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Real-World Treatment Patterns in Patients with Castrate-Resistant Prostate Cancer and Bone Metastases

May 2019 Vol 12, No 3 - Clinical, Original Research
Lonnie Wen, RPh, PhD; Adriana Valderrama, PhD; Mary E. Costantino, PhD; Stacey Simmons, MD
Dr Wen is Deputy Director, Bayer Healthcare Pharmaceuticals, Hanover, NJ; Dr Valderrama was at Bayer Healthcare Pharmaceuticals during this study; Dr Costantino is Senior Healthcare Research Consultant, Humana, Louisville, KY; Dr Simmons is Director of Oncology, US Medical Affairs, Bayer Healthcare Pharmaceuticals.
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BACKGROUND: Prostate cancer is the most frequently diagnosed cancer in men in the United States. There is scant real-world evidence characterizing the care utilization and clinical outcomes associated with the use of therapies currently approved by the US Food and Drug Administration (FDA) for patients with metastatic castrate-resistant prostate cancer (CRPC).

OBJECTIVE: To describe the real-world treatment patterns, healthcare costs, and survival rates of patients with metastatic CRPC and bone metastases who have commercial or Medicare coverage.

METHODS: This retrospective observational study was conducted using medical and pharmacy claims from the Humana research database for male patients who had Medicare or commercial coverage and were aged 55 to 89 years at the initiation of treatment for metastatic CRPC. Three inclusion criteria were used to identify appropriate patients for the 2 cohorts, including (1) a diagnosis of prostate cancer (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 185.x); (2) a diagnosis of bone metastasis (ICD-9-CM code 198.5) between 2013 and 2014; and (3) a healthcare insurance claim indicating a prescription for an FDA-approved first-line treatment for metastatic CRPC. Subsequent lines of treatment were also identified through the healthcare claims data. The 2-year survival rate was calculated and controlled for demographic and clinical characteristics, and the total costs (medical plus pharmacy) were calculated for the 6 months postindex.

RESULTS: A total of 1855 patients met the study inclusion criteria. Of these patients, 660 (35.6%) received at least 1 medication. The patient count by line of treatment was 660 (100%) who received first-line therapy, 380 (57.6%) who received second-line treatment, 204 (30.9%) who received third-line therapy, and 107 (16.2%) who received fourth-line therapy. The medication distribution by line of treatment (using first-, second-, third-, or fourth-line therapy for each drug) was abiraterone acetate (50.5%, 61.3%, 68.6%, 75.7%); enzalutamide (15.6%, 39.2%, 54.4%, 71.0%); sipuleucel-T (9.2%, 13.9%, 20.1%, 20.6%); radium-223 dichloride (1.7%, 2.6%, 7.4%, 13.1%); cabazitaxel (2.3%, 5.5%, 16.2%, 19.6%); and docetaxel (22.1%, 32.1%, 42.6%, 48.6%). The total monthly unadjusted healthcare costs for patients who received an FDA-approved treatment was much higher ($9435) than for patients with metastatic prostate cancer who did not receive an FDA-approved treatment ($5055), and the 2-year survival rate for patients who received an FDA-approved treatment was 57.1% (25th percentile, 250 days; 50th percentile, 541 days).

CONCLUSIONS: The most common first-line treatment for patients with commercial or Medicare coverage who had metastatic CRPC was abiraterone or enzalutamide. Hormone therapies used as monotherapy were the most frequently used treatment, and their concomitant administration with other treatments was the second most common treatment pattern. Additional clinical studies are needed to further elucidate the treatment sequencing for patients with metastatic CRPC.

Key Words: abiraterone acetate, androgen-deprivation therapy, bone metastases, cabazitaxel, docetaxel, enzalutamide, hormone therapy, metastatic castrate-resistant prostate cancer, prostate ­cancer, radium-223 dichloride, real-world treatment, sipuleucel-T

Am Health Drug Benefits.

