Abstract
Aim: Androgen receptor pathway inhibitors (ARPIs) prolong metastasis-free survival and overall survival in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). This study aimed to evaluate real-world treatment patterns, utilization and survival outcomes in patients with nmCRPC.
Patients & methods: This retrospective cohort study used Optum database electronic health records of patients with nmCRPC from 1 January 2007 to 31 December 2020 in the US.
Results: Of 1955 patients, >80% received androgen-deprivation therapy (ADT) alone or ADT + first-generation nonsteroidal antiandrogen (NSAA) as first-line treatment, while only 8.24% received ADT + ARPI. ADT + ARPI remained underutilized even among those with high-risk nmCRPC. Further, ADT + NSAA had no survival benefit compared with ADT alone.
Conclusion: Practice-improvement strategies are needed for treatment intensification with ARPIs for patients with nmCRPC.
Keywords: : androgen receptor pathway inhibitors, nonmetastatic castration-resistant prostate cancer, real-world data, treatment outcomes, treatment patterns, treatment utilization
Plain Language Summary
Prostate cancer cells often use hormones called androgens to grow and survive. Hormone therapy is a treatment that lowers the amount of these hormones in the body to slow down the cancer's growth. It includes androgen-deprivation therapy (ADT), which can either be used alone or along with nonsteroidal antiandrogens (NSAAs) or with androgen receptor pathway inhibitors (ARPIs). Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as prostate cancer that has not spread to other parts of the body but exhibits rising levels of serum prostate-specific antigen despite surgery or ADT to reduce androgens. Research shows that ARPIs can improve survival in patients with nmCRPC, but more data on its use are needed. This study looked at the electronic health records of patients with nmCRPC to review the treatment they had received and their survival. Between 2008 and 2020, most patients received ADT alone or with NSAA. Even though the number of patients receiving ADT with ARPI increased during this period, it remained underused, even in patients with a high risk of cancer spreading to other body parts. Post-2018, even after 2 years of these drugs being available, only about one in five patients received ADT with ARPI. Also, people who received ADT with NSAA did not have a longer survival than patients treated with ADT alone. The study indicates that ARPIs, which could improve survival of patients with nmCRPC, are not being utilized optimally. Strategies that promote early use of ARPIs are needed to improve survival of patients with nmCRPC.
Plain language summary
Summary points.
In this retrospective observational cohort study, treatment patterns and survival outcomes of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) were investigated using electronic health records from the Optum clinical database.
During the study period between 1 January 2007 and 31 December 2020, patients with nmCRPC defined on the basis of recorded prostate-specific antigen (PSA) values after surgical or medical castration were identified as per the inclusion and exclusion criteria.
First-line (1L) regimens included ADT alone, ADT + NSAA ± glucocorticoids (ADT + NSAA), ADT + ARPI ± glucocorticoids ± NSAA (ADT + ARPI) and “other,” which included all remaining regimens.
Between 2008 and 2020, most patients (>80%) were treated with ADT alone or ADT + NSAA as 1L treatment, and only 8% received ADT + ARPIs, suggesting that despite ARPIs having been approved and included in treatment guidelines, they remain underutilized, even in patients at a high risk of metastasis (PSADT ≤10 months or Gleason score ≥8).
Approximately, 55% of patients with nmCRPC developed metastasis during follow-up, and 70% received a new regimen (metastatic 1L treatment); ADT + ARPI was the common metastatic 1L treatment (42%), 2L (44%) and 3L (36.5%) mCRPC regimen.
Time to death was shorter in the ADT + NSAA cohort (median OS: 30.87 months, 95% CI: 28.2–35.73) than the ADT-alone cohort (median OS: 41.70, 95% CI: 37.63–45.60) with statistical significance (HR: 1.33, 95% CI: 1.16–1.52), suggesting that despite ADT + NSAA appearing to be associated with worse clinical outcomes than ADT alone, it still had higher utilization than ADT + ARPI.
Healthcare professionals should recognize the limited efficacy of NSAA and consider using ARPIs to treat patients with severe disease.
Practice-improvement strategies are needed to ensure early treatment with ARPIs in patients with nmCRPC.
1. Background
Nonmetastatic castration-resistant prostate cancer (nmCRPC) was estimated to affect 112,065 men in the United States (US) in 2020, with an incidence of 58,960 cases/year [1]. It is characterized by increasing prostate-specific antigen (PSA) levels despite a castrate testosterone level (<50 ng/dl) after surgical or medical castration and without definite radiological evidence of metastases [2]. Patients with nmCRPC tend to be asymptomatic at diagnosis, with a similar health-related quality of life as age-matched cohorts from the general population [3]. High-risk nmCRPC is characterized by short PSA doubling times (PSADTs; ≤10 months) or high Gleason scores (≥8) [2,4] and carries an increased risk of metastases and prostate cancer-related mortality [5]. Low-risk nmCRPC is characterized by longer PSADT (>10 months) and may or may not eventually progress to high-risk nmCRPC [6]. Metastatic CRPC (mCRPC) is associated with poor prognosis and median overall survival (OS) rates ≤2 years [7]. Therefore, delaying metastasis development in patients with nmCRPC remains a principal treatment goal [8].
Until 2018, treatment options for patients with nmCRPC were limited, and ADT alone or combined with first-generation nonsteroidal antiandrogens (NSAAs) was the mainstay, but with no significant impact on OS [9,10]. Recent trials have shown improvements in clinical outcomes with ARPIs. In the single-arm, Phase II IMAAGEN study, a small cohort of patients (n = 131) with high-risk nmCRPC (PSA ≥10 ng/ml or PSADT ≤10 months) who were treated with ADT and abiraterone plus prednisone experienced significantly reduced PSA50 (≥50% reduction from baseline) and median time to radiographic evidence of metastatic disease of 41.4 months as estimated by sensitivity analysis [11]. Further, several clinical trials showed that intensifying ADT with next-generation androgen receptor pathway inhibitors (ARPIs) reduced the risk of death (enzalutamide by 27%; darolutamide by 31%; and apalutamide by 22%) compared with placebo in patients with high-risk nmCRPC [12–14].
