Abstract
BACKGROUND:
The advent of next-generation imaging will likely reduce nonmetastatic prostate cancer (PC) prevalence and increase identification of metastatic prostate cancer cases, resulting in two predominant advanced stages in the metastatic setting. There is a need to characterize changes in health care resource utilization (HRU) and costs when metastatic castration-sensitive PC (mCSPC) progresses to metastatic castration-resistant PC (mCRPC) to identify value drivers from current and new treatments.
OBJECTIVE:
To describe treatment patterns, HRU, and total health care costs among patients with mCSPC, before and after progression to mCRPC.
METHODS:
Clinical data from the Flatiron Metastatic PC Core Registry (January 1, 2013, to December 1, 2021) and linked claims from Komodo Health (January 1, 2014, to December 1, 2021) were used to identify patients with progression from mCSPC to mCRPC (date of progression was the index date) and subsequently initiated first-line mCRPC therapy on/after January 1, 2017. Treatment patterns and all-cause/PC-related HRU and health care costs were described per-patient-per-month (PPPM), separately for no more than 12 months pre-index (mCSPC disease state) and post-index (mCRPC disease state). Costs (payer’s perspective) included those for services/procedures from medical claims and costs from pharmacy claims. Continuous HRU and costs were compared between the mCSPC and mCRPC disease states using Wilcoxon signed rank tests.
RESULTS:
Among 296 patients with mCSPC progressing to mCRPC (median age 69.0 years, 60.5% White, 15.9% Black), use of systemic therapies with androgen deprivation therapy increased dramatically from 35.1% in the mCSPC disease state to 92.9% in the mCRPC disease state, and use of androgen deprivation therapy monotherapy decreased from 25.7% to 2.4%, respectively. Although 39.2% received none of these therapies in the mCSPC disease state, this proportion decreased to 4.7% after transition to mCRPC. The mean number of days with PC-related outpatient visits increased from 1.57 to 2.16 PPPM in the mCSPC and mCRPC disease states (P < 0.001). From the mCSPC to mCRPC disease states, mean all-cause total health care costs PPPM increased from $4,424 (medical costs: $2,846) to $9,717 (medical costs: $4,654), and mean PC-related total health care costs PPPM increased from $2,859 (medical costs: $1,626) to $8,012 (medical costs: $3,285; all P < 0.001).
CONCLUSIONS:
In this real-world study of patients with disease progression from mCSPC to mCRPC in US clinical practice, nearly 2-in-3 patients did not receive treatment with additional systemic therapies before progression to castration resistance. Post-progression, mean PC-related total costs increased nearly 3-fold, with a more than 2-fold increase in PC-related medical costs. Use of additional systemic therapies may delay the time and cost associated with disease progression to castration resistance.
Plain language summary
In this study of men who advanced from stage IV prostate cancer to stage IV castration-resistant prostate cancer, nearly two-thirds received substandard treatment before progression. Following disease progression, total health care costs were 1.5 to 2 times higher, and these men used more medical services, including hospital and outpatient visits. This study highlights the large cost burden of prostate cancer as it worsens. Use of additional advanced treatments may delay this progression and its associated costs.
Implications for managed care pharmacy
In this real-world study of patients with metastatic castration-sensitive prostate cancer whose disease progressed to castration-resistance in US clinical practice, nearly two-thirds of patients received inadequate advanced treatment before progression, whereas health care resource utilization and costs increased substantially after castration resistance. Use of advanced therapies, including androgen receptor signaling inhibitors, can delay disease progression (as demonstrated in clinical trials) and may consequently reduce the management costs associated with castration resistance among metastatic patients.
Prostate cancer (PC) is the most common cancer in men, affecting 3.3 million individuals in the United States in 2020.1 Although most patients present with localized disease at diagnosis, 1 in 9 have PC that will eventually progress to metastasis, with a 5-year survival rate of 34.1%.1,2
The standard of care for metastatic PC (mPC) has conventionally been androgen deprivation therapy (ADT), which blocks testosterone production via surgical (eg, orchiectomy) or chemical castration (eg, luteinizing hormone-releasing hormone agonists or antagonists).3 Although most mPC initially respond to ADT, a stage called metastatic castration-sensitive PC (mCSPC), over time, most patients experience sequential increases in serum prostate-specific antigen (PSA) level despite castrate testosterone levels (ie, <50 ng/dL), indicating metastatic castration-resistant PC (mCRPC).4,5 Approximately 15%-50% of mCRPC cases transition from mCSPC, whereas the remainder of patients develop disease progression from treatment given in the nonmetastatic disease setting.4,6 Advanced therapies, such as androgen receptor signaling inhibitors ([ARSIs] ie, apalutamide, abiraterone acetate with prednisone, enzalutamide, darolutamide) and docetaxel chemotherapy, have demonstrated improved clinical outcomes when added to ADT for the treatment of mCSPC7-11 and/or mCRPC12-14 and are recommended in clinical guidelines.15 Additional therapeutic options for mCRPC include systemic radiotherapy (ie, radium-223, lutetium Lu 177 vipivotide tetraxetan), chemotherapy (ie, cabazitaxel), and immunotherapy (ie, sipuleucel-T).5,15 For patients with mutations in homologous recombination repair genes like BRCA, poly (ADP-ribose) polymerase (PARP) inhibitors with or without ARSIs (ie, niraparib + abiraterone acetate dual action tablet, olaparib, olaparib + abiraterone acetate, rucaparib, talazoparib + enzalutamide) may also be considered.16-19