Manuscript received July 3, 2018
Accepted in final form October 16, 2018

Disclosures are at end of text

Prostate cancer is the most frequently diagnosed cancer in men in the United States, and was the third leading cause of cancer death among men in 2017.1 Regardless of treatment, progression to the metastatic stage of the disease is typically observed in 20% to 30% of cases, for which the standard treatment is androgen-­deprivation therapy (ADT).2 Surgical castration or medical castration through the use of hormone therapy and a castrate level of serum testosterone is the standard for treating metastatic prostate cancer; however, progression of metastatic disease to metastatic castrate-resistant prostate cancer (CRPC) is inexorable.3

Several classes of drugs are approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic CRPC, including chemotherapeutic agents, such as docetaxel (approved in 2004) and cabazitaxel (approved in 2010), and immunotherapies, such as sipuleucel-T (approved in 2010).4 Additional classes of FDA-approved drugs for the treatment of patients with metastatic CRPC include second-generation hormonal therapies that specifically target the androgen receptor axis, such as abiraterone acetate (approved in 2011) and enzalutamide (approved in 2012), as well as a targeted alpha therapy to treat bone metastases in the absence of visceral metastases using radium-223 dichloride (approved in 2013).4

As knowledge regarding the underlying mechanisms that drive the development and progression of prostate cancer has increased, major shifts have occurred in the treatment options for patients with noncastrate metastatic prostate cancer. In particular, the ECOG 3805 (Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer [CHAARTED]) clinical trial in 2015 demonstrated a major overall survival benefit for patients who received concurrent treatment with docetaxel and ADT. The median overall survival was 13.6 months longer with the combination of ADT plus docetaxel than with ADT alone (57.6 vs 44 months).5 Similar survival results were seen in the STAMPEDE trial, which also evaluated the addition of docetaxel to long-term ADT for men with noncastrate metastatic prostate cancer. The median overall survival was 71 months for standard of care only and 81 months with the addition of docetaxel to standard of care.6 The LATITUDE trial, which included 1199 men with newly diagnosed metastatic prostate cancer and was reported in 2017, showed that the addition of the second-generation hormone abiraterone acetate in conjunction with prednisone to long-term ADT significantly increased progression-free survival from 14.8 months with ADT alone to 33 months with the combination therapy.7

These treatment advances in the noncastrate setting have raised the question which treatment options are appropriate in the castrate setting.8,9 To date, scant data are available that describe complete treatment sequencing beyond 2 lines of treatment in the castrate setting; however, partial treatment sequencing has been previously reviewed and described to a limited extent.4,10,11 Evidence suggestive of cross-resistance between hormone therapies and taxanes, and among different hormone therapies when using treatment sequencing, has been reviewed by a working group in the RADAR II study.12

Although the conclusion of the RADAR II consensus panel recommended a layering approach “of approved therapies with unique or complementary mechanisms of action,”12 phase 3 studies evaluating combinations, layering, or sequencing of these agents are needed to help improve clinical outcomes when patients are in the inevitable castrate clinical state. Given that the current guidelines and existing studies do not provide a complete picture of treatment sequencing in the castrate setting, it is necessary to describe treatment sequencing and outcomes in the real-world setting to inform future studies, clinical practice, and management guidelines.

In addition to determining the best layered approach to treatment, understanding the costs of treatment is also pertinent. In a 2014 study of patients with metastatic CRPC using models that included additional lines of treatment before or after docetaxel, such as abiraterone and cabazitaxel, the modeled mean cost of metastatic CRPC treatment during a mean of 28.1 months was ­estimated to be $48,428 per patient.13 Examining the pharmacy costs associated with the disease, a 2015 study by Ellis and colleagues of patients with metastatic CRPC who were newly initiated on hormone therapies demonstrated that the mean monthly pharmacy costs associated with abiraterone were lower than enzalutamide.14 Given that patients may receive multiple lines of therapy and incur ongoing medical services during the course of their disease, it is important to consider all the available treatments to understand the overall medical and pharmacy costs for these patients.

Considering the limited real-world evidence documenting treatment utilization and costs for the FDA-­approved drugs for metastatic CRPC, the goals of this study were to describe the treatment patterns, healthcare costs, and survival rates for patients diagnosed with me­tastatic CRPC and bone metastases using insurance claims–based evidence, and to elucidate the treatment regimens used beyond early lines of treatment.


