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Survival and Economic Impact of Rapid Prostate-Specific Antigen Doubling Time in Patients with Nonmetastatic Castration-Resistant Prostate Cancer

Open AccessPublished:January 25, 2023DOI:https://doi.org/10.1016/j.clgc.2023.01.003

      Key take-home messages

      • Most patients with nmCRPC have PSADT >12 months and a long natural history
      • However, for those with shorter PSADT, the risk of metastasis and death, as well as healthcare costs, increased
      • These data can help select patients for novel hormonal therapy and conversely those who can safely delay such treatments for nmCRPC

      Abstract

      Introduction

      In patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), prostate-specific antigen doubling time (PSADT) is associated with risk of metastasis and survival. This study evaluated the association of PSADT with clinical and economic outcomes in a real-world setting among patients with nmCRPC not receiving novel hormonal therapy (NHT), using 2-month PSADT thresholds.

      Patients and Methods

      We retrospectively identified Veterans Health Administration patients with nonmetastatic prostate cancer and ≥2 PSA increases after medical/surgical castration (2012–2016). The third measurement was the index (CRPC) date. Patients with ≥3 post-index PSA measurements, including index, were followed until death or ≥12 months until disenrollment, study end, or death and grouped into 2-month cohorts based on post-index PSADT. Cox regression models assessed association between PSADT, time to metastasis, and death. Healthcare resource utilization and costs were evaluated.

      Results

      Among 2800 evaluable patients, median follow-up was 30 months and median PSADT was 17 months. Relative to the reference cohort (PSADT >12 months), all cohorts had significantly higher metastasis risk. PSADT ≤10-month cohorts had significantly greater mortality risk than the reference; hazard ratios (95% confidence intervals) ranged from 12.3 (9.2, 16.4) in the PSADT ≤2-month cohort to 1.3 (0.9, 2.0) in the >10–≤12-month cohort. Total costs were significantly higher for cohorts up to and including the PSADT >8–≤10-month cohort, than for the reference cohort. Mean per patient per month all-cause medical plus pharmacy costs were $6623, $4768, and $4049 in the PSADT ≤2-month, >2–≤4-month cohort, and >4–≤6-month cohorts, respectively, vs. $1911 in the PSADT >12-month cohort (P <0.05).

      Conclusion

      Most patients with nmCRPC have PSADT >12 months and a long natural history. For those with shorter PSADT, the risk of metastasis, death, and costs increased. These data can help select patients for NHT and conversely those who can safely delay NHT for nmCRPC.

      MicroAbstract

      In nonmetastatic castration-resistant prostate cancer (nmCRPC), the assessment of shorter prostate-specific antigen doubling time (PSADT) intervals than those previously studied may help inform clinical risk and economic outcomes. This analysis of 2800 patients in the Veterans Health Administration found that relative to those with PSADT >12 months, cohorts with PSADT ≤2, >2–≤4, >4–≤6, >6–≤8, and >8–≤10 months had significantly higher metastasis and mortality risk and healthcare costs. These results can help select patients for novel hormonal therapy and conversely those who can safely delay such treatments for nmCRPC.