Given the large clinical burden of mPC (from both symptoms and adverse effects of lifelong therapy), mCSPC and mCRPC are also associated with substantial economic burden.5,20,21 Prior studies have reported total health care costs ranging from $69,639 to $108,767 per-patient-per year ([PPPY] 2019 US dollars [USD]) for patients with mCSPC and from $111,060 to $182,156 PPPY (2015-2020 USD) for patients with mCRPC in the United States, depending on health insurance coverage.20-23 As patients experience progression from one PC disease state to another, the increasing clinical burden and complexity of management likely results in considerable rising health care resource utilization (HRU) and costs. Indeed, prior real-world studies in the United States have found that HRU increases by 1.5 to 2.5-fold and health care costs by 4 to 6-fold after transition from nonmetastatic castration-resistant PC (nmCRPC) to mCRPC.21,22 However, US-based studies examining changes in HRU and costs when patients experience progression from mCSPC to mCRPC are lacking. Notably, the advent of next-generation imaging will likely reduce nonmetastatic PC prevalence and increase the identification of metastatic PC cases, potentially resulting in two predominant advanced stages in the metastatic setting.24 Therefore, the current study was conducted to describe HRU and all-cause and PC-related health care costs among patients with mCSPC, before and after progression to mCRPC, to identify value drivers from current and new treatments.
Methods
DATA SOURCE
Clinical data from the Flatiron Metastatic PC Core Registry (January 1, 2013, to December 1, 2021) and linked claims data from Komodo’s Healthcare Map (January 1, 2014, to December 1, 2021) were used. The Flatiron Metastatic PC Core Registry is a longitudinal database that includes deidentified, patient-level structured and unstructured data (curated via technology-enabled abstraction) from approximately 280 US cancer clinics (≈800 sites of care).25,26 Detailed clinical data, including demographics, diagnoses, visits, medication administration, medication prescriptions and orders, laboratory tests and vitals, performance status, and insurance data are extracted from structured electronic medical records (EMRs), as well as unstructured data abstracted from physicians’ notes and other documents, both manually by trained abstractors and using natural language processing. PC-related characteristics that may not be available in other databases (eg, diagnosis dates of initial PC, metastatic PC, and CRPC; stage at initial diagnosis; PSA test results; mortality) are also included in the data. This dataset specifically used a sample of patients with chart-confirmed metastatic PC (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 185.x or ICD-10-CM code C61.x) with 2 or more documented clinical visits in the Flatiron network, on different days, occurring on or after January 1, 2013.
Anonymized patient-level payer medical and pharmacy closed claims for patients with complete medical and prescription benefit information, including insurance eligibility, from Komodo’s Healthcare Map were linked to the Flatiron EMR data to provide information on HRU and costs. Datavant performed the linkage using their patent-pending, machine learning–validated deidentification technology, which allowed for linkage without sharing underlying patient information by creating patient-specific tokens in the Komodo Health and Flatiron data sources.27
The Komodo Health database includes more than 320 million patients with Medicaid, Commercial, and Medicare coverage in the United States. Although costs from a payer’s perspective were typically available for pharmacy claims, these costs were not always directly available for medical claims. Therefore, Komodo used an algorithm to impute medical costs from a payer’s perspective for missing costs, which were derived based on the type of claim, payer channel, type of service, and setting of care.28 For pharmacy claims without costs from a payer’s perspective, costs were imputed using the median cost for the medication by national drug code and payer channel or in reference to National Average Drug Acquisition Cost and Medicare Average Sales Price.28
Data from Flatiron and Komodo Health were deidentified and complied with the Health Insurance Portability and Accountability Act of 1996. Per Title 45 of Code of Federal Regulations, Part 46.101(b)(4), the analysis of this study was exempt from institutional review because it was a retrospective analysis of existing data with no patient intervention or interaction, and no patient identifiable information was included in the EMR and claims datasets.29 Flatiron Health, Inc., Komodo Health Solutions, and Datavant did not participate in any data analyses.
STUDY DESIGN AND SAMPLE SELECTION
A retrospective, longitudinal cohort study was conducted among patients whose disease progressed from mCSPC to mCRPC and subsequently initiated a Flatiron oncologist-defined first-line therapy for mCRPC on or after January 1, 2017, to include a more contemporary analysis focusing on more recently approved regimens for the treatment of mCRPC. The Flatiron oncologist-defined first-line therapy for mCRPC consisted of antineoplastic, systemic treatment for advanced PC, including ARSIs (ie, abiraterone acetate, apalutamide, darolutamide, enzalutamide), chemotherapy (ie, cabazitaxel, carboplatin, cisplatin, docetaxel, etoposide, mitoxantrone), PARP inhibitors (ie, niraparib, olaparib, rucaparib, talazoparib), immunotherapy (ie, sipuleucel-T, pembrolizumab), estrogens (ie, diethystillbestrol, estramustine phosphate, polyestradiol phosphate), and radiopharmaceuticals (ie, radium-223, lutetium-177-PSMA-617). Notably, PARP inhibitor combination therapies were not included as they were approved after the study period. The index date was defined as the date of progression to castration resistance, with the baseline period spanning the prior 12 months (may have included time prior to evidence of metastasis) (Supplementary Figure 1 (213.6KB, pdf) , available in online article). The mCSPC disease state was defined as the up to 12-month period prior to the index date in which there was evidence of metastasis in the absence of castration resistance, whereas the mCRPC disease state spanned the up to 12-month period from the index date until the earliest of the end of continuous insurance eligibility, end of data availability, or death.
