Treatment Sequences and Pharmacy Costs of 2 New Therapies for Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is a leading cause of cancer-related morbidity and mortality in the United States.^1,2 The American Cancer Society estimated that approximately 1 in 7 men will be diagnosed with prostate cancer during his lifetime. Despite important advances in the treatment of prostate cancer, there will be approximately 220,800 new cases in 2015, resulting in approximately 27,540 deaths from the disease.³ Patients with localized prostate cancer may be initially treated with surgery or with radiation therapy.⁴ Disease recurrence occurs in approximately 20% to 30% of patients and can include metastases to other organs.⁵ Typically, androgen-deprivation therapy is prescribed for progressive disease; however, castration resistance or unresponsiveness to androgen-deprivation therapy or to antiandrogens frequently develop over time.²

Historically, treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) was limited to palliative care.⁶ However, recent advances have led to an increase in treatment options that have demonstrated survival benefits in phase 3 clinical trials.⁶ Docetaxel, a taxane approved by the US Food and Drug Administration (FDA) in 2004 for the treatment of patients with mCRPC, has demonstrated a significant impact on survival.^7,8 In the TAX 327 trial, the median survival times for patients receiving docetaxel plus prednisone were 18.9 months (dosed every 3 weeks) and 17.4 months (dosed weekly for 5 of every 6 weeks) compared with 16.5 months in patients receiving mitoxantrone plus prednisone every 3 weeks.⁷ In the Southwest Oncology Group Intergroup protocol 99-16 trial, the median survival of patients with mCRPC who received docetaxel plus estramustine was 17.5 months compared with 15.6 months in patients receiving mitoxantrone plus prednisone (over a maximum of 12 three-week cycles).⁸

The treatment options offering survival benefit for patients with mCRPC (ie, advanced prostate cancer) have expanded in recent years.⁶ Cabazitaxel is a tubulin­binding taxane with antitumor activity in docetaxel­resistant patients.⁹ Given with prednisone, cabazitaxel demonstrated a median overall survival benefit of 2.4 months compared with mitoxantrone plus prednisone (15.1 vs 12.7 months, respectively).⁹ Sipuleucel-T is an active cellular immunotherapy that showed a 4.1-month improvement in median overall survival compared with placebo (25.8 vs 21.7 months, respectively).⁵ Abir­aterone acetate plus prednisone and enzalutamide are 2 oral treatments for mCRPC with different mechanisms of action. Abiraterone acetate, an androgen biosynthesis inhibitor, is a prodrug of abiraterone and the enzyme cytochrome P450 17alpha-hydroxylase, resulting in reduced androgen production in the testes and adrenal glands, and therefore in the prostate tumor.¹⁰

At the time our study was conducted, abiraterone acetate plus prednisone was approved by the FDA for patients who had received previous treatment with chemotherapy and for chemotherapy-naïve patients with mCRPC. Abiraterone acetate plus prednisone was found to have a median overall survival benefit of 3.9 months compared with placebo plus prednisone (14.8 vs 10.9 months, respectively) in patients who had previously received docetaxel,¹⁰ and a median overall survival benefit of 4.4 months compared with placebo plus prednisone (34.7 vs 30.3 months, respectively) in chemotherapy-­naïve patients.¹¹

Enzalutamide belongs to the androgen receptor inhibitor class, of which bicalutamide and flutamide are also members.¹² Androgen receptor inhibitors work by blocking signaling at the androgen receptor. At the time our study was conducted, enzalutamide was indicated by the FDA for patients who had previously received chemotherapy; however, it is now also FDA approved for chemotherapy-naïve patients. Compared with placebo, the use of enzalutamide led to a 4.8-month improvement in median overall survival (18.4 vs 13.6 months, respectively) in patients who previously received chemotherapy,¹² and a 4-month improvement in median overall survival (35.3 vs 31.3 months, respectively) in chemotherapy­naïve patients.¹³

Patients treated with abiraterone acetate plus prednisone receive 1000 mg of abiraterone acetate once daily in combination with 5 mg of prednisone twice daily.¹⁴ Patients treated with enzalutamide receive 160 mg of enzalutamide once daily.¹⁵

