If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Real-World Prostate-Specific Antigen Response and Treatment Adherence of Apalutamide in Patients With Non-Metastatic Castration-Resistant Prostate Cancer
To describe prostate-specific antigen (PSA) response and treatment adherence, overall and stratified by race, for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide.
Methods
Electronic medical records representing 63 urology practices from the United States were used to conduct this study. Patients with ≥2 apalutamide prescription fills and ≥12 months of prior prostate cancer management were identified. Patients were followed from apalutamide initiation until a switch to another antineoplastic treatment, death, or end of data availability (October 4, 2019). PSA response (≥50% decline from baseline PSA) and apalutamide adherence rates are described for the overall nmCRPC population treated and also stratified by race (Black and non-Black cohorts).
Results
Overall, 193 patients with nmCRPC were initiated on apalutamide. Thirty-three patients were Black (17.1%), 138 were non-Black (71.5%), and the remaining had an unknown racial background. The mean baseline PSA level for the overall, Black, and non-Black cohorts, was 7.0 ng/mL, 10.5 ng/mL, and 5.6 ng/mL, respectively. At 12 months of follow-up, PSA response was 86.0%, 93.1%, and 85.9% for the overall, Black, and non-Black cohorts, respectively. During a mean follow-up period of 333 days, 352 days, and 326 days, adherence was 93.6%, 90.1%, and 94.5% for the overall, Black and non-Black cohorts, respectively.
Conclusion
This real-world study of patients with nmCRPC initiated on apalutamide showed that PSA response was robust and consistent with clinical trial data. Moreover, both Black and non-Black patients demonstrated high treatment adherence.
Prostate cancer (PC) is the most prevalent cancer among men and it is the second most common cause of death in men in the United States (US).
Historically androgen deprivation therapy (ADT) has been the standard of care for patients with PC, however, over time most men become resistant to the treatment and develop castration-resistant prostate cancer (CRPC).
although prior to advancing to metastatic disease, PC progresses to non-metastatic CRPC (nmCRPC). Apalutamide, a next-generation androgen signaling inhibitor, has been studied in the phase III randomized, placebo-controlled SPARTAN trial in patients with nmCRPC who were at a high risk of developing metastasis.
Based on that study, which demonstrated that metastasis-free survival and time to progression of symptoms were significantly longer for patients treated with apalutamide vs placebo, apalutamide was approved by the US Food and Drug Administration for treatment of nmCRPC in February 2018.
630P Apalutamide for non-metastatic castration resistant prostate cancer (nmCRPC): a comparison of real-life experience from an international named patient program (NPP) vs the prior phase III clinical study (Abstract).
Additionally, the benefits of apalutamide stratified by race is unknown. Considering some studies suggesting that there are potentially different characteristics of PC and molecular responses based on race, there is an impetus to further examine this possibility.
To help address this knowledge gap, this study was conducted to describe the real-world prostate-specific antigen (PSA) response, treatment patterns, and adherence in men with nmCRPC, stratified by race (ie, Black vs non-Black) across urology practices in the US.
MATERIALS AND METHODS
Data Source
Electronic medical records (EMR) data from the PPS Analytics database were used in this study. PPS Analytics integrated EMR data collected as part of routine clinical care from 95 large urology practices throughout the US. The practices serve a diverse spectrum of patients from a variety of regions (eg, urban and rural areas). EMR data included information on patient demographics and the following clinical variables: an indicator for the date of CRPC diagnosis, prescriptions (eg, use of PC therapies and concomitant medications), and results of laboratory assessments (eg, PSA, testosterone). Most of the urology practices (63 of 95) had additional information on next-generation androgen signaling inhibitor medications dispensed to patients. This study used de-identified retrospective data in compliance with the patient requirements of the Health Insurance Portability and Accountability Act of 1996. Therefore, institutional review board approval was not required.