Patients were included in the study if they (1) had a diagnosis for mPC confirmed via medical charts and CRPC confirmed from Flatiron data (using an algorithm that incorporated physician-reported CRPC in medical charts, rise in PSA levels observed while receiving hormone therapy, or physician-documented rise in PSA levels while receiving hormone therapy plus a change in treatment); (2) had at least 1 Flatiron oncologist-defined line of therapy for mCRPC on or after mCRPC diagnosis and January 1, 2017; (3) had at least 1 claim in Komodo Health closed claims for an agent included as part of the patient’s Flatiron oncologist-defined first-line therapy, initiated on or after mCRPC diagnosis; (4) were aged 18 years or older; and (5) had at least 12 months of continuous insurance eligibility in Komodo Health closed claims data before the index date (ie, 12-month baseline period) (Figure 1).
FIGURE 1.
Identification of Patients Whose Disease Progressed From mCSPC to mCRPC
Patients were excluded from the study if they had (1) mCSPC for less than 3 months prior to mCRPC diagnosis (to avoid identifying patients who may not have been appropriately classified as mCRPC initially, based on input from clinical experts); (2) received a clinical trial therapy as the first post-index mCRPC treatment; or (3) missing claims for the Flatiron oncologist-defined therapy in Komodo Health data.
A subgroup analysis was also performed among patients whose disease progressed from mCSPC to mCRPC after 2019 to assess temporal changes as the treatment landscape evolved.
MEASURES AND OUTCOMES
Patient characteristics included demographic characteristics (from Komodo Health claims) and clinical characteristics (from Flatiron EMR data) measured during the baseline period.
Outcomes were measured during the mCSPC disease state and mCRPC disease state, separately, and included treatment patterns (from Flatiron EMR data, ie, ADT, ARSIs, chemotherapy, immunotherapy, PARP inhibitors) and all-cause and PC-related HRU and costs (from Komodo closed claims). Treatment patterns included any use of advanced therapies (ie, ARSIs, chemotherapy, immunotherapy, or PARP inhibitors) and ADT monotherapy (ie, use of ADT in the absence of any advanced therapy use). All HRU and cost outcomes were reported per-patient-per-month (PPPM). HRU included inpatient admissions, emergency department visits, outpatient visits, pharmacy claims, and other services. Total health care costs included medical (ie, inpatient, emergency department, outpatient, other) and pharmacy costs and were reported in 2022 USD from a payer’s perspective. PC-related HRU and costs were identified as claims with ICD-10-CM code C61 (malignant neoplasm of the prostate) or procedure codes for luteinizing hormone-releasing hormone or other therapies for mCRPC (ie, ARSIs, chemotherapy, PARP inhibitors, immunotherapy, estrogens, and radiopharmaceuticals).
STATISTICAL ANALYSES
All analyses were conducted using SAS Enterprise Guide software Version 7.15. Outcomes were described using means, medians, and SDs for continuous variables and using frequencies and proportions for categorical variables. The minimum, maximum, and interquartile range were additionally reported for the length of the mCSPC and mCRPC disease states. Continuous HRU and cost outcomes were compared between the mCSPC and mCRPC disease states using Wilcoxon signed rank tests, with P values reported. All analyses were repeated for the subgroup of patients whose disease progressed from mCSPC to mCRPC after 2019.
Results
BASELINE CHARACTERISTICS
A total of 296 patients with mCSPC whose disease progressed to mCRPC were included in the study. The mean age was 69.2 years and 60.5% were White and 15.9% were Black (Table 1). Most patients had commercial (46.3%) or Medicare (42.9%) insurance, and 91.6% were treated in a community practice. Two-thirds (65.2%) of patients had mCSPC at the time of initial PC diagnosis, and the mean time between mCSPC and mCRPC was 17.6 months. Almost all patients (94.9%) had evidence of ADT use prior to the index date. The mean (median) duration of the mCSPC disease state was 10.2 (12.0) months and the mean and median duration of the mCRPC disease state was 10.3 months.
TABLE 1.