The recent introduction of new treatment paradigms has provided physicians with greater options to treat ­patients with mCRPC, and has altered the historical treatment patterns that were established with docetaxel.⁶ In their recent literature review on treatment sequencing for patients with mCRPC based on clinical trial evidence for docetaxel, cabazitaxel, sipuleucel-T, abiraterone acetate, enzalutamide, and radium Ra 223 dichloride, Sartor and ­Gillessen emphasized that there is still little known about the real-world sequencing of the new therapies in mCRPC and their potential optimal sequences.¹⁶ They identified a need for additional data, particularly in the post–­abiraterone acetate and post–enzalutamide settings.¹⁶

Because the costs of treating cancer are an increasing public concern¹⁷ and can be impacted by treatment sequences, it has become important to identify sequences in which new agents are utilized. Using 3 healthcare claims databases, the present study aimed at identifying, in a real-world setting, the sequences in which abir­aterone acetate and enzalutamide are most often used with respect to one another and to other treatments for mCRPC, along with their associated treatment costs.

Methods
Data Source
Three separate databases were used to conduct the analysis—Symphony Health Solutions’ Patient Transactional Datasets (data set 1), the IMS PharMetrics Plus database (data set 2), and the Truven Health Market­Scan^® Research Databases (data set 3); data used were from June 2009 to October 2013, January 2010 to October 2013, and January 2005 to July 2014, respectively.

The Symphony Health Solutions database is comprised of US pharmacy and medical claims submitted by approximately 30,000 pharmacies, 1000 hospitals, 800 outpatient facilities, and 80,000 physician practices. Compared with other claims data sources representing commercially insured populations (eg, data sets 2 and 3 described below), this Symphony Health Solutions database includes claims from patients participating in commercial health plans, as well as a large proportion of claims from patients participating in public insurance programs (eg, Medicaid and Medicare). This database contains approximately 4.8 billion prescription claims representing more than 190 million patients receiving unique prescriptions. Medical claims with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes are linked to nearly 91 million patients in the database receiving prescription drugs.

The IMS PharMetrics Plus database is comprised of adjudicated claims for more than 150 million unique enrollees across the United States. Enrollees with medical and pharmacy coverage in 2012 represent 40 million active lives. The metropolitan statistical areas of the United States are represented, with data coverage from 90% of US hospitals and 80% of all US doctors, and representation from 85% of the Fortune 100 companies. This database notably contains information on inpatient and outpatient diagnoses and procedures, retail and mail order prescription records, and detailed information on pharmacy and medical benefits (ie, copayment and deductible). Because of the broad reach of the data, patients in the IMS PharMetrics Plus database are similar to the national commercially insured population in terms of age and sex for persons aged ≤65 years.

The Truven Health MarketScan Research Databases combines 2 separate databases—the Commercial Claims and Encounters database, and the Medicare Supplemental and Coordination of Benefits database—to cover all age-groups. These databases contain claims from approximately 100 employers, health plans, and government and public organizations, representing approximately 30 million covered lives. All census regions are represented, but the South and North Central (Midwest) regions of the United States are predominant.

The data elements used in the present study include health plan enrollment and clinical activity records, participant demographics, inpatient and outpatient medical services, and outpatient prescription drug dispensing records.

All data collected from each database were deidentified in compliance with the patient confidentiality requirements of HIPPA (the Health Insurance Portability and Accountability Act).

Study Design
A retrospective longitudinal study design was used, and patients with prostate cancer who received abir­aterone acetate or enzalutamide therapy from September 1, 2012, to October 31, 2013, for data sets 1 and 2, and to July 31, 2014, for data set 3, were selected to form the study population. The date of the first dispensing of abiraterone acetate or enzalutamide after September 1, 2012 (the first date when abiraterone acetate and enzalutamide were both commercially available in the United States) was identified as the index date.

Enrolled patients were also required to have at least 1 diagnosis of prostate cancer (ICD-9-CM, 185.xx) within 12 months before the index date, be aged ≥18 years, and have at least 12 months of continuous clinical activity (data set 1) or continuous eligibility (data sets 2 and 3) before the index date. Patients with exposure to abir­aterone acetate or to enzalutamide before September 2012 and patients with a diagnosis for another type of cancer (ICD-9-CM, 140.xx-184, 186.xx-195, 200.xx-209.xx) in the year before the index date were excluded from the study.

In each database, patients were separated into 2 cohorts based on their first dispensing of abiraterone acetate or enzalutamide. The observation period spanned from the index date to the earliest between the end of clinical activity or eligibility, or the data cutoff date. The information recorded in the 12 months before the first dispensing of abiraterone acetate or enzalutamide was used to evaluate the patients’ baseline characteristics.

