during the study were 90%, 73%, and 68%, respectively, which are higher percentages than observed in our patient population (80.9%, 56.8%, and 63.4%, respectively). This observation likely reflects the broader characteristics of a real-world population not restricted by clinical trial eligibility criteria, which are likely to include patients who are older and frailer. For example, the median age of patients in our study was 73 years vs 69 years in TITAN, and 13% of our patients had a CCI of 2 or more.9,16 It is possible that this study’s population included more patients with poor prognostic factors than were enrolled in TITAN.
A further post hoc analysis of the TITAN study of apalutamide plus ADT in patients with mHSPC and the SPARTAN study of apalutamide plus ADT in patients with metastatic castration-resistant prostate cancer showed that early and rapid decreases in PSA level correlated strongly with maintenance of health-related quality of life, specifically physical functioning and time to worsening of symptoms.17 The benefits of rapid and deep PSA decreases induced by apalutamide plus ADT are therefore consistently observed in clinical trials in patients with different disease states (metastatic castration-resistant prostate cancer and mHSPC) and are duplicated in realworld studies.
The limitations of our study include potential selection bias because only patients with PSA test results available were included. Patients unable or unwilling to undergo tests or those patients receiving palliative treatment may not have been represented by the study population, so these results might overestimate the true proportion of patients who achieved favorable PSA responses. We were unable to make adjustment for disease volume, location of metastases, or Gleason score because of the incompleteness of the data for these categories, all of which are known to be clinically significant prognostic variables. Finally, unrelated comorbidities may be underreported in this oncology database.
This real-world study confirms clinical trial findings that apalutamide plus ADT induces rapid and deep decreases in PSA levels in the majority of patients and that these responses are associated with improved survival. Further investigation of the utility of PSA response kinetics in predicting outcomes in subgroups of patients with different prognostic indicators is needed.
Lowrance W, Dreicer R, Jarrard DF, et al. Updates to advanced prostate cancer: AUA/SUO Guideline (2023). J Urol. 2023;209(6):1082-1090. doi:10.1097/JU.0000000000003452
Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71(4):630-642. doi:10.1016/j.eururo.2016.08.002
Hall ME, Huelster HL, Luckenbaugh AN, et al. Metastatic hormone-sensitive prostate cancer: current perspective on the evolving therapeutic landscape. Onco Targets Ther. 2020;13:3571-3581. doi:10.2147/OTT.S228355
Parker DC, Cookson MS. The changing landscape in the management of newly diagnosed castration sensitive metastatic prostate cancer. Investig Clin Urol. 2020;61(suppl 1):S3-S7. doi:10.4111/icu.2020.61.S1.S3
National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: prostate cancer. Accessed October 2, 2023. https://seer.cancer.gov/statfacts/html/prost.html
España S, Ochoa de Olza M, Sala N, et al. PSA kinetics as prognostic markers of overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate. Cancer Manag Res. 2020;12:10251-10260. doi:10.2147/CMAR.S270392
Miyazawa Y, Sekine Y, Shimizu N, et al. An exploratory retrospective multicenter study of prognostic factors in mCRPC patients undergoing enzalutamide treatment: focus on early PSA decline and kinetics at time of progression. Prostate. 2019;79(12):1462-1470. doi:10.1002/pros.23865
Matsubara N, Chi KN, Özgüroğlu M, et al. Correlation of prostate-specific antigen kinetics with overall survival and radiological progression-free survival in metastatic castrationsensitive prostate cancer treated with abiraterone acetate plus prednisone or placebos added to androgen deprivation therapy: post hoc analysis of phase 3 LATITUDE Study. Eur Urol. 2020;77(4):494-500. doi:10.1016/j.eururo.2019.11.021
Chowdhury S, Bjartell A, Agarwal N, et al. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Ann Oncol. 2023;34(5):477-485. doi:10.1016/j.annonc.2023.02.009