Baseline Demographic and Clinical Characteristics Among Patients Whose Disease Progressed From mCSPC to mCRPC
| All patients | Patients with an index date on or after 2019 | |
|---|---|---|
| N = 296 | n = 131 | |
| Age, mean±SD [median] | 69.2 ± 9.2 [69.0] | 69.1 ± 9.7 [69.0] |
| Race and ethnicity, n (%) | ||
| White | 179 (60.5) | 70 (53.4) |
| Black | 47 (15.9) | 24 (18.3) |
| Other | 51 (17.2) | 25 (19.1) |
| Unknown | 19 (6.4) | 12 (9.2) |
| Practice type, n (%) | ||
| Community | 271 (91.6) | 118 (90.1) |
| Academic | 22 (7.4) | 10 (7.6) |
| Both | 3 (1.0) | 3 (2.3) |
| Insurance plan type, n (%) | ||
| Commercial | 137 (46.3) | 65 (49.6) |
| Medicare | 127 (42.9) | 49 (37.4) |
| Medicaid | 31 (10.5) | 17 (13.0) |
| Unknown | 1 (0.3) | 0 (0.0) |
| Stage at initial PC diagnosis, n (%) | ||
| Localized PC | 103 (34.8) | 39 (29.8) |
| mCSPC | 193 (65.2) | 92 (70.2) |
| Year of index date, n (%) | ||
| 2015 | 1 (0.3) | — |
| 2016 | 11 (3.7) | — |
| 2017 | 83 (28.0) | — |
| 2018 | 70 (23.6) | — |
| 2019 | 51 (17.2) | 51 (38.9) |
| 2020 | 53 (17.9) | 53 (40.5) |
| 2021 | 27 (9.1) | 27 (20.6) |
| Time from initial PC diagnosis to mCSPC, months, mean±SD [median] | 28.2 ± 54.3 [0.0] | 45.7 ± 58.3 [21.9] |
| Time from mCSPC diagnosis to mCRPC, months, mean±SD [median] | 17.6 ± 3.1 [14.5] | 19.3 ± 15.1 [15.1] |
| Most recent ECOG performance scorea, n (%) | ||
| 0 | 93 (44.9) | 48 (49.5) |
| 1 | 92 (44.4) | 39 (40.2) |
| 2 | 18 (8.7) | 8 (8.2) |
| 3 | 3 (1.4) | 2 (2.1) |
| 4 | 1 (0.5) | 0 (0.0) |
| Gleason score at initial PC diagnosis, n (%) | ||
| ≤6 | 15 (5.1) | 6 (4.6) |
| 7 | 42 (14.2) | 15 (11.5) |
| 8 | 49 (16.6) | 21 (16.0) |
| 9 | 86 (29.1) | 38 (29.0) |
| 10 | 26 (8.8) | 9 (6.9) |
| Not available | 78 (26.4) | 42 (32.1) |
| Prior evidence of ADT use b , n (%) | 281 (94.9) | 122 (93.1) |
| ADT monotherapy,c,d n (%) | 178 (63.4) | 65 (53.3) |
| Quan-Charlson Comorbidity Index, mean±SD [median] | 9.0 ± 3.3 [9.0] | 9.1 ± 3.1 [9.0] |
a ECOG scores were considered at any time prior to and including the index date.
b Prior evidence of ADT use was defined as any ADT at any time prior to (and excluding) the index date.
c Evaluated in the 12-month baseline period.
d Defined as ADT use without use of ARSIs, chemotherapy, PARP inhibitors, immunotherapy, estrogens, or radiopharmaceuticals.
ADT = androgen deprivation therapy; ARSI = androgen receptor signaling inhibitor; ECOG = Eastern Cooperative Oncology Group; mCRPC = metastatic castration-resistant prostate cancer; mCSPC = metastatic castration-sensitive prostate cancer; PC = prostate cancer; PARP = poly ADP-ribose polymerase.
In the subgroup analysis, 131 patients whose disease progressed from mCSPC to mCRPC after 2019 were included. The mean age was 69.1 years, 53.4% were White, and 18.3% were Black (Table 1). Patient characteristics in the subgroup were generally similar to those of the overall population, with a mean time between mCSPC and mCRPC of 19.3 months. Additionally, 93.1% had evidence of ADT use prior to the index date. The mean (median) duration of the mCSPC disease state was 10.5 (12.0) months and the mean and median duration of the mCRPC disease state was 9.9 months.
TREATMENT PATTERNS
From the mCSPC disease state to the mCRPC disease state, the proportion of patients using any advanced systemic therapy increased from 35.1% to 92.9%, the proportion of patients treated with ADT monotherapy decreased from 25.7% to 2.4%, and the proportion of patients receiving none of these therapies decreased from 39.2% to 4.7% (Figure 2). Use of ARSIs increased dramatically from 26.0% during the mCSPC disease state to 81.1% in the mCRPC disease state. In fact, use of abiraterone acetate increased from 18.9% to 49.3%, whereas use of enzalutamide increased from 8.1% to 45.9%. The proportion of patients treated with chemotherapy increased from 11.8% in the mCSPC disease state to 31.1% in the mCRPC disease state, mostly from docetaxel use, which increased from 11.1% to 27.7%. Leuprolide was the most used ADT agent with it being used in 42.6% of patients during the mCSPC disease state and its use increasing to 55.1% during the mCRPC disease state (Supplementary Table 1 (213.6KB, pdf) ). Although all patients initiated a Flatiron oncologist-defined first-line therapy for mCRPC, the date of initiation was after the up to 12-month mCRPC disease state among 7.1% of patients.