Study End Points
The treatment sequencing of therapies for patients with mCRPC during the observation period was reported. Treatment sequences were defined as successive lines of therapies for mCRPC that were stratified into chemotherapy (which was further stratified into docetaxel, cabazitaxel, or other chemotherapies), immunotherapy (sipuleucel-T), and oral agents (abiraterone acetate or enzalutamide).

The lines of therapy were defined, using a common convention,^18,19 as the period starting from the date of the first claim for a type of therapy and up to either 90 days without treatment with that therapy, a claim for a different therapy, or the earliest of the end of eligibility or data availability.

Patients who were receiving corticosteroids were identified. Payers’ costs for treatment with abiraterone acetate or enzalutamide were also reported.

Statistical Analysis
Descriptive statistics were used to summarize the baseline characteristics and treatment sequences. Frequency counts and percentages were used to summarize the categorical variables, and means and standard deviations were used for the continuous variables. The treatment sequences were identified for each patient and were then aggregated and reported for each data set.

Of note, because of the descriptive nature of the study, parametric tests or nonparametric tests assessing the statistical inference between treatment sequences were not conducted. Nonetheless, statistical significance was assessed for costs through a Wilcoxon rank-sum test and through a Pearson’s chi-square test for counts of patients receiving corticosteroids. All costs were inflation­adjusted to 2014 US dollars based on the medical care component of the Consumer Price Index.

Results
A total of 3525 patients from data set 1 (2611 patients receiving abiraterone acetate and 914 receiving enzalutamide as first-line therapies), 499 patients from data set 2 (407 receiving abiraterone acetate and 92 receiving enzalutamide as first-line therapies), and 1949 patients from data set 3 (1568 receiving abiraterone acetate and 381 receiving enzalutamide as first-line therapies) were selected (Figure 1).

Table 1 presents the baseline characteristics for patients receiving first-line abiraterone acetate or first-line enzalutamide, as well as the overall population of each data set. The mean patient ages were 72.9 years in data set 1, 67.5 years in data set 2, and 73.0 years in data set 3. The proportions of patients participating in a public insurance program (Medicaid or Medicare) were different across the data sets; 61.8% of patients from data set 1 had healthcare claims reimbursed through such a program compared with 12.2% and 75.0% of patients, from data sets 2 and 3, respectively.

As expected, hormone treatment for prostate cancer was reported for most patients, 90.2% in data set 1; 95.4% in data set 2; and 96.2% in data set 3. Few patients had treatment with chemotherapy in the preindex period—18.2% of patients in data set 1 (abiraterone acetate, 14.6%; enzalutamide, 28.6%); 27.5% of patients in data set 2 (abiraterone acetate, 21.4%; enzalutamide, 54.3%); and 21.9% in data set 3 (abiraterone acetate, 19.3%; enzalutamide, 32.5%). Overall, 5.4%, 14.2%, and 11.6% of patients from data sets 1, 2, and 3, received sipuleucel-T, respectively.

Observed Lines of Therapy
Most patients received only 1 line of therapy during the observation period (ie, the index date to data cutoff or loss to follow-up). As shown in Table 2, a single line of therapy was observed in 86.8% of patients overall (abiraterone acetate, 64.3%; enzalutamide, 22.5%) in data set 1, in 80.4% (abiraterone acetate, 66.7%; enzalutamide, 13.6%) of patients in data set 2, and in 69.6% (abiraterone acetate, 55.3%; enzalutamide, 14.4%) of patients overall in data set 3.

A second-line therapy was observed in a subset of patients (13.2% of patients from data set 1, 19.6% from data set 2, and 30.4% from data set 3).

The average observation duration times were 212 days, 165 days, and 275 days for data sets 1, 2, and 3, respectively.

Treatment Sequences
Figure 2 illustrates the proportion of patients who started first-line therapy with abiraterone acetate or with enzalutamide in each data set. The majority of patients were initiated with abiraterone acetate as the first-line agent (74.1% of patients from data set 1, 81.6% of patients from data set 2, and 80.5% of patients from data set 3). Table 2 presents the distribution of first-line and subsequent-line treatment sequences observed from the data.