While studies have examined real-world treatment patterns for patients with nmCRPC and have shown that ADT alone or ADT + NSAAs remains the predominant first-line treatment (1L), there are limited data on survival outcomes for these patients. The aim of this study was to assess patient characteristics and treatment patterns among patients with nmCRPC who were on ADT alone, ADT + NSAA or ADT + ARPI and to evaluate time to metastasis-free survival (MFS) and OS among patients with nmCRPC who were on ADT alone or ADT + NSAA in a real-world setting.
2. Materials & methods
2.1. Study design & data source
This was a retrospective observational cohort study of patients with nmCRPC using Optum's clinical electronic health record (EHR) database. The database includes a network of >140,000 providers from >7000 clinicals and 700 hospitals across the US. As of 2020, the database has an average of 45 months of observed data per patient from over 104 million unique patients. It contains longitudinal, de-identified patient data related to their demographics, medications prescribed and administered, immunizations, allergies, lab results, vital signs, in-patient administrative data, coded diagnoses and procedures, etc. Data were collected in compliance with US patient confidentiality requirements, including the Health Insurance Portability and Accountability Act (HIPAA) of 1996. The data are certified as de-identified by an independent statistical expert following HIPAA statistical de-identification rules and managed according to Optum® customer data use agreements, which allow Optum to use the de-identified data in research studies. The study was conducted in accordance with the protocol, applicable regulations and guidelines governing clinical study conduct and ethics principles outlined in the Declaration of Helsinki. Informed consent was not required because this was not an interventional study, and the study was exempt from institutional review board approval because it involved routinely collected, anonymized data.
The study period extended from 1 January 2007 to 31 December 2020, while the identification period was from 1 July 2007 to 31 December 2019. With the earliest data available from 2007, thorough follow-ups were conducted to monitor patients' progress using PSA data and confirm nmCRPC diagnosis. The index date for nmCRPC was defined as the date on which the first rising PSA measurement of ≥2 ng/ml and a PSA level ≥25% higher than the nadir PSA level measured after medical or surgical castration were recorded. The nadir PSA value was defined as the lowest PSA value occurring ≥2 days after surgical castration or ≥14 days following the initiation of medical castration while the patient was still using luteinizing hormone-releasing hormone agonists. Surgical castration was defined as a bilateral orchiectomy with or without antiandrogen therapy after the prostate cancer diagnosis and prior to the metastatic date or study end date (if no metastatic date was recorded), with a minimum of 6 months between the procedure and metastatic date or study end date. Patients who underwent medical castration, either with or without antiandrogen therapy, after a prostate cancer diagnosis but prior to the metastatic date or the study end date were required to have a minimum of six consecutive months of therapy between the start of medical castration and the metastatic date or study end date. The baseline period was 12 months preceding the index date. The follow-up period was defined as the time from the nmCRPC index date to the end of the follow-up period, which ended at the earliest of the following events: completion of clinical activity, end of the study, occurrence of death or occurrence of metastasis. The detailed study design is presented in Supplementary Figure S1.
2.2. Study population
Patients with nmCRPC were included if they had at least one record for prostate cancer (ICD-9: 185 or ICD-10: C61) during the identification period; at least two PSA test results; patient activity in the database 180 days prior to and after the cancer diagnosis date; and no records of metastatic disease in the 6 months prior to the prostate cancer diagnosis date. Evidence of castration resistance after surgical or medical castration was required. Figure 1 presents detailed patient inclusion and exclusion criteria.
Figure 1.
Patient selection and attrition. aDate of the first observed record was the cancer diagnosis date. bPlease refer to supplementary information for definitions of surgical and medical castration.
1L: First-line treatment; ICD.CM: International Classification of Diseases, Clinical Modification; nmCRPC: Nonmetastatic castration-resistant prostate cancer; PC: Prostate cancer; PSA: Prostate-specific antigen; PSA1: Nadir PSA measurement; PSA2: Rising PSA measurement >14 days following PSA1; PSADT: PSA doubling time.
An algorithm was used to extract treatment regimens, duration and sequences from the 1L until treatment completion. Patients were categorized into 4 1L regimens and stratified by risk of developing metastasis and by index year – ‘pre-2018’ vs. ‘post-2018’ – to account for the availability of intensified treatment with ARPIs (abiraterone, enzalutamide, and apalutamide). First-line regimens included ADT alone, ADT + NSAA ± glucocorticoids (ADT + NSAA hereafter), ADT + ARPI ± glucocorticoids ± NSAA (ADT + ARPI hereafter) and ‘other’, which included all remaining regimens. Patients with nmCRPC who had a PSADT ≤10 months or a Gleason score of ≥8 were classified as having high-risk disease, and the rest were classified as having low-risk disease.
2.3. Study measures
2.3.1. Baseline patient characteristics
Patient demographics and clinical characteristics assessed at baseline included the Charlson Comorbidity Index (CCI) score, comorbidities, prior prostate cancer treatments, PSA value at nmCRPC diagnosis and PSADT category.
2.3.2. Line of treatments
First-line regimens comprised all agents prescribed within the first 90 days on or after the start of the 1L for nmCRPC. Given that the nmCRPC index occurred while the patient was on ADT or after bilateral orchiectomy, ADT was assumed to be included in all subsequent lines of treatment regimens. Therefore, the 1L regimen was either a continuation of treatment or comprised new agents added to a backbone of ADT therapy.