FIGURE 2.
Treatmentsa,b,c Used During the mCSPC and mCRPC Disease States Among the Overall Population
Similar trends were observed in the subgroup of patients whose disease progressed from mCSPC to mCRPC after 2019, though ARSIs were more commonly used in the mCSPC disease state in the subgroup relative to the overall population (Supplementary Table 1 (213.6KB, pdf) ). The proportion of patients using any advanced systemic therapy increased from 44.3% to 92.4%, the proportion of patients treated with ADT monotherapy decreased from 22.9% to 2.3%, and the proportion of patients receiving none of these therapies decreased from 32.8% to 5.3% from the mCSPC disease state to the mCRPC disease state (Supplementary Figure 2 (213.6KB, pdf) ). Use of ARSIs increased dramatically from 38.2% during the mCSPC disease state to 80.9% in the mCRPC disease state (abiraterone acetate increased from 28.2% to 42.7%; enzalutamide increased from 12.2% to 45.0%). The proportion of patients treated with chemotherapy increased from 9.9% during the mCSPC disease state to 32.8% during the mCRPC disease state, mostly because of docetaxel use, which increased from 9.9% to 28.2%. During the mCSPC disease state, 51.1% of patients used leuprolide relative to 62.6% during the mCRPC disease state. Though all patients initiated a Flatiron oncologist-defined first-line therapy for mCRPC, the date of initiation was after the up to 12-month mCRPC disease state among 7.6% of patients in the subgroup whose disease progressed after 2019.
HEALTH CARE RESOURCE UTILIZATION
During the mCSPC disease state, 39.5% of patients had an all-cause inpatient admission, with a mean of 9.54 days per stay, relative to 45.3% and a mean of 10.19 days per stay during the mCRPC disease state (P = 0.259 for days per stay) (Table 2). Nearly all patients had a PC-related outpatient visit in the mCSPC disease state (95.9%) and mCRPC disease state (96.6%). The number of days with all-cause outpatient visits increased from 2.66 to 3.10 PPPM, whereas PC-related outpatient visits increased from 1.57 to 2.16 PPPM during the mCSPC and mCRPC disease states (both P < 0.001).
TABLE 2.
HRU PPPM During mCSPC and mCRPC Disease States Among Patients Whose Disease Progressed From mCSPC to mCRPC, Obtained From Komodo Claims
| Mean±SD [median] or n (%) | All patients | Index date on or after 2019 | ||||
|---|---|---|---|---|---|---|
| mCSPC disease state a | mCRPC disease state a | P valueb | mCSPC disease state a | mCRPC disease state a | P valueb | |
| N = 296 | N = 296 | n = 131 | n = 131 | |||
| Length of disease state, months | 10.2 ± 2.7 [12.0] | 10.3 ± 3.0 [10.3] | — | 10.5 ± 2.5 [12.0] | 9.9 ± 3.1 [9.9] | — |
| Minimum, maximum [IQR] | 3.0, 12.0 [3.6] | 1.0, 12.0 [2.4] | — | 3.0, 12.0 [3.1] | 1.0, 12.0 [3.6] | — |
| All-cause | ||||||
| Inpatient admissions | ||||||
| Had ≥1 inpatient admission | 117 (39.5) | 134 (45.3) | — | 58 (44.3) | 56 (42.7) | — |
| No. of admissions | 0.13 ± 0.30 [0.00] | 0.16 ± 0.30 [0.00] | 0.078 | 0.12 ± 0.21 [0.00] | 0.12 ± 0.22 [0.00] | 0.893 |
| No. of days | 1.41 ± 4.30 [0.00] | 1.88 ± 4.61 [0.00] | 0.080 | 1.65 ± 4.77 [0.00] | 1.71 ± 4.60 [0.00] | 0.995 |
| No. of days per admission | 9.54 ± 12.80 [5.00] | 10.19 ± 10.59 [6.33] | 0.259 | 11.12 ± 15.20 [6.33] | 10.04 ± 9.65 [6.25] | 0.764 |
| Emergency department visits | ||||||
| Had ≥1 emergency department visit | 82 (27.7) | 101 (34.1) | — | 39 (29.8) | 45 (34.4) | — |
| No. of days with visits | 0.06 ± 0.17 [0.00] | 0.08 ± 0.21 [0.00] | 0.076 | 0.07 ± 0.21 [0.00] | 0.07 ± 0.15 [0.00] | 0.412 |
| Outpatient visits | ||||||
| Had ≥1 outpatient visit | 289 (97.6) | 291 (98.3) | — | 127 (96.9) | 129 (98.5) | — |
| No. of days with visits | 2.66 ± 2.27 [2.21] | 3.10 ± 2.15 [2.76] | <0.001c | 2.77 ± 2.70 [2.34] | 3.20 ± 2.53 [2.76] | 0.020c |
| Pharmacy claims | ||||||
| Had ≥1 pharmacy claims | 280 (94.6) | 292 (98.6) | — | 125 (95.4) | 128 (97.7) | — |