      Graphical abstract

      Keywords

      Introduction

      Castration-resistant prostate cancer (CRPC) is defined as disease that progresses despite a castrate level of serum testosterone (< 50 ng/dL; < 1.7 nmol/L).
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      Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
      Progression to CRPC often presents as an increase in serum prostate-specific antigen (PSA) or the emergence of new metastases.
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      Absent metastases (i.e., rising PSA only), it is classified as nonmetastatic CRPC (nmCRPC). Patients with nmCRPC are at high risk of developing metastatic CRPC (mCRPC), for which real-world data have shown that median overall survival (OS) is < 3 years with best available pharmacotherapy.
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      Progression to mCRPC is also associated with greatly increased healthcare resource utilization (HCRU) and costs.
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      • Freedland SJ
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      Predictors of survival, healthcare resource utilization, and healthcare costs in veterans with non-metastatic castration-resistant prostate cancer.
      In nmCRPC, higher PSA velocity or shorter PSA doubling time (PSADT) in the control arms of clinical trials and in real-world practice is associated with greater risk of metastasis, all-cause mortality (ACM), and PC-specific mortality (PCSM).
      • Smith MR
      • Cook R
      • Lee KA
      • Nelson JB.
      Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer.
      • Smith MR
      • Kabbinavar F
      • Saad F
      • et al.
      Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.
      • Smith MR
      • Saad F
      • Oudard S
      • et al.
      Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.
      • Howard LE
      • Moreira DM
      • De Hoedt A
      • et al.
      Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer.
      Guidelines recommend continuous androgen deprivation therapy (ADT) and observation for patients with nmCRPC and PSADT > 10 months.
      • Lowrance WT
      • Breau RH
      • Chou R
      • et al.
      Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.
      Continuous ADT plus novel hormonal therapy (NHT) is recommended for patients with nmCRPC and PSADT ≤ 10 months.
      • Lowrance WT
      • Breau RH
      • Chou R
      • et al.
      Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.
      In clinical trials, ADT plus NHTs enzalutamide, apalutamide, and darolutamide significantly prolonged metastasis-free survival (MFS) by approximately 22–24 months and OS by approximately 10–14 months, and increased time to PSA progression vs. placebo (ADT alone).
      • Hussain M
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer.
      • Sternberg CN
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide and Overall Survival in Prostate Cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide.
      However, a higher incidence of some adverse events of particular concern for older patients was observed.
      • Hussain M
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer.
      ,
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      ,
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.
      The balance between efficacy and tolerability should be carefully considered to create personalized medicine strategies for patients with nmCRPC.
      • Mori K
      • Mostafaei H
      • Pradere B
      • et al.
      Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.
      Given the availability of NHT but also considering clinical burden and costs associated with prolonged treatment, it is critical to identify and treat the patients most likely to progress to metastatic disease, while identifying patients who may be best served by conservative strategies to balance risks and costs. Recognizing the predictive power of PSADT, stratification into shorter time intervals represents one way to better resolve clinical risk and economic outcomes in nmCRPC. Several studies have examined the impact of post-treatment PSADT on outcomes such as metastasis risk and ACM.
      • Teeter AE
      • Presti Jr., JC
      • Aronson WJ
      • et al.
      Does PSADT after radical prostatectomy correlate with overall survival?–a report from the SEARCH database group.
      • D'Amico AV
      • Moul JW
      • Carroll PR
      • Sun L
      • Lubeck D
      • Chen MH.
      Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy.
      • Klayton TL
      • Ruth K
      • Buyyounouski MK
      • et al.
      PSA Doubling Time Predicts for the Development of Distant Metastases for Patients Who Fail 3DCRT Or IMRT Using the Phoenix Definition.
      A retrospective database analysis of the Veterans Health Administration (VHA) including 441 patients at 5 hospitals used PSADT thresholds of < 3, 3–8.9, 9–14.9, and ≥ 15 months to stratify risk of metastasis, OS, and PCSM.
      • Howard LE
      • Moreira DM
      • De Hoedt A
      • et al.
      Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer.
      Another VHA database analysis used PSADT thresholds of unknown, < 3, 3–9, 9–15, and ≥ 15 months to evaluate MFS and OS, and separately assessed the cost associated with nmCRPC and mCRPC diagnosis; however, cost was not assessed by PSADT cohorts.
      • Freedland SJ
      • Pilon D
      • Bhak RH
      • Lefebvre P
      • Li S
      • Young-Xu Y.
      Predictors of survival, healthcare resource utilization, and healthcare costs in veterans with non-metastatic castration-resistant prostate cancer.
      The objective of our study was to investigate the predictive ability of PSADT by evaluating the association of 2-month PSADT thresholds with time to metastasis (TTM), OS, and all-cause and PC-related HCRU and costs in patients with nmCRPC in a real-world setting. Our study aimed to add to the literature by assessing cost by PSADT cohorts. We hypothesized an inverse relationship between PSADT and outcomes and that a difference would be observed between the 2-month PSADT cohorts and the reference cohort of PSADT > 12 months. The study covers a large patient population treated at VHA clinics across the US and is the first to assess HCRU and costs as outcomes associated with PSADT differences.