Data sources for this study included enrollment rec­ords and medical and pharmacy claims from the Humana national research database between January 1, 2012, through June 30, 2015, which included the identification and observation periods for this study. The data in the Humana database included patient demographics and dates of healthcare coverage. The medical claims data included hospital inpatient stays, emergency department visits, and outpatient visits. The diagnosis codes were based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, Current Procedural Terminology (CPT) for tests and procedures, and the Health Care Procedure Coding System (HCPCS) for various procedures (ie, injections). The pharmacy claims data included details of each prescription fill; specific medication by National Drug Code and Generic Product Identifier codes, fill date, quantity dispensed, and days’ supply. Pharmacy claims were used to capture the oral medications only.

Study Sample

This was a retrospective, observational study of patients with metastatic prostate cancer or metastatic CRPC using administrative claims data. For the cohort with metastatic prostate cancer, patients with a diagnosis of bone metastases (ICD-9-CM code 198.5) and a diagnosis of prostate cancer (ICD-9-CM code 185.x) were identified. The patients in the metastatic CRPC cohort were required to have received an FDA-approved treatment for metastatic CRPC (ie, abiraterone acetate, enzalutamide, sipuleucel-T, radium-223 dichloride, cabazitaxel, or docetaxel) between January 1, 2013, and December 31, 2014. The first claim with an indicated agent served as the index date.

Male patients aged 55 to 89 years at the index date who were enrolled in commercial or Medicare plans and had continuous insurance coverage during the study period were included in the study. Continuous health plan eligibility and enrollment during a 12-month preindex observation period were required; patients were then followed for a minimum of 6 months postindex until death or until the study end date, whichever occurred first.

Patients with a diagnosis of any cancer other than prostate cancer before the index date were excluded. The diagnosis of an additional cancer was defined as the presence of 1 inpatient or 2 outpatient claims with a primary or secondary diagnosis of malignant neoplasms other than prostate cancer.

Line of Treatment and Treatment Patterns

The first- to fourth-line of treatment was defined as follows: the first line consisted of an FDA-approved treatment received by the patient after a diagnosis of bone metastases; a new line of treatment was defined as the initiation of a new treatment at least 28 days after the start date of the previous line of treatment. An additional therapy initiated within the 28 days was considered concomitant to the first-line treatment. Information regarding treatments was obtained from pharmacy and medical claims and was used to describe the combinations of concomitant therapies, by the line of treatment. First-, second-, third-, or fourth-line treatment was considered to be the same line of therapy if no gaps of >90 days occurred after the date of the last claim plus the days of supply for oral drugs, and the last date of administration for injectable drugs, which was defined as the termination date for the same treatment.

The number of cycles was calculated for injectable drugs. The discontinuation of only 1 agent from a line of treatment during a later cycle was not counted as a new line of treatment. The mean number of days was reported for each line of treatment. In addition, the average number of prescription fills was calculated for oral medications. The duration of treatment was defined as the last pharmacy prescription fill date plus the days of supply minus the first pharmacy fill date. All prescription fills were normalized to 30 days (ie, prescription fills for a ­60-day supply would count as 2 fills). Prescription fills that occurred toward the beginning or end of the study were monitored, and the data were censored accordingly.

For injectable drugs, the cycle length (ie, number of days) was based on FDA-approved prescribing information for radium-223 dichloride (28 days), sipuleucel-T (14 days), cabazitaxel (21 days), and docetaxel (21 days), and 21 days for all other injectable chemotherapy agents. A length of 21 days was used for all other injectable ­anticancer medications, given that all FDA-approved injectable drugs for prostate cancer are administered every 14 to 28 days.

To determine the specialty of the physicians treating patients enrolled in the study (eg, oncologist, urologist, radiation oncologist), medical claims with a diagnosis of prostate cancer or bone metastasis were evaluated. This method had the potential to yield multiple providers and multiple specialties of those providers for each patient but provided direct evidence of the treating providers. We developed an algorithm based on chart extraction data to identify the provider who was most likely to have administered treatment for metastatic CRPC.