Second- and third-line treatment (2L and 3L, respectively) regimens were subsequent treatments stratified by nmCRPC or mCRPC (with evidence of metastatic diagnosis code). The mCRPC line of treatment was defined as any systemic therapy that started within 30 days prior to, or any time after, the date of metastasis in the follow-up period.
2.3.3. Survival outcomes
MFS was defined as the time from the start of 1L to the earliest date of metastasis or death. Similarly, time to death was defined as the time from the start of 1L to the date of death, including for deaths that occurred after metastasis. Due to the small sample size, we did not evaluate MFS and OS for patients in the ADT + ARPI or other cohorts.
2.3.4. Sources of bias & study sample
Sources of potential bias include misclassification bias, which can be related to study definitions, including nmCRPC disease states, classification of line of treatment regimens based on prescriptions and administered medications. Further, there is a possibility of residual confounding as some of the variables could not be adjusted for due to high amounts of missing data. Quality assurance checks were performed during construction of the dataset and analysis. During feasibility analysis, the required sample size was calculated based on the point estimates and the Wald 95% confidence interval, and a sample size of 1500 was shown to provide high precision for the point estimates. Data of all patients who met the inclusion criteria were analyzed.
2.4. Statistical analysis
Descriptive analyses for continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR), and for categorical variables, as counts/percentages. As the proportion of patients receiving “other” treatments was quite low, the study results focus mainly on patients who received ADT alone, ADT + NSAA and ADT + ARPI. The distributions of baseline patient and clinical characteristics across cohorts were evaluated using standardized mean differences (STD), with STDs >10% relative to ADT alone used to indicate imbalance [15]. Sankey diagrams were used to visualize treatment patterns across lines of therapy. Multivariable analysis with inverse probability of treatment weighting (IPTW) was applied using weights based on propensity scores to control for confounding variables and to reduce bias when comparing outcomes between the ADT-alone and ADT + NSAA cohorts. After IPTW was applied, all patient characteristics were balanced, with standardized differences <10%. Post-IPTW baseline demographic and clinical characteristics included index year, age group, body mass index, race, region, provider specialty, insurance type, baseline CCI group, diseases of the heart, log PSA value on nmCRPC index date and PSADT group.
Kaplan–Meier (KM) curves were generated to estimate the time to event for metastasis/death or death. Among patients with high-risk nmCRPC, a Cox proportional hazards model was used to model time from 1L start date to metastasis/death or death. The list of covariates used in this model included 1L regimen, index year, age group, race, region, 1L provider specialty, time from prostate cancer diagnosis to index date, baseline CCI score, diseases of the heart according to the Agency for Healthcare Research and Quality, log PSA value and PSADT group.
3. Results
3.1. Patient characteristics & 1L treatments
A total of 1955 patients with nmCRPC were identified (Figure 1). Overall, compared with the ADT-alone cohort, the ADT + ARPI and ADT + NSAA cohorts had younger patients, slightly more African American patients, and a higher proportion of patients with commercial insurance (ADT + ARPI only; 20.50%) (Table 1). Compared with the ADT-alone cohort, the ADT + ARPI cohort also included a higher proportion of patients who underwent baseline prostatectomy (3.11%) or radiation (4.35%), as well as those who received bone-sparing agents (12.42%) during the baseline period. Furthermore, the ADT + ARPIs cohort had a higher proportion of patients with hypertension (60.25%), diseases of the urinary system (55.28%) and a fast mean PSADT value (5.73 months) compared with the ADT-alone cohort (7.64 months) (Table 1).
Table 1.
Baseline demographic and clinical characteristics of the study patients.
| Overall population | High-risk nmCRPC | |||||||
|---|---|---|---|---|---|---|---|---|
| Total nmCRPC | ADT alone | ADT + NSAA | ADT + ARPI | Total nmCRPC | ADT alone | ADT + NSAA | ADT + ARPI | |
| First-line regimens | (N = 1955) | n = 980 | n = 627 | n = 161 | (N = 1572) | n = 757 | n = 517 | n = 139 |
| Age (continuous), mean (SD) | 76.41 (6.94) | 76.88 (6.52) | 76.06 (7.10) | 75.88 (7.87) | 75.84 (7.11) | 76.34 (6.72) | 75.33 (7.26) | 75.37 (7.95) |
| Age (categorical), n (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| <65 years | 150 (7.67) | 66 (6.73) | 51 (8.13) | 16 (9.94) | 138 (8.78) | 58 (7.66) | 50 (9.67) | 15 (10.79) |
| 65–74 years | 434 (22.20) | 185 (18.88) | 155 (24.72) | 49 (30.43) | 384 (24.43) | 161 (21.27) | 139 (26.89) | 45 (32.37) |
| 75–79 years | 632 (32.33) | 358 (36.53) | 179 (28.55) | 35 (21.74) | 509 (32.38) | 273 (36.06) | 155 (29.98) | 30 (21.58) |
| ≥80 years | 739 (37.80) | 371 (37.86) | 242 (38.60) | 61 (37.89) | 541 (34.41) | 265 (35.01) | 173 (33.46) | 49 (35.25) |