      Patients and Methods

      Study Design and Patient Eligibility

      This was a retrospective analysis of claims data from the VHA from January 1, 2012 through December 31, 2016, with 12 months of pre- and post-index data availability. All PC-related diagnoses and procedures were identified by medical claims with the pertinent codes, and death status and date were obtained from the Vital Status File. In accordance with guidelines in 45 CFR 164.514(a) and (b) (Code of Federal Regulations Title 45, Public Welfare), Institutional Review Board approval was not required.
      Eligible patients were males aged ≥ 18 years with ≥ 1 claim with a PC diagnosis code and evidence of surgical or medical castration (Figure 1). CRPC was defined as ≥ 2 PSA increases from the first measurement (PSA1) after castration (PSA1 < PSA2 < PSA3). Each PSA measurement was ≥ 14 days apart. PSA3 had to be ≥ 2 ng/mL and 25% higher than PSA1. For surgically castrated patients, PSA1 was measured ≥ 2 days post-surgery; for medically castrated patients, PSA1 was measured ≥ 14 days post-initiation of ADT and while the patients were still using luteinizing hormone-releasing hormone (LHRH) agonists. PSA3 was defined as the index date. Only patients with ≥ 3 post-index PSA measurements (including PSA3) qualified for analysis. Those with metastasis prior to index (PSA3) were excluded from the final population.
      Figure 1
      Figure 1Patient attrition.
      Abbreviations: CRPC = castration-resistant prostate cancer; LHRH = luteinizing hormone-releasing hormone; PC = prostate cancer; PSA = prostate-specific antigen.
      *Diagnosis codes for PC (ICD-9-CM: 185; ICD-10-CM: C61).
      Defined by Current Procedural Terminology (54520, 54522, 54530, 54535, 54690), ICD-9-CM Procedure (62.3, 62.41, 62.42), ICD-9-CM Diagnosis (V45.77) codes or HCPCS (J1675, J1950, J3315, J9202, J9217, J9218, J9219, J9225, J9226) and national drug codes for LHRH agonists (leuprolide, goserelin, triptorelin, and histrelin implant). A minimum of 8 weeks of continuous castration therapy was required to define medical castration, although patients needed to maintain continuous castration during the period of evaluation for CRPC.
      For all patients, the third PSA value must have been ≥ 25% and 2 ng/mL higher than the first PSA value, and each of the three PSA values must have been ≥ 14 days apart. The third PSA value date needed to be during the identification period (January 1, 2013–December 31, 2016) and was designated as the CRPC date. The index date was defined as the CRPC date.
      §Therefore, the index date was required to have been identified between January 1, 2013 and December 31, 2015.
      ǁExclusion criteria included the presence of other cancers (ICD-9-CM: 140-184, 186-195, 200-209), chemotherapy use prior to the index date, metastatic solid tumors (ICD-9-CM: 197-199.1), and prescriptions of abiraterone acetate or enzalutamide during the baseline period (to ensure exclusion of patients with mCRPC).
      #Including the index measurement.

      Study Measures

      Sociodemographic and clinical characteristics were evaluated on the index date (PSA3), while individual comorbidities (hypertension, stroke, angina pectoris, arrhythmia, congestive heart failure, hyperlipidemia, type II diabetes, liver abnormality/damage, and myocardial infarction) and the modified comorbidity index by Quan
      • Quan H
      • Sundararajan V
      • Halfon P
      • et al.
      Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
      were evaluated during the 12-month pre-index period. All sociodemographic and clinical characteristics were described for all eligible patients.
      As not all PSA recurrences are at equal risk of progression, PSADT is considered a useful indicator for risk of death
      • D'Amico AV
      • Moul JW
      • Carroll PR
      • Sun L
      • Lubeck D
      • Chen MH.
      Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy.
      and is used extensively in registrational studies.
      • Hussain M
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer.
      ,
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.
      ,
      • Fizazi K
      • Shore N
      • Tammela TL
      • et al.
      Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.
      PSA values were captured directly from medical records and estimation of PSADT was calculated by log(2) divided by the slope of linear regression of log(PSA) over time expressed in months.
      • Arlen PM
      • Bianco F
      • Dahut WL
      • et al.
      Prostate Specific Antigen Working Group guidelines on prostate specific antigen doubling time.
      Statistical analysis of PSADT adopted the method of Howard et al.
      • Howard LE
      • Moreira DM
      • De Hoedt A
      • et al.
      Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer.
      Patients with PSADT < 0 or > 120 were assigned 120 months for ease of analysis.
      • Howard LE
      • Moreira DM
      • De Hoedt A
      • et al.
      Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer.
      All PSA values on and after the index date but before development of metastasis were used to calculate PSADT. This calculation required ≥ 2 PSA values over ≥ 3 months. Post-index PSA values were used, as many PSA values were expected to be of undetectable concentration prior to the index date and increase exponentially over time thereafter.
      • Howard LE
      • Moreira DM
      • De Hoedt A
      • et al.
      Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer.
      PSADT was measured in months and patients were assigned to cohorts based upon post-index 2-month cutoffs (≤ 2, > 2–≤ 4, > 4–≤ 6, > 6–≤ 8, > 8–≤ 10, > 10–≤ 12 and > 12).
      TTM was defined as the time from index to metastasis based on the presence of secondary malignant neoplasm diagnosis codes (ICD-9-CM: 197-199.1) or a prescription claim for enzalutamide (approved for mCRPC but not nmCRPC during the study period), abiraterone acetate, or docetaxel following the index date. Time to ACM was defined as the period between the index date and death. Outcome events were captured from diagnostic and prescription codes in approximately equal proportions.
      During the 12-month post-index period, per patient per month (PPPM) all-cause and PC-related HCRU and direct costs were evaluated. This included outpatient visits, inpatient stays, and pharmacy utilization, and would have included any costs for treating complications related to local progression. PC-related HCRU and costs were identified by medical claims (outpatient and inpatient) with primary or secondary diagnoses of PC, and abiraterone, enzalutamide, LHRH agonists, or bicalutamide pharmacy claims. All costs were adjusted for inflation to 2019 US dollars using the medical care component of the Consumer Price Index.
      The Economics Daily, Consumer Price Index: 2019 in review.