| No. of pharmacy claims | 3.37 ± 2.95 [2.67] | 3.88 ± 2.92 [3.18] | 0.006c | 3.26 ± 22.97 [2.51] | 3.56 ± 2.79 [2.92] | 0.168 |
| Other servicesd | ||||||
| Had ≥1 other service | 9 (3.0) | 13 (4.4) | — | 4 (3.1) | 7 (5.3) | — |
| No. of days with other services | 0.02 ± 0.18 [0.00] | 0.05 ± 0.64 [0.00] | 0.380 | 0.02 ± 0.25 [0.00] | 0.10 ± 0.95 [0.00] | 0.346 |
| PC-related e | ||||||
| Inpatient admissions | ||||||
| Had ≥1 inpatient admission | 106 (35.8) | 121 (40.9) | — | 54 (41.2) | 49 (37.4) | — |
| No. of admissions | 0.10 ± 0.24 [0.00] | 0.14 ± 0.27 [0.00] | 0.093 | 0.10 ± 0.18 [0.00] | 0.10 ± 0.19 [0.00] | 0.736 |
| No. of days | 1.29 ± 4.00 [0.00] | 1.67 ± 4.17 [0.00] | 0.117 | 1.50 ± 4.45 [0.00] | 1.50 ± 4.18 [0.00] | 0.863 |
| No. of days per admission | 10.77 ± 13.70 [5.58] | 11.45 ± 11.66 [7.00] | 0.270 | 12.13 ± 16.01 [6.50] | 11.44 ± 9.98 [7.00] | 0.369 |
| Emergency department visits | ||||||
| Had ≥1 emergency department visit | 39 (13.2) | 55 (18.6) | — | 14 (10.7) | 22 (16.8) | — |
| No. of days with visits | 0.02 ± 0.05 [0.00] | 0.04 ± 0.14 [0.00] | 0.064 | 0.02 ± 0.05 [0.00] | 0.03 ± 0.08 [0.00] | 0.168 |
| Outpatient visits | ||||||
| Had ≥1 outpatient visit | 284 (95.9) | 286 (96.6) | — | 127 (96.9) | 127 (96.9) | — |
| No. of days with visits | 1.57 ± 1.25 [1.34] | 2.16 ± 1.41 [1.92] | <0.001c | 1.61 ± 1.19 [1.42] | 2.19 ± 1.38 [2.01] | <0.001c |
| Pharmacy claims | ||||||
| Had ≥1 pharmacy claims | 173 (58.4) | 252 (85.1) | — | 81 (61.8) | 108 (82.4) | — |
| No. of pharmacy claims | 0.49 ± 0.49 [0.17] | 0.61 ± 0.54 [0.54] | <0.001c | 0.5 ± 0.57 [0.25] | 0.59 ± 0.60 [0.42] | 0.095 |
| Other servicesd | ||||||
| Had ≥1 other service | 1 (0.3) | 2 (0.7) | — | 0 (0.0) | 1 (0.8) | — |
| No. of days with other services | 0.00 ± 0.06 [0.00] | 0.00 ± 0.01 [0.00] | 0.560 | 0.00 ± 0.00 [0.00] | 0.00 ± 0.00 [0.00] | 0.317 |
a The mCSPC disease state was defined as the portion of the up to 12-month period from the date of metastasis until the date prior to patients’ evidence of castration resistance. The mCRPC disease state was defined as the time from the date of castration resistance (index date) until the earliest of (1) 12 months post-index (365 days), (2) end of continuous insurance eligibility, (3) end of data availability, or (4) death (if available).
b Continuous HRU was compared between the mCSPC and mCRPC disease states using Wilcoxon signed rank tests.
c Denotes statistical significance based on a threshold of P < 0.05.
d Other services include medical claims for dental/vision care, durable medical equipment, mass immunization center, and claims at an “other place of service.”
e PC-related HRU and costs were identified with ICD-10-CM code C61 and procedure codes for LHRH or of the following guideline-recommended therapies for mCRPC: androgen ARSIs, chemotherapy, PARP inhibitors, immunotherapy, estrogens, and radiopharmaceuticals.
ARSI = androgen receptor signaling inhibitor; HRU = health care resource utilization; ICD-10-CM = International Classification of Diseases 10th Revision, Clinical Modification ; IQR = interquartile range; LHRH = luteinizing hormone-releasing hormone; LOT = line of therapy; mCRPC = metastatic castration-resistant prostate cancer; mCSPC = metastatic castration-sensitive prostate cancer; PARP = poly ADP-ribose polymerase; PC = prostate cancer; PPPM = per-patient-per-month.
In the subgroup analysis, all-cause inpatient admissions were relatively similar between the two disease states (44.3% and 11.12 days per stay in the mCSPC disease state, 42.7% and 10.04 days per stay in the mCRPC disease state; P = 0.764 for days per stay) (Table 2). Similar to the overall population, 96.9% of patients had a PC-related outpatient visit during both disease states. The number of days with all-cause outpatient visits increased from 2.77 to 3.20 PPPM (P = 0.020), whereas PC-related outpatient visits increased from 1.61 to 2.19 PPPM during the mCSPC and mCRPC disease states (P < 0.001).