| BMI, n | ||||||||
|---|---|---|---|---|---|---|---|---|
| Mean (SD) | 29.27 (5.80) n = 1708 | 29.16 (5.36) n = 832 | 29.47 (6.40) n = 549 | 29.70 (5.84) n = 151 | 29.42 (5.85) n = 1374 | 29.33 (5.36) n = 641 | 29.57 (6.57) n = 454 | 30.20 (5.85) n = 129 |
| Race, n (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| African American | 230 (11.76) | 108 (11.02) | 82 (13.08) | 26 (16.15) | 170 (10.81) | 67 (8.85) | 69 (13.35) | 23 (16.55) |
| Caucasian | 1612 (82.46) | 813 (82.96) | 510 (81.34) | 130 (80.75) | 1304 (82.95) | 639 (84.41) | 417 (80.66) | 113 (81.29) |
| Asian/other/unknown | 113 (5.78) | 59 (6.02) | 35 (5.58) | 5 (3.10) | 98 (6.23) | 51 (6.74) | 31 (6.00) | 3 (2.16) |
| Region, n (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Northeast | 207 (10.59) | 105 (10.71) | 60 (9.57) | 18 (11.18) | 173 (11.01) | 84 (11.10) | 50 (9.67) | 16 (11.51) |
| Midwest | 1143 (58.47) | 561 (57.24) | 368 (58.69) | 94 (58.39) | 921 (58.59) | 441 (58.26) | 303 (58.61) | 79 (56.83) |
| South | 376 (19.23) | 195 (19.90) | 119 (18.98) | 33 (20.50) | 284 (18.07) | 133 (17.57) | 97 (18.76) | 29 (20.86) |
| West | 193 (9.87) | 102 (10.41) | 64 (10.21) | 15 (9.32) | 164 (10.43) | 84 (11.10) | 55 (10.64) | 14 (10.07) |
| Unknown/other | 36 (1.84) | 17 (1.73) | 16 (2.55) | 1 (0.62) | 30 (1.91) | 15 (1.98) | 12 (2.32) | 1 (0.72) |
| Insurance type, n (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Commercial | 316 (16.16) | 145 (14.80) | 104 (16.59) | 33 (20.50) | 268 (17.05) | 119 (15.72) | 91 (17.60) | 28 (20.14) |
| Medicare | 969 (49.57) | 508 (51.84) | 305 (48.64) | 70 (43.48) | 780 (49.62) | 393 (51.92) | 250 (48.36) | 61 (43.88) |
| Commercial/Medicare | 512 (26.19) | 248 (25.31) | 165 (26.32) | 49 (30.43) | 396 (25.19) | 182 (24.04) | 132 (25.53) | 42 (30.22) |
| Unknown/Other | 83 (4.25) | 45 (4.59) | 26 (4.15) | 4 (2.48) | 70 (4.45) | 36 (4.76) | 22 (4.26) | 4 (2.88) |
| Treatment during 12-month pre-nmCRPC | ||||||||
|---|---|---|---|---|---|---|---|---|
| Baseline prostatectomy | 39 (1.99) | 14 (1.43) | 17 (2.71) | 5 (3.11) | 34 (2.16) | 12 (1.59) | 14 (2.71) | 5 (3.60) |
| Baseline radiation | 49 (2.51) | 16 (1.63) | 22 (3.51) | 7 (4.35) | 47 (2.99) | 16 (2.11) | 21 (4.06) | 6 (4.32) |
| Baseline bone-sparing agent use | 174 (8.90) | 65 (6.63) | 55 (8.77) | 20 (12.42) | 140 (8.91) | 48 (6.34) | 48 (9.28) | 15 (10.79) |
| Baseline opioid use | 713 (36.47) | 344 (35.10) | 223 (35.57) | 59 (36.65) | 596 (37.91) | 277 (36.59) | 191 (36.94) | 52 (37.41) |
| CCI, n | ||||||||
|---|---|---|---|---|---|---|---|---|
| CCI, mean (SD) | 0.83 (1.39) | 0.81 (1.33) | 0.79 (1.42) | 0.86 (1.54) | 0.83 (1.42) | 0.81 (1.37) | 0.80 (1.45) | 0.80 (1.50) |
| Most common AHRQ CCS comorbidities, n (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Hypertension | 1066 (54.53) | 534 (54.49) | 328 (52.31) | 97 (60.25) | 843 (53.63) | 403 (53.24) | 268 (51.84) | 85 (61.15) |
| Diseases of the urinary system | 950 (48.59) | 477 (48.67) | 312 (49.76) | 89 (55.28) | 779 (49.55) | 376 (49.67) | 262 (50.68) | 80 (57.55) |
| Disorders of lipid metabolism | 890 (45.52) | 455 (46.43) | 270 (43.06) | 80 (49.69) | 717 (45.61) | 354 (46.76) | 223 (43.13) | 69 (49.64) |
| Diseases of the heart | 831 (42.51) | 427 (43.57) | 241 (38.44) | 69 (42.86) | 661 (42.05) | 331 (43.73) | 193 (37.33) | 57 (41.01) |
| Index PSA value | ||||||||
|---|---|---|---|---|---|---|---|---|
| Median (IQR) | 5.60 (3.40–12.46) | 5.10 (3.20–10.13) | 6.30 (3.60–14.50) | 5.80 (3.00–18.09) | 5.64 (3.41–13.44) | 5.10 (3.20–10.62) | 6.16 (3.60–15.13) | 5.95 (2.99–18.60) |
| PSADT | ||||||||
|---|---|---|---|---|---|---|---|---|
| Mean (SD) | 7.05 (7.47) | 7.64 (7.90) | 6.63 (6.61) | 5.73 (5.41) | 4.28 (2.76) | 4.42 (2.78) | 4.26 (2.80) | 4.09 (2.70) |
| Median (IQR) | 4.56 (2.53–8.70) | 5.14 (2.62–9.71) | 4.53 (2.58–7.95) | 3.87 (2.49–7.01) | 3.70 (2.21–5.98) | 3.84 (2.15–6.45) | 3.74 (2.35–5.74) | 3.30 (2.28–5.19) |
| PSADT (categorical); n (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| ≤2 months | 336 (17.19) | 169 (17.24) | 99 (15.79) | 24 (14.91) | 336 (21.37) | 169 (22.32) | 99 (19.15) | 24 (17.27) |
| 2 months <PSADT ≤4 months | 531 (27.16) | 230 (23.47) | 186 (29.67) | 60 (37.27) | 531 (33.78) | 230 (30.38) | 186 (35.98) | 60 (43.17) |
| 4 months <PSADT ≤6 months | 314 (16.06) | 140 (14.29) | 113 (18.02) | 29 (18.01) | 314 (19.97) | 140 (18.49) | 113 (21.86) | 29 (20.86) |
| 6 months <PSADT ≤8 months | 228 (11.66) | 124 (12.65) | 74 (11.80) | 14 (8.70) | 228 (14.50) | 124 (16.38) | 74 (14.31) | 14 (10.07) |
| 8 months <PSADT ≤10 months | 142 (7.26) | 85 (8.67) | 39 (6.22) | 9 (5.59) | 142 (9.03) | 85 (11.23) | 39 (7.54) | 9 (6.47) |
| PSADT >10 months | 404 (20.66) | 232 (23.67) | 116 (18.50) | 25 (15.53) | 21 (1.34) | 9 (1.19) | 6 (1.16) | 3 (2.16) |
Note: In the overall population, 93 patients received ADT + glucocorticoids, 31 patients received ADT + ketoconazole + glucocorticoids and 63 patients received other treatments. In high-risk population, 73 patients received ADT + glucocorticoids, 23 patients received ADT + ketoconazole + glucocorticoids and 57 patients received other treatments. Bold text indicates >10% standardized difference between ADT alone versus ADT + NSAA or ADT alone versus ADT + ARPI.