      Statistical Analysis

      Continuous variables were presented as means (standard deviation [SD]) or medians (interquartile range [IQR]). Categorical variables were presented as counts (n) and percentages (%). Kaplan–Meier analysis, log-rank tests, and Cox proportional hazards models were used to compare TTM and time to all-cause death between the reference (PSADT > 12 months) and the remaining cohorts. Age, race, and individual comorbidities were included as covariates in the Cox models. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) supported the strength and significance of these findings, respectively.
      HCRU and costs were compared between the reference and the other cohorts. P-values for comparison of HCRU and costs between cohorts were obtained from the t-test for continuous variables and chi-square test for categorical variables. All statistical analyses were performed using SAS (v9.4; SAS Institute Inc., Cary, NC).

      Results

      Study Population

      A total of 3579 patients ≥ 18 years of age with PC and ≥ 2 PSA increases after castration, and continuous VHA enrollment for ≥ 12 months pre- and post-index date were identified (Figure 1). A total of 2800 eligible patients had ≥ 3 PSA measurements after the index period. Mean age was 72.6 years and 59% were White. The most prevalent comorbidities were hypertension (73%), hyperlipidemia (60%), and type II diabetes (33%). Median Quan-Charlson comorbidity index (CCI) score was 3 (Table 1). Median PSA concentration (index plus all post-index PSA) was 3.3 ng/mL (IQR, 12.8; Q1, 0.75; Q3, 13.51). All values after index (third PSA value) but before observed metastasis were included. The average number of PSA measurements for the study population was 7.4. During a median follow-up of 30 months (range, 3.7–48), median PSADT was 17 months. Patients were assigned to the following cohorts based on post-index PSADT: ≤ 2 months (n = 94, 3%), > 2–≤ 4 months (n = 274, 10%), > 4–≤ 6 months (n = 264, 9%), > 6–≤ 8 months (n = 186, 7%), > 8–≤ 10 months (n = 172, 6%), > 10–≤ 12 months (n = 140, 5%), and > 12 months (n = 1670, 60%). During the study follow-up period, 672 patients developed metastases and 1400 patients died.
      Table 1Baseline demographic and clinical characteristics
      StatusPatients

      (N = 2800)
      Patients with ≥ 3 PSA values in the follow-up, including index PSA.
      Age, mean (SD) – years72.6 (8.0)
      Age category, n (%)
       18–64331 (11.8)
       65–741035 (37.0)
       75–87995 (35.5)
       ≥ 88439 (15.7)
      Race, n (%)
       White1642 (58.6)
       Black910 (32.5)
       Other63 (2.3)
       Unknown185 (6.6)
      Index PSA (PSA3), mean (SD) – ng/mL10.8 (40.7)
      Index PSA, median (IQR) – ng/mL1.9 (6.9)
      Index PSA, range – ng/mL0.0–2274.4
      Quan-CCI score – median (SD)3 (1.7)
      Individual comorbidities, n (%)
       Hypertension2038 (72.8)
       Stroke201 (7.2)
       Angina pectoris34 (1.2)
       Arrhythmia156 (5.6)
       Congestive heart failure164 (5.9)
       Hyperlipidemia1665 (59.5)
       Type 2 diabetes914 (32.6)
       Liver damage/abnormality126 (4.5)
       Acute coronary syndrome/myocardial infarction33 (1.2)
      Abbreviations: CCI = Charlson comorbidity index; IQR = interquartile range; PSA = prostate-specific antigen; SD = standard deviation.
      a Patients with ≥ 3 PSA values in the follow-up, including index PSA.