Because of the magnitude of the results when individually calculated, the treatments were grouped by therapy class for the treatment pattern analysis—hormone treatments were abiraterone or enzalutamide; chemotherapy, docetaxel or cabazitaxel; immunotherapy, sipuleucel-T; targeted alpha therapy, radium-223; and “other treatments” were all other therapies, including other chemotherapies. The other chemotherapies included abarelix, anastrozole, bicalutamide, degarelix acetate, doxorubicin, estramustine phosphate, etoposide, flutamide, gose­relin, histrelin, iodine I-131 plus tositumomab, leuprolide acetate, mitotane, nilutamide, paclitaxel, polyestradiol phosphate, teniposide, triptorelin pamoate, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

Because abiraterone and enzalutamide are oral therapies and are reported on pharmacy claims, the mean duration of treatment was calculated based on the dispensing dates recorded in the claims data; however, the duration of treatment for the remaining injectable therapies was measured using HCPCS and CPT codes (for medical claims), resulting in the calculation of the mean treatment cycles.

Survival Analysis

A Cox proportional hazards regression model was used to examine the factors associated with survival for patients with metastatic CRPC. The model controlled for age, geographic region, race, skeletal-related events (ie, spinal cord compression, bone fracture, bone surgery, and radiation to the bone for patients with metastatic CRPC), insurance type, and Klabunde-enhanced Deyo-­Charlson Comorbidity Index score. This score is an ­adaptation of the Charlson Comorbidity Index, which incorporates data from Medicare physician claims into a numerical assessment of comorbidity level.15 The model did not estimate survival by treatment patterns; instead, it looked at the overall survival of the patients, including all factors.


The total healthcare costs were the sum of the health plan–allowed amounts for services identified in the medical and pharmacy claims for all enrolled patients. The total healthcare costs were adjusted to 2015 dollars using the Medical Consumer Price Index and were reported as mean monthly costs. Descriptive analyses (ie, mean, standard deviation, median, and range) were conducted for an unadjusted assessment of healthcare costs by pharmacy, medical, and total (ie, pharmacy plus medical) categories.

All analyses were conducted using SAS Enterprise Guide version 7.1 (SAS Institute Inc; Cary, NC). All statistical tests were two-tailed, with an a priori alpha level of 0.50.


Initially, 7144 patients were identified who might have had administrative evidence of metastatic CRPC and bone metastasis during the study period. More than 50% (N = 3710) of the patients were excluded as a result of a concurrent diagnosis of another cancer before the index date, and 73 were excluded as a result of gaps in insurance coverage. Only patients with Medicare or commercial coverage could be included in the study, which excluded an additional 370 patients. In addition, 6 patients who were miscoded as female were excluded, as well as 1 patient who did not have medical and pharmacy benefits. An additional 871 patients were excluded because they were not continuously enrolled in the insurance program for 12 months before the index date. Finally, 72 patients were excluded because of a lack of plan enrollment 6 months after the index date. These exclusions resulted in a final total cohort size of 1855 patients who were diagnosed with metastatic prostate cancer and bone metastases.

In addition, 660 patients with metastatic CRPC and bone metastases who received treatment with at least 1 FDA-approved drug for metastatic CRPC were identified and were included in the study. Of these 660 patients, only 3% of the cohort had commercial coverage, and the rest had Medicare coverage; therefore, these groups were evaluated together (Table 1), except for the cost data, which were reported separately. The mean age of this cohort was 74.4 years (standard deviation, 7 years). The greatest proportion of these patients resided in the South, and the mean length of time that patients were enrolled in the healthcare plan was 527.7 days. Approximately 33% of patients had a Klabunde Comorbidity Index score of ≥2 and 41.7% of the patients had a score of 0 (Table 1).

Table 1

Line of Treatment

For the 660 patients who received at least 1 FDA-approved treatment for metastatic CRPC, abiraterone had the longest mean duration of treatment (7.24 months), followed closely by enzalutamide, with a mean duration of treatment of 5.39 months (Table 2). The number of mean treatment cycles of docetaxel was 6.6, followed by cabazitaxel at 5.5 cycles. For radium-223, the number of mean treatment cycles was 3.7, and sipuleucel-T had a mean of 2.8 cycles.