ADT: Androgen-deprivation therapy; AHRQ: Agency for Healthcare Research and Quality; ARPI: Androgen receptor pathway inhibitor; BMI: Body mass index; CCI: Charlson comorbidity index; CCS: Clinical classification software; IQR: Interquartile range; nmCRPC: Nonmetastatic castration-resistant prostate cancer; NSAA: Nonsteroidal antiandrogen; PSADT: Prostate-specific antigen doubling time; SD: Standard deviation.
Based on risk stratification, 1572 (80.4%) and 383 (19.6%) patients were categorized as having high- and low-risk disease, respectively. The median (IQR) PSADT was 3.7 (2.21–5.98) months for the high-risk subgroup (Table 1) and 15.44 (11.96–20.94) for the low-risk subgroup (Supplemental Table S1). Similar trends in differences in baseline characteristics across the 1L regimen cohorts were observed among the high-risk cohort and the overall population (Table 1). Of the high-risk cohort, the ADT + ARPI cohort had a higher proportion of patients aged 65–74 years and African American patients (16.55%) compared with the ADT-alone cohort (8.85%). During the baseline period, the ADT + ARPI cohort also had a higher percentage of patients who underwent baseline prostatectomy (3.60%) or radiation (4.32%) and received bone-sparing agents (10.79%) than the ADT-alone cohort. Furthermore, the ADT + ARPI cohort had a higher proportion of patients with hypertension (61.15%), diseases of the urinary system (57.55%) and a faster mean PSADT value (4.09) compared with those in the ADT-alone cohort (Table 1).
Of the overall population, 980 (50.13%) patients received ADT alone, 627 (32.07%) received ADT + NSAA and 161 (8.24%) received ADT + ARPI (Table 1) as 1L regimens. Supplemental Table S2 provides the list of treatments that patients received under the category “other treatments.” Among high-risk patients, a total of 757 (48.16%) received ADT alone, 517 (32.89%) received ADT + NSAA, 139 (8.84%) received ADT + ARPI and 57 (3.62%) received other treatments as 1L (Table 1).
3.2. 1L treatment patterns by year for the overall population & high-risk subgroup (pre-2018 & post-2018 populations)
From 2008 to 2020, most patients (>80%) were treated with ADT alone or ADT + NSAA as 1L (Figure 2A). Even among patients with high-risk nmCRPC, the percentage of patients receiving ADT alone or ADT + NSAA as 1L declined during this period (ADT alone: 50.4% in 2008–2013 to 44.50% in 2018–2020; ADT + NSAA: 34.5% in 2008–2013 to 26.2% in 2018–2020), whereas the percentage of patients receiving ADT + ARPI as 1L increased but remained less than 25% (Figure 2A). When 1L patterns were stratified by PSADT, the utilization of ADT alone or ADT + NSAA was found to decrease slightly from 2008 to 2020 for most subgroups, except for patients with 6 months <PSADT ≤10 months, for whom a slight increase was observed in the ADT-alone subgroup. In contrast, ADT + ARPI use increased but it remained less than a third of all 1L regimens by 2020, even among patients with PSADT ≤4 months (Figure 2B). Between 2018 and 2020, although there was an increased use of ADT + ARPI among both patients with high-risk and low-risk nmCRPC, the majority of patients received either ADT alone or ADT + NSAA (Figure 2B).
Figure 2.
Distribution and treatment patterns among nmCRPC patients between 2008 and 2020. (A) Treatment trends in the (i) overall population with nmCRPC and (ii) patients with high-risk nmCRPC. (B) Distribution of first line of treatment among patients with high-risk and low-risk nmCRPC stratified by index year and PSADT.
Note: ADT + NSAA was ±glucocorticoids. ADT + ARPI was ±NSAA and ±glucocorticoids.
ADT: Androgen-deprivation therapy; ARPI: Androgen receptor pathway inhibitor; nmCRPC: Nonmetastatic castration-resistant prostate cancer; NSAA: Nonsteroidal antiandrogen; PSADT: Prostate-specific antigen doubling time.