      Association of Post-index PSADT and Clinical Outcomes

      Cohorts with PSADT ≤ 12 months experienced significantly shorter TTM relative to the reference cohort (Figure 2a). In multivariable analysis, all cohorts had a significantly higher risk of metastasis than the reference cohort in an inverse relationship; i.e., the shorter the PSADT, the higher the risk of metastasis (Figure 2b). Compared with PSADT > 12 months, the adjusted HRs (95% CIs) for TTM ranged from 33.77 (25.93, 43.96) in the ≤ 2-month cohort to 1.82 (1.32, 2.53) in the > 10–≤ 12 month-cohort (Figure 2b).
      Figure 2
      Figure 2Kaplan–Meier estimates of time to metastasis (A) and adjusted relative risk of metastasis (B) by PSADT cohort (relative to the reference cohort, PSADT > 12 months). Abbreviations: CI = confidence interval; HR = hazard ratio; mo = month; PSADT = prostate-specific antigen doubling time.
      Reference cohort (PSADT > 12 months) median time to metastasis was 28.82 months.
      HRs calculated using a stratified Cox proportional hazards model with age, race, and individual comorbidities as covariates and a value < 1.00 favoring PSADT > 12 months. The adjusted variables included age as categorical variables, race, PSADT as categorical variables, baseline comorbidities (urinary tract infection, impotence, hypertension, stroke, angina pectoris, arrhythmia, congestive heart failure, hyperlipidemia, type II diabetes, liver abnormality/damage, and acute coronary syndrome/myocardial infarction).
      Cohorts with PSADT ≤ 12 months had significantly shorter time to all-cause death relative to the reference cohort (Figure 3a). All cohorts with PSADT ≤ 10 months had significantly higher mortality risk than the reference cohort (Figure 3b); adjusted HRs (95% CIs) ranged from 12.27 (9.20, 16.35) in the PSADT ≤ 2-month cohort to 1.34 (0.90, 2.00) in the > 10–≤ 12-month cohort (Figure 3b).
      Figure 3
      Figure 3Kaplan–Meier estimates of time to death (A) and adjusted relative risk of death (B) by PSADT cohort (relative to the reference cohort, PSADT > 12 months).
      Abbreviations: CI = confidence interval; HR = hazard ratio; mo = month; PSADT = prostate-specific antigen doubling time.
      Reference cohort (PSADT > 12 months) median time to death was 31.53 months.
      HRs calculated using a stratified Cox proportional hazards model with age, race, and individual comorbidities as covariates and a value < 1.00 favoring PSADT > 12 months.

      Post-Index PSADT and HCRU

      Throughout the 12-month follow-up, shorter PSADT was associated with higher all-cause and PC-related HCRU in the first year after nmCRPC diagnosis (Figure 4). For example, the PSADT ≤ 2-month cohort experienced significantly greater all-cause inpatient (0.08 vs. 0.02), outpatient (3.03 vs. 1.90), and pharmacy visits (2.95 vs. 2.24) PPPM than the reference cohort. Significantly greater HCRU was reported for the PSADT > 2–≤ 4 and > 4–≤ 6-month cohorts vs. the reference cohort. Similar relationships were observed for PC-related HCRU among all cohorts up to and including the PSADT > 8–≤ 10-month cohort.
      Figure 4
      Figure 4Mean all-cause (A) and PC-related (B) HCRU PPPM by PSADT cohort.
      Abbreviations: HCRU = healthcare resource utilization; mo = month; PC = prostate cancer; PPPM = per patient per month; PSADT = prostate-specific antigen doubling time.
      *P < 0.05 vs. PSADT > 12 months.

      PSADT and 12-Month Follow-up Healthcare Costs

      Throughout the 12-month follow-up, shorter PSADT was associated with greater all-cause and PC-related costs (Figure 5). PPPM costs were significantly higher for cohorts up to and including the PSADT > 8–≤ 10-month cohort than for the reference cohort, except for inpatient costs in the > 6–≤ 8 and > 8–≤ 10 cohorts. As PSADT shortened, more costs were related to PC. For example, average PPPM all-cause medical plus pharmacy costs were $6623, $4768, and $4049 in the PSADT ≤ 2-month, > 2–≤ 4-month cohort, and > 4–≤ 6-month cohorts, respectively, vs. $1911 in the PSADT > 12-month cohort (P < 0.05 for all comparisons).
      Figure 5
      Figure 5Mean all-cause (A) and PC-related (B) healthcare costs PPPM by PSADT cohort (Consumer Price Index to 2019).
      Abbreviations: mo = month; PC = prostate cancer; PPPM = per patient per month; PSADT = prostate-specific antigen doubling time.
      *P < 0.05 vs. PSADT > 12 months.