Study Design
A retrospective longitudinal cohort design was used in this study. The index date was defined as the date of the first apalutamide prescription following a CRPC diagnosis without prior bone metastasis. Baseline characteristics (ie, demographics, treatments, laboratory assessments) were evaluated over the 12-month period that preceded the index date (ie, baseline period). Study outcomes were assessed from the index date until the end of data availability (October 4, 2019), a switch to another first next-generation androgen signaling inhibitor (if prior to metastatic involvement), or death, whichever occurred first (ie, follow-up period).
Sample Selection and Study Cohorts
A randomly selected sample of 1000 patients with advanced PC who had ≥1 apalutamide prescription were provided by PPS Analytics. Patients were eligible for inclusion in the current study if they received care at one of the 63 clinics with information on next-generation androgen signaling inhibitor medications dispensed to patients. Patients were required to have ≥2 dispensations for apalutamide on or after February 14, 2018 (ie, the date apalutamide received approval by the US Food and Drug Administration for nmCRPC
). The requirement for ≥2 dispensations of apalutamide was used as a proxy to confirm the use of the previous dispensing. Additionally, patients were required to have a CRPC diagnosis based on the presence of 2 consecutive increases in PSA while receiving continuous luteinizing hormone-releasing hormone therapy for ≥6 months prior to the index date.
Patients were excluded if they were: female, under 18 years of age at the index date, prescribed an additional next-generation androgen signaling inhibitor (ie, enzalutamide, abiraterone acetate, darolutamide) on the index date, or had evidence of bone metastasis prior to the index date.
Patients from the 32 practices that did not have dispensing information on next-generation androgen signaling inhibitor medications, including apalutamide, were excluded from the study because it would not be possible to confirm if the patient filled a prescription and assess adherence and persistence metrics from the clinical data alone. Supplemental Table 1 summarizes baseline characteristics of patients from practices with and without dispensing information.
Baseline Characteristics
Baseline patient demographics included age, race, year of CRPC diagnosis, treatment initiation (ie, index date), prior luteinizing hormone-releasing hormone treatment, and test results (ie, PSA, PSA doubling time, and testosterone). PSA doubling time was calculated for all patients with ≥3 PSA measures any time prior to and including the index date. Baseline PSA doubling time was used as a marker for poor prognosis, with shorter doubling times (ie, <10 months) indicating an increase in disease severity.
Study Outcomes
PSA response was assessed during the follow-up period among patients with ≥1 PSA measurement during the baseline period and one measurement during the first 6-months or first 12-months of the follow-up period. A rising PSA was defined as a current PSA value that was higher than the previous PSA value. The PSA response was defined as ≥50% decline from the most recent PSA level assessed during the baseline period (including index date) to any PSA measurement during the first 6-months or 12-months of the follow-up period. Bone metastasis was assessed during the entire follow-up period.
During the follow-up period, apalutamide treatment patterns were assessed, including continuous treatment duration, as well as adherence (ie, medication possession ratio [MPR], proportion of days covered [PDC]) and persistence. Continuous treatment duration was defined as the time from the date of the first filled prescription to the last day of supply before a gap of ≥90 days. MPR was defined as the number of days of supply (ie, the number of days a prescription was supposed to last) within the entire exposure to therapy (ie, the number of days between the date of the first prescription fill [the index date] and the last prescription refill plus the number of days of supply of the last refill). The MPR was calculated as the sum of the days of supply divided by the exposure to therapy. The proportion of patients with an MPR ≥80%, which is typically considered the threshold for adherence,
was also reported. The PDC assessed the number of calendar days that were covered by a prescription within a pre-determined period of time following treatment initiation (ie, 6 and 12 months). During each time interval, the PDC was calculated as the sum of non-overlapping days of supply divided by the length of the time interval. Patients were required to have complete follow-up during the time period to be included in each PDC calculation. The proportion of patients with PDC ≥80% at each time point was also reported. Persistence to treatment was assessed as the proportion of patients who did not have a specific gap in treatment (ie, >45 or 90 days) within a fixed period of time (ie, 6 and 12 months) following the index date. Treatment gaps were assessed from the end of the days of supply of the previous prescription to the earliest of the next prescription or the end of data availability. Patients were required to have complete follow-up data during the time period to be included in each persistence calculation.