3.3. Subsequent nmCRPC treatment patterns (2L & 3L) for the overall population & high-risk subgroup
In the overall population, 40.2% (n = 786) received 2L, and their disease remained nonmetastatic. Of the 2L therapies, ADT + NSAA was the most common (39.44%, n = 310), followed by ADT + ARPI (30.15%, n = 237) (Figure 3). The most common 3L was ADT + ARPI (49.57%, n = 116), while only 13.68% (n = 32) received ADT + NSAA. Similar trends were observed for 2L and 3L for patients with high-risk nmCRPC. In high-risk patients, 40.4% (n = 636) received 2L and their disease remained nonmetastatic (Supplemental Table S3). Further, ADT + NSAA (38.99%, n = 248) was the most common 2L therapy, followed by ADT + ARPI (31.13%, n = 198). Additionally, the use of ADT + NSAA as a 2L decreased between the period before 2018 (41.52%, n = 235) and after 2018 (18.57%, n = 13). However, the utilization of ADT + ARPI increased between these periods (26.5% [n = 148] before 2018 vs 71.43% [n = 50] after 2018) (Supplemental Table S3).
Figure 3.
Treatment patterns for patients with nmCRPC by line of therapy (overall population).
Note: All percentages were rounded off to the nearest whole number.
1L: First line of treatment; 2L: Second line of treatment; 3L: Third line of treatment; ADT: Androgen-deprivation therapy; ARPI: Androgen receptor pathway inhibitors; gluco: Glucocorticoid; keto: Ketoconazole; nmCRPC: Nonmetastatic castration-resistant prostate cancer; NSAA: Nonsteroidal antiandrogen.
3.4. Treatment patterns among patients with nmCRPC diagnosed with metastatic disease in the follow-up period by line of systemic therapy (1L–3L) for the overall population
Overall, 1079 (55.19%) patients with nmCRPC developed metastasis during follow-up, and 757 (70.16%) received a new regimen (metastatic 1L treatment); ADT + ARPI was the most common metastatic 1L treatment (42.27%, n = 320), followed by ADT + NSAA (17.83%, n = 135) (Supplemental Figure S2). ADT + ARPI remained the most common metastatic 2L (44.07%, n = 173/397) (Supplemental Figure S2) and metastatic 3L (36.5%, n = 85/233) mCRPC regimen (footnote, Supplemental Figure S2). Among patients with high-risk nmCRPC, 932 patients developed metastasis and a total of 660 received metastatic 1L treatment; ADT + ARPI was the most common metastatic 1L treatment (29.40%, n = 274), followed by ADT + NSAA (12.34%, n = 115). ADT + ARPI remained the most common metastatic 2L (23.64%, n = 156/660) and metastatic 3L (21.47%, n = 76/354) mCRPC regimen.
3.5. Survival outcomes
The unweighted median follow-up time for the overall population was 18.78 months for patients who received ADT alone and 11.43 months for patients who received ADT + NSAA. All patient characteristics were balanced after applying IPTW. The median MFS of the weighted post-IPTW population from the ADT + NSAA cohort was 13.40 months (95% confidence interval [CI]: 11.50–15.57), which was shorter than that of the ADT-alone cohort (median MFS: 20.40 months; 95% CI: 18.23–23.67), with statistical significance (hazard ratio [HR]: 1.48; 95% CI: 1.32–1.67) (Figure 4A). Similarly, time to death was shorter in the ADT + NSAA cohort (median OS: 30.87 months, 95% CI: 28.2–35.73) than the ADT-alone cohort (median OS: 41.70, 95% CI: 37.63–45.60), with statistical significance (HR: 1.33, 95% CI: 1.16–1.52) (Figure 4B).
Figure 4.
Survival outcomes of the overall nmCRPC patient population. (A) Kaplan–Meier curve for MFS in the overall patient population – post-IPTW analysis. (B) Kaplan–Meier curve for OS in the overall patient population – post-IPTW analysis.
ADT: Androgen-deprivation therapy; CI: Confidence interval; HR: Hazard ratio; IPTW: Inverse probability of treatment weighting; MFS: Metastasis-free survival; NSAA: Nonsteroidal antiandrogen; OS: Overall survival.
For patients with high-risk nmCRPC, the unweighted median follow-up time was 16.87 months in the ADT-alone cohort and 9.80 months for the ADT + NSAA cohort. The unweighted median MFS and OS were shorter in the ADT + NSAA cohort (median MFS: 9.80 months, 95% CI: 8.30–11.43; median OS: 28.67 months, 95% CI: 26.10–32.77) than the ADT-alone cohort (median MFS: 19.10 months, 95% CI: 16.80–22.67 months; median OS: 38.43 months, 95% CI: 35.07–43.05 months) (Supplemental Figure S3A & B). Further, the adjusted risk of metastasis or death was 1.60-times higher (95% CI: 1.41–1.83) (Supplemental Table S4) and the adjusted risk of death was 1.42-times higher (95% CI: 1.22–1.65) (Supplemental Table S5) in the ADT + NSAA cohort than in the ADT-alone cohort.
4. Discussion
The standard of care for patients with nmCRPC has continuously evolved and progressed since the 2018 approval of ARPIs in the US [12–14]. This study showed that ADT alone or ADT + NSAA were the most utilized 1L during the study period (2008–2020). Even in patients with shorter PSADT, ADT + ARPI remained underused (<25%) compared with ADT alone or ADT + NSAA as recently as 2020. Although the number of patients receiving ADT alone or ADT + NSAA as the 1L decreased to 46.5% and 25.5%, respectively, and that of patients receiving ADT + ARPI as the 1L increased to 20% between 2008 and 2020, ADT + ARPI remained underutilized compared with ADT alone or ADT + NSAA. Our data suggest that there are few differences in treatment patterns between the pre- and post-2018 periods, despite ARPIs having been approved and included in treatment guidelines. The criteria for considering patients with nmCRPC with PSADT ≤10 months on ADT as high-risk patients have been used previously in several pivotal Phase III clinical trials, but with the addition of patients with Gleason score ≥8 due to increased risk of distant metastases [4,16–20]. Previous real-world studies have used similar definitions for high-risk nmCRPC and the requirement for ≥2 consecutive increases in PSA while receiving continuous ADT for confirmation of castration resistance [21,22].