      Discussion

      This real-world retrospective study assessed the association of PSADT simultaneously with clinical and economic outcomes in patients with nmCRPC not receiving NHT. In the single-payer VHA, using a stratification of PSADT by 2-month cohorts, an inverse relationship was observed between PSADT and outcomes. Shorter PSADT was associated with higher risk of metastasis and death as well as higher all-cause and PC-related HCRU and costs. Based on the stratification of PSADT by 2-month cohorts, there was an inverse relationship between PSADT and clinical and economic outcomes. Of note, 32.5% of patients in this analysis were Black, providing applicability of the study findings to this patient population with a disproportionately high prostate cancer incidence and mortality.
      • Giaquinto AN
      • Miller KD
      • Tossas KY
      • Winn RA
      • Jemal A
      • Siegel RL.
      Cancer statistics for African American/Black People 2022.
      For patients with nmCRPC, the increased risk of metastasis for those with PSADT ≤ 12 months and risk of death for those with PSADT ≤ 10 months versus the PSADT > 12-month reference cohort are consistent with results from previous clinical trials and real-world studies demonstrating that the shorter the PSADT, the greater the predisposition to metastasis or death.
      • Smith MR
      • Cook R
      • Lee KA
      • Nelson JB.
      Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer.
      • Smith MR
      • Kabbinavar F
      • Saad F
      • et al.
      Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.
      • Smith MR
      • Saad F
      • Oudard S
      • et al.
      Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.
      • Howard LE
      • Moreira DM
      • De Hoedt A
      • et al.
      Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer.
      ,
      • Sternberg CN
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.
      ,
      • Pound CR
      • Partin AW
      • Eisenberger MA
      • Chan DW
      • Pearson JD
      • Walsh PC.
      Natural history of progression after PSA elevation following radical prostatectomy.
      In the placebo (treatment with ADT only) arms of nmCRPC trials, the median PSADT was < 6 months, and our study shows increased risk of metastasis and death among those with a PSADT under 6 months. Importantly, by examining the outcomes associated with multiple, discrete PSADT cohorts, we demonstrated that a rolling, real-time estimation of PSADT might be adopted in clinical practice upon nmCRPC diagnosis. This may assist healthcare providers to elect NHT for appropriate patients with nmCRPC or to determine eligibility for clinical trials.
      PSADT ≤ 6 months was associated with higher HCRU, and PSADT ≤ 10 months was associated with higher healthcare expenditure. A simple explanation for these associations is that the shorter PSADT in patients with nmCRPC substantially increases metastasis risk, resulting in increased HCRU and costs.
      • Appukkuttan S
      • Tangirala K
      • Babajanyan S
      • Wen L
      • Simmons S
      • Shore N.
      A Retrospective Claims Analysis of Advanced Prostate Cancer Costs and Resource Use.
      Given that mCRPC-related costs are approximately four times higher than for nmCRPC,
      • Appukkuttan S
      • Tangirala K
      • Babajanyan S
      • Wen L
      • Simmons S
      • Shore N.
      A Retrospective Claims Analysis of Advanced Prostate Cancer Costs and Resource Use.
      it follows that delaying disease progression by appropriately allocating treatment might mitigate or delay some of these costs through savings that increase with longer PSADT. However, while clinical trials show NHTs increase survival (by 10–14 months) and do not adversely affect quality of life in nmCRPC patients,
      • Sternberg CN
      • Fizazi K
      • Saad F
      • et al.
      Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.
      ,
      • Smith MR
      • Saad F
      • Chowdhury S
      • et al.
      Apalutamide and Overall Survival in Prostate Cancer.
      ,
      • Tombal B
      • Saad F
      • Penson D
      • et al.
      Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial.
      ,
      • Saad F
      • Cella D
      • Basch E
      • et al.
      Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.