Across all data sets, abiraterone acetate was the most frequently prescribed agent in patients receiving a single line of therapy. Multiple lines of therapy were prescribed in 13.2%, 19.6%, and 30.4% of patients in data sets 1, 2, and 3, respectively. In patients receiving multiple lines of therapy, the most common treatment followed by a second-line treatment sequence was abiraterone acetate followed by enzalutamide, which occurred in 5.0% of patients from data set 1, 5.2% of patients from data set 2, and 12.4% of patients from data set 3.

Corticosteroid Use and Costs
Table 3 shows the observed concomitant use of corticosteroids and the related costs. The concomitant use of corticosteroids was observed in all cohorts (81.2% of patients receiving first-line abiraterone acetate and 32.1% of patients receiving first-line enzalutamide in data set 1; 86.2% of patients receiving first-line abir­aterone acetate and 38.0% of patients receiving first-line enzalutamide in data set 2; and 86.4% of patients receiving first-line abiraterone acetate and 33.6% of patients receiving first-line enzalutamide in data set 3).

The monthly pharmacy payer cost of abiraterone acetate therapy was significantly lower than the monthly cost to payers of enzalutamide therapy in all 3 data sets ($5756 for abiraterone acetate vs $6879 for enzalutamide in data set 1; $6171 for abiraterone acetate vs $7549 for enzalutamide in data set 2, and $6412 for abiraterone acetate vs $7661 for enzalutamide in data set 3; P <.0001 for all data sets).

Discussion
Based on healthcare claims data, this large retrospective analysis of the use of abiraterone acetate and enzalutamide with 3 different commercially available databases reveals that a large majority of patients (approximately 87%, 80%, and 70% in data sets 1, 2, and 3, respectively) received only a single line of therapy during an observation period of 13 to 22 months. The majority of patients receiving a single line of therapy received abiraterone acetate. Among patients with 2 or more lines of treatment, the most frequent sequence observed was first-line abiraterone acetate followed by enzalutamide.

Chemotherapy treatment before the use of an oral agent was observed infrequently; however, a higher proportion of patients receiving first-line enzalutamide in this study had a history of chemotherapy use during most of the study period, which is consistent with enzalutamide’s indication.

To our knowledge, this study is one of the first to investigate the real-world sequencing of oral therapies for mCRPC in a broad population of patients.

With the addition of several new treatment options for patients with mCRPC, including, but not limited to, abiraterone acetate and enzalutamide, the possible treatment-sequencing options for patients with mCRPC have exponentially expanded. Several institutions and individual physicians have tried to provide guidance on treatment sequences based on clinical experience or on literature reviews^4,6,20-26; a consensus among these reviews is the need to better understand real-world practices and the associated outcomes to identify the optimal treatment sequence for patients with mCRPC, taking into consideration patient status, such as clinical characteristics, prostate cancer stage and progression criteria, comorbidities, and concomitant medication use.^22,27

Although this research does not provide information about why physicians or patients selected certain medication sequences, multiple considerations clearly exist. Clinical guideline recommendations, such as those provided by the National Comprehensive Cancer Network (NCCN), are a primary resource available to guide treatment selection.⁴ The current guidelines by the NCCN do not discriminate in the sequence for which abiraterone acetate plus prednisone or enzalutamide should be utilized; however, it is well known that providers do not necessarily adhere to the guidelines as strictly as they are written.²⁸

Indeed, a physician may identify treatments for a given patient based on familiarity or experience with a particular medication or medication class, or based on differences in mechanisms of action between several possible treatments (eg, an androgen biosynthesis inhibitor vs an androgen receptor inhibitor in the cases of abiraterone acetate and enzalutamide, respectively).

From a physician’s perspective, treatment sequencing for mCRPC may be considered as a strategy for managing the effects of cross-resistance between treatments for mCRPC, particularly among taxanes (eg, docetaxel and cabazitaxel) and androgen inhibitors.²⁹ The physician’s treatment sequence selection observed in this study may be influenced by real-world exploratory or pilot studies suggesting that enzalutamide may demonstrate clinical benefit in patients who do not respond to chemotherapy and to treatment with abiraterone acetate.^30,31 Furthermore, with limited understanding of the optimal sequential treatments related to specific patient outcomes, and with uncertainty regarding timing optimization to avoid the effects of cross-resistance, physicians may opt for a single-line treatment for patients with mCRPC. Additional phase 3 trials may provide more information on physicians’ prescribing of treatment.³²

The clinical characteristics and preferences of patients, and physicians’ assessment of the risk–benefit profile for patients’ respective therapies may also impact the order in which a treatment is given.²⁰ Corticosteroids have long been used to treat the symptoms of prostate cancer, and concomitant corticosteroid use is not required in patients receiving enzalutamide.¹⁵ Real-world evidence from our study shows that nearly 40% of patients receiving enzalutamide concomitantly received corticosteroids.