In line with our study, preliminary results from a Veterans Affairs (VA) database study with a similar study period (2006–2020) reported that bicalutamide (72%) was the most common 1L, followed by ketoconazole (8%), abiraterone (7%) and enzalutamide (6%), and although the use of first-generation NSAAs declined with the introduction of abiraterone and enzalutamide, bicalutamide remained the predominant 1L treatment for patients with nmCRPC [22]. Thus, upfront intensification with ARPIs seemed infrequent, and increasing awareness among prescribing physicians and gradual adoption of treatment guidelines may increase ARPI utilization in patients with nmCRPC.
In our study, ADT + ARPI was the most common 1L (n = 320; 42.27%) in patients who developed metastasis during follow-up. While ARPIs are relatively underused as 1L for nmCRPC, they are still the most preferred line of treatment in patients developing metastasis, as also shown previously [7,23].
In the multivariable analysis, the median MFS and OS were shorter in the ADT + NSAA cohort than the ADT-alone cohort. It should be noted that in this study, despite having more homogenous disease severity than the overall study population, patients with high-risk nmCRPC receiving ADT + NSAA also had worse OS and MFS outcomes than those receiving ADT alone. However, the reported survival outcomes should be interpreted with caution as the results may be affected by differences in prognostic variables that were not captured, such as Eastern Cooperative Oncology Group performance status, alkaline phosphatase, or lactate dehydrogenase, which could also have influenced the physician's treatment choice.
With the emergence of more sensitive diagnostic imaging such as prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) [4,24], nmCRPC as a disease space may decrease with earlier detection of metastases, which can affect subsequent treatment decisions. Although the impact of PSMA-PET on the nmCRPC diagnosis and treatment paradigm is unknown, the use of PSMA-PET imaging is approved in patients with suspected metastasis or biochemical recurrence [25], leading to an increase in diagnosis in metastatic castration-sensitive prostate cancer (mCSPC). Notably, these patients also suffer from a lack of treatment intensification observed in real-world studies [26–29], suggesting applicability of the findings of this analysis in nmCRPC, which would not be remedied by metastatic diagnosis in PSMA-PET. One of the identified barriers to treatment intensification included physicians intensifying only high-volume disease; this may be further exacerbated by PSMA-PET imaging that can identify smaller metastases [30]. Regardless, studies in both nmCRPC and mCSPC demonstrated superiority of ADT + ARPI compared with ADT alone on survival outcomes and ARPIs continue to be recommended by guidelines for use in patients with nmCRPC with PSADT ≤10 months and mCSPC [12–14,25,31–34]. Meanwhile, there continues to be no consensus on the use of PSMA-PET to detect metastases in patients diagnosed with nmCRPC using conventional imaging.
In addition, the therapeutic landscape is rapidly evolving with the recent US Food and Drug Administration approval of enzalutamide for patients with high-risk biochemical recurrence non-mCSPC, triplet systemic therapy in mCSPC, and biomarker targeted poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and radioligand combination therapies in mCRPC [35–39]. The advent of novel prostate cancer treatment options and more sensitive diagnostic techniques underscores the need for optimal treatment sequencing to guide future clinical decisions.
This study has limitations that are inherent to retrospective studies utilizing EHR databases, including potential coding errors, lack of generalizability beyond studied population and incomplete data that may have resulted in unmeasured confounding and affected the reported treatment-intensification patterns and survival outcomes [40]. However, we adjusted for known confounders, defined nmCRPC using captured PSA based on the Prostate Cancer Working Group 3 criteria [41] for diagnosis of CRPC, and evaluated events of metastasis during the 12-month period that preceded the index date and that were similar in method to other real-world studies in CRPC [42–44]. There is a possibility that some patients might have experienced metastasis more than 12 months before the index period, and this event would not have been captured by our database. While a 12-month pre-index period is common in real-world studies [45–48], findings from a VA study (between 2006 and 2020) suggest that bicalutamide and ADT were the most common 1L treatments [22] and the majority of patients aligned with similar treatments for nonmetastatic prostate cancer in this study. Finally, because the end of study data availability at that time was December 2020, we could not capture all death events after the required follow-up of 12 months post-index date. Nevertheless, inclusion of ARPIs—particularly in patients with high-risk nmCRPC—as recommended by the National Comprehensive Cancer Network (NCCN) guidelines should continue to be prioritized as they have been shown to improve survival in patients.
5. Conclusion
This study provides real-world insights on the treatment patterns and clinical outcomes of patients with nmCRPC. Although 1L use of ADT + ARPI increased during the study period, it remained underutilized compared with ADT alone or ADT + NSAA, even in those with high-risk nmCRPC and as recently as 2020. Further, in this study, ADT + NSAA appeared to be associated with worse clinical outcomes than ADT alone, but still had higher utilization than ADT + ARPI. Practice-improvement strategies are needed for treatment intensification with ARPIs in patients with nmCRPC as continued use of these guideline-recommended therapies could improve outcomes.
Supplementary Material
Acknowledgments
The authors would also like to thank L Puli, J Patel, R Kurtkoti, S Sakhabuth and L Huber from IQVIA for medical writing, graphic design and editorial support.