      any cost savings could be offset by increased therapy costs. That being said, the addition of NHT to ADT in the nmCRPC setting has been found to be within accepted ranges of cost-effectiveness in recent analyses by the US Institute for Clinical and Economic Review and the UK National Institute for Health and Care Excellence.
      Antiandrogen Therapies for Nonmetastatic Castration-Resistant Prostate Cancer: Effectiveness and Value Final Evidence Report.
      Darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer: Technology appraisal guidance [TA660].
      Technology Appraisal Guidance: Apalutamide with Androgen Deprivation Therapy for Treating High-risk Hormone-relapsed Nonmetastatic Prostate Cancer [TA740].
      Our study (N = 2800) collected inpatient and outpatient information from VHA providers nationwide during the 5-year interval of 2012–2016 and assessed both clinical and economic outcomes according to 2-month PSADT cohort. We found that for most patients, PSADT was > 12 months. Our use of 2-month PSADT thresholds allowed for a granular analysis of these relationships. Unlike our analysis, the smaller Howard et al. study (2000–2015; N = 441) explored the association between PSADT and survival but not economic outcomes
      • Howard LE
      • Moreira DM
      • De Hoedt A
      • et al.
      Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer.
      and the larger Freedland et al. study (2007–2017; N = 12,083)
      • Freedland SJ
      • Pilon D
      • Bhak RH
      • Lefebvre P
      • Li S
      • Young-Xu Y.
      Predictors of survival, healthcare resource utilization, and healthcare costs in veterans with non-metastatic castration-resistant prostate cancer.
      looked at economic outcomes attributable to mCRPC, not by PSADT cohort. Both previous analyses used 6-month PSADT thresholds from < 3 months to ≥ 15 months. Despite methodological differences, shorter PSADT was consistently associated with worse outcomes, reinforcing the importance of monitoring PSADT in nmCRPC.
      • Freedland SJ
      • Pilon D
      • Bhak RH
      • Lefebvre P
      • Li S
      • Young-Xu Y.
      Predictors of survival, healthcare resource utilization, and healthcare costs in veterans with non-metastatic castration-resistant prostate cancer.
      ,
      • Howard LE
      • Moreira DM
      • De Hoedt A
      • et al.
      Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer.
      ,
      • Lowrance WT
      • Breau RH
      • Chou R
      • et al.
      Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.
      Limitations inherent to claims-based studies include reliance on diagnostic coding, use of pharmacy claims as a surrogate for actual medication administration, and the possibility of treatment outside the studied healthcare system. Requiring ≥ 3 post-index PSA measurements may exclude patients with a very short PSADT, because they would likely develop metastases by that time and therefore be ineligible. The use of bicalutamide was not captured and therefore its impact on PSADT was not accounted for; however, a less accurate PSADT should bias the results toward the null and underestimate associations with outcomes. Restricting the identification of metastasis to secondary malignant neoplasm diagnostic codes and enzalutamide, abiraterone acetate, or docetaxel claims following the index date would have overlooked a small number of patients who received sipuleucel-T or radium-223 dichloride for mCRPC. While type of metastatic imaging was not captured, given the time period of the study (2012–2016), we anticipate nearly all imaging would have been conventional bone scans or computerized tomography (CT) scans. Additionally, the population could include patients with suspected metastatic disease who were started on treatment prior to being officially diagnosed with mCRPC. Gleason scores were not available in the dataset and could not be accounted for, although this may not be an important predictor when PSA is consistently monitored after nmCRPC diagnosis.
      • Moreira DM
      • Howard LE
      • Sourbeer KN
      • et al.
      Predicting bone scan positivity in non-metastatic castration-resistant prostate cancer.
      HCRU and cost analyses were not adjusted for differences in baseline characteristics. Additionally, we evaluated all-cause deaths, not specifically PC deaths, though our study population included only patients with PC. Finally, this study does not examine the details behind the increased all-cause and PC-related costs; we hope future studies building upon our work can identify the specific drivers of the increased costs we identified.