HEALTH CARE COSTS
From the mCSPC to mCRPC disease states, mean (median) all-cause total health care costs PPPM increased from $4,424 ($1,569) to $9,717 ($7,622), with all-cause medical costs PPPM increasing from $2,846 ($865) to $4,654 ($1.655), respectively (both P < 0.001) (Figure 3 and Supplementary Table 2 (213.6KB, pdf) ). Mean (median) PC-related total health care costs PPPM increased from $2,859 ($900) in the mCSPC disease state to $8,012 ($6,873) in the mCRPC disease state, with PC-related medical costs PPPM increasing from $1,626 ($490) to $3,285 ($851), respectively (both P < 0.001). Mean (median) PC-related inpatient costs PPPM were $924 ($0) in the mCSPC disease state and $1,031 ($0) in the mCRPC disease state (P = 0.220), whereas PC-related outpatient costs PPPM increased from $685 ($296) to $2,196 ($505), respectively (P < 0.001).
FIGURE 3.
All-Cause and PC-Related Health Care Costs PPPM During the mCSPC and mCRPC Disease Statesa
Similar trends were observed in the subgroup analysis of patients whose disease progressed from mCSPC to mCRPC after 2019 (Figure 3 and Supplementary Table 2 (213.6KB, pdf) ). From the mCSPC to mCRPC disease states, mean (median) PC-related total health care costs PPPM increased from $3,344 ($1,039) to $7,294 ($4,753; P < 0.001), with PC-related medical costs PPPM increasing from $1,470 ($504) to $3,455 ($722), respectively (P = 0.020). Mean (median) PC-related inpatient costs PPPM were $774 ($0) in the mCSPC disease state and $688 ($0) in the mCRPC disease state (P = 0.551), whereas PC-related outpatient costs PPPM increased from $684 ($286) to $2,734 ($425), respectively (P < 0.001).
Discussion
In this retrospective, real-world study of patients whose disease progressed from mCSPC to mCRPC, most patients were inadequately pharmaceutically treated before disease progression to castration resistance, as nearly two-thirds did not receive treatment with any advanced systemic therapies. After onset of castration resistance, all-cause and PC-related total health care costs were 2.2-2.8 times higher, whereas all-cause and PC-related medical costs were 1.5-2 times higher. Similarly, all-cause and PC-related HRU were higher after disease progression to mCRPC, mostly driven by significant increases in outpatient visits. The findings remained robust in the subgroup analysis of patients whose disease progressed from mCSPC to mCRPC on or after 2019. This analysis highlights the substantial economic burden associated with PC disease progression and the unmet need for clinical interventions that may delay this costly progression.
To our knowledge, this is the first study to describe the real-world treatment patterns, HRU, and economic burden of disease progression to castration resistance among mCSPC patients in US clinical practice. By linking clinical information from Flatiron with claims data from Komodo Health, this study was able to identify patients with mCRPC more accurately using medical information that is not typically found in insurance claims. As such, HRU and health care costs could be evaluated in patients with physician-validated progression from mCSPC to mCRPC. This represents an important advantage compared with prior studies in other PC disease stages, which relied solely on claims data to both identify staging and also document changes in economic outcomes as PC progressed.21,22
The impact of PC disease progression on HRU and costs has been evaluated in previous studies, though the majority of prior work evaluated transitions between other stages of PC disease rather than the incremental burden associated with castration resistance specifically among metastatic patients.21,22,30 For instance, Wu et al and Appukkuttan et al conducted separate claims-based studies of commercially/Medicare Supplemental–insured patients whose disease progressed from nmCRPC to mCRPC and found that all-cause HRU was approximately 1.5-2.5 times greater and all-cause health care costs were 4-6 times higher after the onset of metastasis.21,22 In another study using US Veterans Health Administration data, large increases in all-cause HRU and health care costs were observed as Veterans transitioned from pre-nmCRPC to nmCRPC and eventually to mCRPC.30
With regards to the disease progression from mCSPC to mCRPC, a few publications from other countries have assessed cost differences between the mCSPC and mCRPC disease states and have reported 1.6-3.6 times higher health care or medical costs after castration resistance.6,31,32 Although not directly comparable, our cost estimates may be contextualized based on prior US studies evaluating the health care costs of each PC state separately, but interpretation is limited by not examining the same patients whose disease progresses between stages. For patients with mCSPC, Ryan et al conducted a claims-based study and found that all-cause health plan–paid costs were higher than those of the present study, potentially because of the inclusion of patients with various insurance types, including 10.5% with Medicaid coverage, which may reflect a more comorbid population.20 Similarly, for mCRPC, Wu et al and Appukkuttan et al reported higher all-cause health care costs among their respective commercially/Medicare Supplemental–insured population.21,22 This discrepancy may be explained by the fact that less than half of the current study sample had commercial insurance coverage. Indeed, Swami et al evaluated the economic burden of mCRPC among men with Medicare coverage and reported all-cause health care costs of $9,255 PPPM (2020 USD), which is closer to the current estimate.23 Additionally, their PC-related health care costs of $8,295 PPPM were consistent with the current estimate of $8,011 PPPM.23 Together with the prior literature, the present study demonstrates the increased economic burden associated with disease progression to castration resistance among mCSPC patients, but further research specifically evaluating this transition in the United States is warranted to confirm the findings.