Funding Statement
U Swami certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are as follows: S Gupta reports research funding to institution from Mirati Therapeutics, Novartis, Pfizer, Viralytics, Hoosier Cancer Research Network, Rexahn Pharmaceuticals, Five Prime Therapeutics, Incyte, MedImmune, Merck, Bristol Myers Squibb, Clovis Oncology, LSK BioPharma, QED Therapeutics, Daiichi Sankyo/Lilly, Immunocore, Seattle Genetics, Astellas, Acrotech, AstraZeneca and EMD Serono; research support from Astellas; and grant funding from the National Comprehensive Cancer Network and the US Department of Veterans Affairs. A Hong is a former employee of Astellas Pharma Inc. and received medical writing support for this manuscript. A Hong holds stocks in Veru Inc. and Revance Therapeutics Inc. S Bunner is a former employee of Optum, Inc., and has received research funding from Astellas Pharma Inc. for the present publication. S Bunner has worked on several protocol-driven research projects in an analytic role while at Optum, Inc., funded by Bristol Myers Squibb, GlaxoSmithKline (now GSK), Astellas Pharma Inc., AstraZeneca, Gilead Sciences, Inc., Incyte, Clovis Oncology, Acadia Pharmaceuticals Inc. and AbbVie Inc. S Bunner holds stock ownership or options in UnitedHealth Group (which ended on 8/26/2022, when he left Optum, Inc.). B Diessner is an employee of Optum, Inc. and holds stocks in UnitedHealth Group, and has received support from Astellas Pharma Inc. for the present publication. B Chastek is an employee of Optum, Inc., and holds stocks in UnitedHealth Group. N El Chaar is an employee of Astellas Pharma Inc., has received travel support from Astellas Pharma Inc., and has received support from Astellas Pharma Inc. for the present publication. K Ramaswamy is an employee of Pfizer Inc. and holds stock in Pfizer Inc. C Young received publication support from Astellas Pharma Inc. for the present work and is an employee of Astellas Pharma US, Inc. B Xie received publication support from Astellas Pharma Inc. for the present work and is an employee of Astellas Pharma US, Inc. U Swami reports consultancy to Astellas, AstraZeneca, Adaptimmune, Exelixis, Gilead, Imvax, Pfizer, Seattle Genetics, and Sanofi; and research funding to institute from Janssen, Exelixis, and Astellas/Seattle Genetics.
Supplemental material
Supplemental data for this article can be accessed at https://doi.org/10.1080/14796694.2024.2373681
Author contributions
The study was designed and conceptualized by U Swami, A Hong, C Young, B Xie, K Ramaswamy, N El Chaar and S Gupta. SH Bunner and B Chastek were involved in data curation. B Diessner, SH Bunner, B Xie and B Chastek were involved in data validation. Data analysis was carried out by U Swami, A Hong, B Diessner, C Young, SH Bunner, K Ramaswamy and N El Chaar. All authors contributed to interpreting the data, drafting the manuscript and have approved the final version for submission.
Financial disclosure
U Swami certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are as follows: S Gupta reports research funding to institution from Mirati Therapeutics, Novartis, Pfizer, Viralytics, Hoosier Cancer Research Network, Rexahn Pharmaceuticals, Five Prime Therapeutics, Incyte, MedImmune, Merck, Bristol Myers Squibb, Clovis Oncology, LSK BioPharma, QED Therapeutics, Daiichi Sankyo/Lilly, Immunocore, Seattle Genetics, Astellas, Acrotech, AstraZeneca and EMD Serono; research support from Astellas; and grant funding from the National Comprehensive Cancer Network and the US Department of Veterans Affairs. A Hong is a former employee of Astellas Pharma Inc. and received medical writing support for this manuscript. A Hong holds stocks in Veru Inc. and Revance Therapeutics Inc. S Bunner is a former employee of Optum, Inc., and has received research funding from Astellas Pharma Inc. for the present publication. S Bunner has worked on several protocol-driven research projects in an analytic role while at Optum, Inc., funded by Bristol Myers Squibb, GlaxoSmithKline (now GSK), Astellas Pharma Inc., AstraZeneca, Gilead Sciences, Inc., Incyte, Clovis Oncology, Acadia Pharmaceuticals Inc. and AbbVie Inc. S Bunner holds stock ownership or options in UnitedHealth Group (which ended on 8/26/2022, when he left Optum, Inc.). B Diessner is an employee of Optum, Inc. and holds stocks in UnitedHealth Group, and has received support from Astellas Pharma Inc. for the present publication. B Chastek is an employee of Optum, Inc., and holds stocks in UnitedHealth Group. N El Chaar is an employee of Astellas Pharma Inc., has received travel support from Astellas Pharma Inc., and has received support from Astellas Pharma Inc. for the present publication. K Ramaswamy is an employee of Pfizer Inc. and holds stock in Pfizer Inc. C Young received publication support from Astellas Pharma Inc. for the present work and is an employee of Astellas Pharma US, Inc. B Xie received publication support from Astellas Pharma Inc. for the present work and is an employee of Astellas Pharma US, Inc. U Swami reports consultancy to Astellas, AstraZeneca, Adaptimmune, Exelixis, Gilead, Imvax, Pfizer, Seattle Genetics, and Sanofi; and research funding to institute from Janssen, Exelixis, and Astellas/Seattle Genetics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
The medical writing and editorial service was provided by L Puli, J Patel, R Kurtkoti and L Huber from IQVIA and was funded by Astellas Pharma Inc.
Ethical conduct of research
The study was conducted in accordance with the protocol, applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. Deidentified patient data were collected in compliance with US patient confidentiality requirements, including the Health Insurance Portability and Accountability Act (HIPAA) of 1996. Informed consent was not required because this was not an interventional study, and routinely collected, anonymized data were used and therefore were exempted from Institutional Review Board approval. The data are certified as de-identified by an independent statistical expert following HIPAA statistical de-identification rules and managed according to Optum® customer data use agreements, which allow Optum to use the de-identified data in research studies.
Data availability statement
Researchers may request access to anonymized participant-level data, trial-level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing see: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx
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