      Conclusions

      The findings of this study align with existing literature to confirm that PSADT is a strong predictor of metastasis and death and is moreover highly associated with HCRU and costs in patients with nmCRPC (see the graphical abstract summarizing the analysis in the online publication). Importantly, the majority of patients had long PSADT (> 12 months) and were at low risk of progression or significant HCRU. For those with shorter PSADT, however, the clinical and economic sequalae of a short PSADT in nmCRPC provides rationale to treat with approved therapies, although cost-effectiveness and potential adverse effects of therapy must be considered.
      The current information can help to better determine high-risk patients potentially eligible for NHT and conversely low-risk patients best served with conservative strategies to balance risks and costs. It can also help identify patients for clinical trials. Future studies in different patient populations and other healthcare settings are needed to generalize these results.
      Video: A video summary of this article is available here: [please see document entitled “PSADT nmCRPC VHA video summary for journal review”]

      Author contributions

      SJF, KR, RS, NMS, and DJG contributed to study conception and design, and AH, JM, and NJ were responsible for data acquisition and statistical analysis. All authors contributed to the interpretation of data. All authors contributed to the drafting of the manuscript and critical revision of scientific content and approved the final manuscript.

      Data sharing statement

      Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

      Clinical Practice Points

      PSADT is known to be predictive of outcomes in nmCRPC. This study evaluated the association of shorter (2-month) PSADT intervals with both clinical and economic outcomes. Among 2800 evaluable patients in the VHA, the median PSADT was 17 months. Relative to the reference cohort (PSADT > 12 months), all cohorts had significantly higher metastasis risk. PSADT ≤ 10-month cohorts had significantly greater mortality risk than the reference; HRs (95% CIs) range from 12.3 (9.2, 16.4) in the PSADT ≤ 2-month cohort to 1.3 (0.9, 2.0) in the > 10–≤ 12-month cohort. Total healthcare costs were also higher among those cohorts with PSADT up to 10 months.
      The majority of patients had long PSADT (> 12 months) and were at low risk of progression or significant healthcare resource utilization and costs. For those with shorter PSADT, however, the clinical and economic sequalae of a short PSADT in nmCRPC provides rationale to treat with approved therapies, although cost-effectiveness and potential adverse effects of therapy must be considered. By examining the outcomes associated with multiple, discrete PSADT cohorts, we demonstrated that a rolling, real-time estimation of PSADT might be adopted in clinical practice upon nmCRPC diagnosis. This may assist healthcare providers to choose NHT for appropriate patients with nmCRPC and, conversely, to identify low-risk patients best served with conservative strategies to balance risks and costs.

      Funding

      This study was sponsored by Pfizer (New York, NY, USA) and Astellas Pharma (Northbrook, IL, USA), the co-developers of enzalutamide. STATinMED received compensation from the sponsors for the overall conduct of the study and development of this manuscript. The sponsors were involved in the study design, collection, analysis, and interpretation of data, and review of the manuscript; employees of the sponsor companies are coauthors. Ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

      CRediT authorship contribution statement

      Stephen J. Freedland: Conceptualization, Methodology, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization, Supervision. Krishnan Ramaswamy: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Funding acquisition. Ahong Huang: Methodology, Software, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization. Rickard Sandin: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Funding acquisition. Jack Mardekian: Methodology, Software, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Neil M. Schultz: Conceptualization, Methodology, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization, Funding acquisition. Nora Janjan: Methodology, Software, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization. Daniel J. George: Conceptualization, Methodology, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization.

      Conflicts of Interest

      SJF reports consulting and honoraria to Astellas Pharma, AstraZeneca, Bayer, Exact Sciences, Janssen Biotech, Merck, Myovant Sciences, Pfizer, and Sanofi. KR is an employee of Pfizer and owns stocks or stock options. AH was employed by STATinMED during the time of the study; STATinMED received compensation from the sponsors for the overall conduct of the study and development of this manuscript. RS is an employee of Pfizer and owns stocks or stock options. JM was employed by Pfizer during the time of the study and owns stock or stock options. NMS is an employee of Astellas Pharma and owns stocks or stock options. NJ was employed by STATinMED during the time of the study; STATinMED received compensation from the sponsors for the overall conduct of the study and development of this manuscript. DJG reports grants from Acerta Pharmaceuticals, other from American Association for Cancer Research, grants and personal fees from Astellas, personal fees from AstraZeneca, personal fees from Axess Oncology, grants, personal fees and non-financial support from Bayer H/C Pharmaceuticals, grants and personal fees from BMS, grants from Calithera, grants from Capio Biosciences, grants from EMD Serona, grants, personal fees, and non-financial support from Exelixis, Inc., personal fees from Flatiron, personal fees from Ipsen, grants and personal fees from Janssen Pharmaceuticals, personal fees from Merck, Sharp & Dohme, personal fees from Michael J Hennessey Assoc, personal fees from Millennium Medical Publishing, personal fees from Modra Pharmaceuticals B.V., personal fees from Myovant Sciences, Inc., personal fees from NCI Genitourinary, personal fees from Nektar Therapeutics, grants and personal fees from Novartis, personal fees from Physician Education Resource, grants and personal fees from Pfizer, grants, personal fees and non-financial support from Sanofi, personal fees from UroGPO, personal fees and non-financial support from UroToday, personal fees from Vizuri Health Sciences, personal fees from Platform Q, outside the submitted work.

      Acknowledgements

      We thank Stanislav Lechpammer, MD, PhD, of Pfizer and John Tonrey, Keshia Maughn, and Virginia Noxon of STATinMED for their contributions to the analysis and manuscript. STATinMED received compensation from the sponsors for the conduct of the study and development of this manuscript. Medical writing and editorial support funded by the sponsors was provided by Malcolm Darkes, Stephanie Vadasz, and Dena McWain of Ashfield Healthcare Communication and Kirstie Anderson and Matthieu Larochelle of Onyx (a Prime Global agency).

      Appendix. Supplementary materials

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