Table 2

Of the 660 patients, 409 (61.9%) received abiraterone during the study period, and 284 (69.4%) visited an oncologist. Of the total number (283) of patients who received enzalutamide, 220 (77.7%) were seen by an oncologist. Among the 219 patients who received docetaxel during the study, 122 (55.7%) patients visited an oncologist (Table 3). The patients who received docetaxel, cabazitaxel, or radium-223 did not have a claim from a urologist.

Table 3

Abiraterone was the most frequently used first-line FDA-approved treatment, followed by docetaxel. Enzalutamide (15.6%), sipuleucel-T (9.2%), cabazitaxel (2.3%), and radium-223 (1.7%) were less frequently used as first lines of therapy (Table 4). Across all lines of therapy, abiraterone was the most frequently used FDA-approved treatment, followed by docetaxel and enzalutamide. Sipuleucel-T slowly decreased in frequency from first-line treatment to fourth-line treatment; comparatively, cabazitaxel and radium-223 showed an increase from first- to third-line treatment.

Table 4

In analyzing the treatment patterns across lines of therapy, we found 188 variations, and the top 10 variations accounted for 51% of the total treatments received by patients. Hormone therapy used as a monotherapy was the most frequently (15%) used treatment, and the concomitant administration of hormone therapy with other treatments was the second most common (12%) treatment pattern (Table 5).

Table 5


Of the 1855 patients included in this study, 521 were reported as deceased during the study period. Age and Klabunde Comorbidity Index score were significant (P <.05) factors associated with death in patients with metastatic CRPC (data not shown); as patients’ age increased or as the comorbidity score increased, the likelihood of death increased during the study time period. A total of 57.1% of the patients who received treatment with an FDA-approved treatment survived 2 years after the start of treatment.

Of the 521 deceased patients, only 5 (1%) had been enrolled in a commercial health plan; the majority (99%) were Medicare beneficiaries. The mortality data for the commercially enrolled population might have slightly skewed these survival results, because they are not reliable and could not be removed from the data pool.


The total monthly unadjusted healthcare costs for patients with an FDA-approved treatment for metastatic CRPC was much higher ($9435) than for the patients with metastatic prostate cancer ($5055), as a result of higher mean monthly prescription costs per patient ($4618 vs $1238, respectively; Table 6).

Table 6


The results of this retrospective study using admin­istrative claims data demonstrated that abiraterone, docetaxel, and enzalutamide were the most common FDA-approved treatments prescribed up to the fourth line of treatment in patients with metastatic CRPC. Furthermore, although provider specialty is difficult to measure with pharmacy claims data, our findings show that claims for these 3 treatments were most often associated with claims from oncologists compared with all other specialties. In all, 57.6% of the 660 patients in this study received more than 1 line of treatment (Table 4). The frequent use of abiraterone, enzalutamide, and docetaxel in the first 2 lines of treatment reflects the recommendations provided in the National Comprehensive Cancer Network (NCCN) guidelines; however, the use of these drugs in the third and fourth lines of treatment are indicative of patients receiving other treatments before these hormone therapies.

These findings are consistent with the results of other studies, such as Flaig and colleagues’ 2016 study that showed that after the FDA’s approval of abiraterone and enzalutamide, these drugs were more frequently used than docetaxel in the first line of treatment, and cabazitaxel in the second line of therapy for the treatment of patients with metastatic CRPC.11 In our study, we found 188 different treatment sequences in this cohort of patients, in which more than 50% received either abir­aterone or enzalutamide. This is consistent with the findings by Flaig and colleagues, who demonstrated that abiraterone and enzalutamide were predominantly used as first- and second-line treatments11; however, the large variation in the combinations of treatments suggests that there is a need to understand outcomes for specific sequences, and specific guidelines may be needed for particular groups of patients. Because the NCCN’s guidelines do not specify a preferred sequence for treatment with these agents, providers independently decide treatment sequencing.