The large economic burden associated with disease progression to mCRPC may be related to the limited utilization of advanced therapies during the mCSPC disease state, with more than one-third of patients using any advanced systemic therapy. Abiraterone acetate was approved by the US Food and Drug Administration for the treatment of mCSPC in 2018 and enzalutamide and apalutamide were approved in 2019,33-35 but only 26.0% of patients received ARSIs during the mCSPC disease state in this study. Even when restricting the index date to 2019 or later (ie, following approval of abiraterone acetate, enzalutamide, and apalutamide for mCSPC), this proportion increased to only 38.2%. These findings are particularly noteworthy considering the ample evidence demonstrating better clinical outcomes (including time to castration resistance) with ARSIs plus ADT relative to ADT monotherapy.7-9 Consistently, Ryan et al also observed an underutilization of abiraterone acetate in their claims-based analysis of patients with mCSPC (enzalutamide and apalutamide were not yet approved during their data cut).20 The common use of ARSIs during the mCRPC disease state in this study suggests that physicians are comfortable prescribing these agents, thus signaling an opportunity for earlier use of ARSIs (ie, during the mCSPC disease state) to potentially delay disease progression and reduce the associated management costs. Indeed, HRU and medical costs (and specifically PC-related outpatient costs) increased after disease progression to castration resistance in this study, highlighting the increased reliance on medical care and elevated cost of managing disease progression. Prior studies evaluating costs among patients with mCRPC have also found that costs for hospitalizations and outpatient visits comprise the majority of medical costs.21-23 Thus, reducing the time spent in the mCRPC disease state may help to decrease this HRU and its associated costs overall. Additional real-world research with longer follow-up is warranted to determine if earlier use of ARSIs (ie, during the mCSPC disease state) may delay disease progression and reduce HRU and costs incurred by patients over their entire metastatic disease journey.
LIMITATIONS
The results should be interpreted within the context of some limitations. The Flatiron algorithm used to identify progression to CRPC relied on physician report or observed rise in PSA values. Since testosterone levels were not evaluated, this may have led to some misclassification or reporting inaccuracies. However, this approach likely still increased precision relative to relying solely on claims data to identify progression to CRPC. The study findings may not be generalizable to the entire population of patients with mCSPC or mCRPC, or patients treated in urology practices in the United States, since the data sources represented the community and academic oncology perspective and administrative claims data. Relatedly, the relatively high proportion of patients diagnosed with de novo mCSPC in our study sample (65.2%) may have impacted the generalizability of the results. Despite having a high level of precision, the Datavant Match method used to link the two data sources did not guarantee perfect accuracy in identifying all claims for a patient or all matches. Additionally, since costs were not always available in Komodo Health data (≈30% of claims had missing costs), Komodo imputed missing costs, which may not have represented true costs incurred by payers. Relatedly, caregiver costs and indirect costs (eg, related to loss of productivity) were not available in the data sources. Additionally, the mCSPC and mCRPC disease states were restricted to no more than 12 months each; outcomes may have been different outside of these 12-month periods, especially during end-of-life care for mCRPC. Treatments approved after the study period (eg, triplet therapy, PARP inhibitor combination therapy, lutetium Lu 177 vipivotide tetraxetan) were also not included in the study. Finally, as with all studies using claims data, the information reported depended on correct diagnosis, procedure, and drug codes; therefore, coding inaccuracies may have led to case misidentification.
Conclusions
In this real-world study of patients whose mCSPC progressed to mCRPC in US clinical practice, nearly 2 in 3 patients did not receive treatment with any advanced therapy before progression to castration resistance. Mean all-cause total costs doubled and PC-related total costs increased nearly 3-fold after progression to castration resistance, with a more than 2-fold increase in PC-related medical costs. PC-related inpatient and outpatient visits also increased after progression, and PC-related outpatient costs more than tripled, showing the clinical complexity of managing these patients. Earlier use of ARSIs may delay the costly progression to castration resistance in patients with metastatic PC.
DATA TRANSPARENCY
The authors declare that the data supporting the findings of this study are available within the article and its supplementary information files.
DATA AVAILABILITY STATEMENT
Data that support the findings of this study were used under license from Flatiron Health, Inc., and Komodo Health Solutions. Restrictions apply to the availability of these data, which are not publicly available and cannot be shared. The data are available through request made directly to the data vendor, subject to the data vendor’s requirements for data access.
ACKNOWLEDGMENTS
Medical writing assistance was provided by Christine Tam, MWC, an employee of Analysis Group, Inc., a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, a Johnson & Johnson company, which funded the development and conduct of this study and manuscript.
Funding Statement
This study was funded by Janssen Scientific Affairs, LLC, a Johnson & Johnson company.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data that support the findings of this study were used under license from Flatiron Health, Inc., and Komodo Health Solutions. Restrictions apply to the availability of these data, which are not publicly available and cannot be shared. The data are available through request made directly to the data vendor, subject to the data vendor’s requirements for data access.