Finally, in some cases, the economic considerations imposed by insurance reimbursement and/or by a patient’s financial status may impact the treatment sequences selected. Previous studies have assessed the cost-effectiveness of therapies for mCRPC in chemotherapy-refractory and chemotherapy-naïve patients, and have concluded that abiraterone acetate is a cost­effective treatment option.^33-35 By contrast, our study demonstrates that treatment with abiraterone acetate results in significantly lower pharmacy costs than treatment with enzalutamide.

Limitations
Our study is subject to several limitations. As is the case with claims databases, the Symphony Health Solutions’ Patient Transactional Datasets, the IMS Phar­Metrics Plus database, and the Truven Health Market­Scan Research Databases may have contained in­accuracies or omissions in procedures, diagnoses, or costs, and no information was provided as to whether the medication was taken as prescribed. There is potential for the 3 data sets to overlap, but the actual overlap cannot be determined, because the databases are not linked. In addition, the 3 databases used in this study are not completely comparable: data set 1 is transactionally based and reflects a higher proportion of patients covered under public insurance programs than data sets 2 and 3, which are insurance based.

Instead of combining the data sets, this analysis was conducted on each data set separately. Data set 1 may not contain records on some prescriptions or healthcare services that were processed through different claims transaction networks. Because of this particularity, an apparent treatment interruption observed in the data may, in fact, be a patient receiving healthcare services outside of the networks that were not captured in the database.

For data set 2, the small sample size may limit the generalizability of the findings, particularly within the subgroups. Even though the prevalence of prostate cancer has a definite racial influence, which might have impacted the study population,³⁶ the ethnicity distribution was not presented here, because data sets 2 and 3 were lacking the necessary information to do so. Nevertheless, it is unclear if ethnicity distribution has an influence on treatment sequencing in this patient population.

Finally, the treatment-sequencing analysis was limited to the described agents of interest (abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, or sipuleucel-T) after enzalutamide became available (in September 2012), and had a limited observation period that may not have been sufficient to capture sequences of treatment that may be used over multiple years. Future research may include other agents used for prostate cancer treatment and a longer follow-up period. However, the consistency of the results across these 3 distinct databases adds to the validity and robustness of the study results.

Conclusions
In this large retrospective study, most patients with mCRPC received abiraterone acetate or enzalutamide before the use of chemotherapy. This study also revealed that in a vast majority of cases, patients received monotherapy over the study period, with abiraterone acetate being the most common first-line agent. The concomitant use of a corticosteroid was frequently observed in the abiraterone acetate and the enzalutamide groups. Moreover, patients receiving abiraterone acetate had significantly lower monthly treatment costs than patients receiving enzalutamide. These results can provide useful insights on real-world treatment sequencing for patients with mCRPC who receive abiraterone acetate or enzalutamide.

Funding Source
This research was funded by Janssen Scientific Affairs.

Author Disclosure Statement
Dr Ellis is an employee of Janssen Scientific Affairs, and a stockholder of Johnson & Johnson. Ms Lafeuille, Dr Gozalo, Mr Pilon, and Mr Lefebvre are employees of Groupe d’analyse, Ltée, a consulting company that has received research grants from Janssen Scientific Affairs. Dr McKenzie is an employee of Janssen Scientific Affairs, and a stockholder of Johnson & Johnson.

Dr Ellis is Associate Director, Health Economics and Outcomes Research, Janssen Scientific Affairs, Horsham, PA; Ms Lafeuille is Senior Economist, Groupe d’analyse, Ltée, Montréal, Québec, Canada; Dr Gozalo is Economist, Groupe d’analyse, Ltée, Montréal, Québec, Canada; Mr Pilon is Economist, Groupe d’analyse, Ltée, Montréal, Québec, Canada; Mr Lefebvre is Vice President, Groupe d’analyse, Ltée, Montréal, Québec, Canada; Dr McKenzie is Senior Director, Health Economics and Outcomes Research, Janssen Scientific Affairs, Horsham, PA.

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