Of note, approximately 65% of patients received treatment with novel hormone treatments in the first line of treatment (Table 4). This is a concern, because several studies have been conducted suggesting cross-resistance of abiraterone and enzalutamide.16-19 These studies suggested that the efficacy of enzalutamide is reduced when used after abiraterone in abiraterone-naïve patients. ­Enzalutamide and abiraterone target androgen receptor signaling, but do so through different mechanisms.20,21 In addition, a 2015 study by Azad and colleagues looked at the efficacy of enzalutamide treatment after abiraterone treatment for chemotherapy-naïve patients with metastatic CRPC.22 The study showed that patients who previously received docetaxel had the potential for cross-­resistance between abiraterone and enzalutamide that was not related to the previous docetaxel treatment.22

The higher average monthly healthcare costs for ­patients with metastatic CRPC who receive FDA-­approved agents versus patients with metastatic prostate cancer was expected because of the cost of the treatments examined in this study. Most studies that have examined the cost of metastatic CRPC were published before the release of the new treatments23-25; however, a 2017 study by Pollard and colleagues showed that patients with metastatic CRPC accumulated a mean annual healthcare cost of $92,523, which was significantly more than the $58,036 for patients without metastatic prostate cancer (P = .0001).26 These results are similar to our own observations in this study. In addition, Pollard and colleagues found a comparable survival benefit for patients who received treatment with FDA-approved agents to what we observed (20.1 months and 24 months, respectively).26

With the increasing number of FDA-approved treatments for metastatic CRPC, and those treatments moving early in the treatment paradigm (hormone-­sensitive prostate cancer), defining the optimal sequencing within the treatment plan with the goal of increasing survival27 and improving cost-effectiveness is critical14; however, additional research is needed to make these decisions.


The limitations that are common to studies using administrative claims data apply to this study. ICD-9 codes, specifically for bone metastases, do not always provide a reliable date of diagnosis. A patient may be diagnosed with metastatic disease by the physician, but the claim may not occur until the time of first treatment. The reasons for stopping and starting new treatments cannot be specified within a claims database.

An algorithm for CRPC has not been validated in the literature. In addition, given our definition of lines of treatment, we may have overestimated the number of lines of treatment. For example, if a patient begins radium-223 after 6 weeks of abiraterone therapy, this would be considered second-line treatment, but to the physician this may be a first-line treatment. However, even if we have overestimated the number of lines of treatment, we did capture every treatment that was prescribed during the study period. The duration of treatment might also have been confounded by the short follow-up.

In addition, the study period ending in 2015 might not have allowed the capture of sufficient patients for newer treatments, such as radium-223.

Docetaxel is not exclusively used for the treatment of CRPC.28 It may also be used in the noncastrate setting, although given the time period for this study, most patients with noncastrate disease predated the CHAARTED trial’s publication.29

A lack of certain information in the database (eg, laboratory results, weight, and health behavior information) and errors in claims coding are also limitations of using administrative claims.

Furthermore, the presence of an FDA-approved treatment for metastatic CRPC treatment was used as a proxy to define the cohort of patients with metastatic CRPC. However, without clinical and laboratory information or a physician diagnosis, metastatic CRPC status could not be confirmed. This should be considered when interpreting the study’s results. No causal inference can be ascertained from this study, because it is an observational study using retrospective claims data.

Finally, because this study uses data from Humana members only, the results may not be generalized to the overall population, because Humana serves patients mainly located in the southern region of the United States.


The most common first-line treatment for metastatic CRPC was abiraterone or enzalutamide. Across the 4 lines of therapy, we found almost 200 variations in treatment patterns. Hormone therapies, used as monotherapy, were the most frequently used treatment and their concomitant administration with other treatments was the second most common treatment pattern. This suggests a lack of consensus on the best approach to the treatment of this patient population. Because treatment guidelines do not delineate treatment sequencing for patients with metastatic CRPC, there is a need for additional clinical studies on treatment sequencing for these patients to allow for the development of these necessary guidelines.

Funding Source

This study was funded by Bayer Healthcare Pharmaceuticals, and was conducted by Humana Healthcare Research.

Author Disclosure Statement

Dr Wen is an employee and owns stocks of Bayer Healthcare Pharmaceuticals; Dr Valderrama was an employee of Bayer Healthcare Pharmaceuticals during this study and owns company stocks; Dr Costantino is an employee and owns stocks of Humana; Dr Simmons is an employee and owns stocks of Bayer US.


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Last modified: August 30, 2021