Gebrael G, Sayegh N, Thomas VM, et al. Survival outcomes of real world patients with metastatic hormone-sensitive prostate cancer who do not achieve optimal PSA response with intensified androgen deprivation therapy with docetaxel or androgen receptor pathway inhibitors. Prostate Cancer Prostatic Dis. 2024;27(2):279-282. doi:10.1038/s41391-023-00696-w
Mori K, Mostafaei H, Sari Motlagh R, et al. Systemic therapies for metastatic hormone-sensitive prostate cancer: network meta-analysis. BJU Int. 2022;129(4):423-433. doi:10.1111/bju.15507
Córdoba Sanchez J, Picola N, Rodriguez-Vida A, et al. Apalutamide for prostate cancer: multicentre and multidisciplinary real-world study of 227 patients. Cancer Med. 2023;12(24):21969-21977. doi:10.1002/cam4.6769
López-Abad A, Ramírez Backhaus M, Server Gómez G, et al. Real-world prostate-specific antigen reduction and survival outcomes of metastatic hormone-sensitive prostate cancer patients treated with apalutamide: an observational, retrospective, and multicentre study. Prostate Int. 2024;12(1):20-26. doi:10.1016/j.prnil.2023.10.003
Chesnaye NC, Stel VS, Tripepi G, et al. An introduction to inverse probability of treatment weighting in observational research. Clin Kidney J. 2022;15(1):14-20. doi:10.1093/ckj/sfab158
Maughan BL, Liu Y, Mundle S, Wang X, Nematian-Samani M, Karsh LI. 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
Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488
Small EJ, Chi KN, Chowdhury S, et al. Post hoc analysis of rapid and deep prostate-specific antigen decline and patient-reported health-related quality of life in SPARTAN and TITAN patients with advanced prostate cancer. Eur Urol Oncol. 2024;7(4):844-852. doi:10.1016/j.euo.2023.11.015
Published: June 23, 2025.
Conflict of Interest Disclosures: B. Maughan has received financial compensation as a paid consultant or advisor to AbbVie Inc, Astellas Pharma, AVEO Oncology, Bayer Oncology, Bristol Myers Squibb, Clovis, Exelixis, Janssen, Lilly, Merck, Peloton Therapeutics, Pfizer, Tempus, Sanofi, and Telix; Huntsman Cancer Institute has received research funding from Bavarian Nordic, Bristol Myers Squibb, Clovis, and Exelixis on Dr Maughan’s behalf.
L. Karsh holds stock or other ownership in Swan Valley Medical; has received honoraria from AbbVie, Astellas, AstraZeneca, Bayer, Dendreon, Janssen, Merck, Myovant, Pfizer, and Sanofi; and has received financial compensation as a paid consultant or advisor to Abb-Vie, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Dendreon, Ferring Pharmaceuticals, Janssen, Merck, Myovant, Pfizer, and Sanofi, and at the speakers bureau for Astellas, AstraZeneca, Bayer, Dendreon, Janssen, Merck, Myovant, and Pfizer. Dr Karsh’s institution has received research funding from Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Cleveland Diagnostics, Dendreon, Epizyme, Janssen, KDx Diagnostics, Myovant, Nucleix, OncoCell, Pfizer, and Vaxiion Therapeutics on his behalf.
Y. Liu, S. Mundle, and X. Wang are employees of Johnson & Johnson LLC. Y. Liu and S. Mundle hold stock or shares in Johnson & Johnson, LLC.
Funding/Support: This work was supported by Janssen Global Services, LLC.
Author Contributions: S. Mundle, Yanfang Liu, B. Maughan, and L. Karsh conceived of and designed the study. Y. Liu and S. Mundle supervised its execution. Y. Liu acquired data, and X. Wang performed statistical analysis. B. L. Maughan, L. I. Karsh, S. Mundle, and Y. Liu analyzed and interpreted the data. Critical revision of the manuscript for important intellectual content was conducted by all authors.
Data Availability Statement: Data were obtained under license, and their deposition in a public repository is prohibited by ConcertAI. Interested researchers can obtain the data through formal application to ConcertAI.
Acknowledgments: The authors thank Joanne Wolter (independent on behalf of Johnson & Johnson Pte Ltd) for copyediting, editorial support, and production assistance.
Citation: Maughan BL, Liu Y, Mundle S, Wang X, Karsh LI. Correlations between rapid and deep prostate-specific antigen response and survival after apalutamide plus androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer in real-world US practice (OASIS project). Rev Urol. 2025;24(2):e29-e39.
Corresponding author: Lawrence I. Karsh, MD, AdventHealth Medical Group Urology Denver, 850 E Harvard Ave, Denver, CO 80210 (larrykarsh@gmail.com)