Statistical Analysis
All analyses were descriptive; no hypothesis testing was performed. Study measures and outcomes were summarized using means, standard deviations (SD), and medians for continuous variables; categorical variables were reported using frequencies and proportions.
Subgroup analyses were performed to assess outcomes among Black patients and non-Black patients (ie, white, Hispanic, Asian). All analyses were performed using SAS Enterprise Guide 7.1 (Cary, NC).
RESULTS
Baseline Characteristics
A total of 193 patients with nmCRPC met all inclusion criteria and were included in the analysis (Supplementary Fig. 1). Of these patients, 33 were Black (17.1%), 138 were non-Black (71.5%), and the remaining 22 (11.4%) patients had an unknown racial background (Table 1). In the overall cohort, most patients (n = 146; 75.6%) were between 71 and 90 years of age at the index date. Mean baseline PSA levels (ng/mL) were 7.0, 10.5, and 5.6 among patients in the overall (n = 190), Black (n = 33), and non-Black (n = 135) cohorts, respectively. The mean PSA doubling time was similar across cohorts (10.1-10.8 months). Mean testosterone levels (ng/dL) were 16.3, 15.1, and 17.3, among patients in the overall (n = 146), Black (n = 22), and non-Black (n = 105) cohorts, respectively. Hypertension was the most prevalent comorbidity and was observed among 43 (22.3%), 9 (27.3%), and 29 (21.0%) patients in the overall, Black, and non-Black cohorts, respectively.
Table 1Baseline characteristics of apalutamide patients
The most recent test result during the baseline period (including tests occurring on the index date) was used to calculate the time from the last test result to index date.
PSA doubling time was calculated as the natural log of 2 divided by the slope of the linear regression of log PSA vs time. All PSA values (≥2 ng/dL) in the maximum of 2 y following the nadir or between the nadir and the end of continuous ADT were included in the regression model.
Nadir was defined as the lowest PSA value following both a prostate cancer diagnosis and either continuous ADT, a bilateral orchiectomy, or castration levels of testosterone. If patients experienced continuous ADT, castrate levels of testosterone, and/or a bilateral orchiectomy, the nadir was defined based on the following hierarchy: (1) bilateral orchiectomy, (2) continuous ADT, and (3) castrate levels of testosterone.
The most recent test result during the baseline period (including tests occurring on the index date) was used to calculate the time from the last test result to index date.
The most recent test result during the baseline period (including tests occurring on the index date) was used to calculate the time from the last test result to index date.
85.2 ± 72.0 [74.5]
131.5 ± 46.0 [131.5]
87.2 ± 75.6 [72.0]
CT scan, n (%)
100 (51.8)
20 (60.6)
65 (47.1)
Time from index date to last scan, days, mean ± SD [median]
The most recent test result during the baseline period (including tests occurring on the index date) was used to calculate the time from the last test result to index date.
87.1 ± 93.7 [43.0]
72.7 ± 69.6 [54.0]
92.7 ± 103.4 [43.0]
PET scan, n (%)
33 (17.1)
5 (15.2)
26 (18.8)
Time from index date to last scan, days, mean ± SD [median]
The most recent test result during the baseline period (including tests occurring on the index date) was used to calculate the time from the last test result to index date.
Prior ADT use was assessed at any prior to the index date, including time before the start of the baseline period.
† Index date was defined as the first prescription for apalutamide, on or after February 14, 2018.
‡ Evaluated during the 12-mo baseline period, including the index date.
§ Evaluated as the mean of mean test values for each patient.
║ Rising PSA was defined as the current PSA value that was higher than the previous PSA value.
¶ The most recent test result during the baseline period (including tests occurring on the index date) was used to calculate the time from the last test result to index date.
# PSA doubling time was calculated as the natural log of 2 divided by the slope of the linear regression of log PSA vs time. All PSA values (≥2 ng/dL) in the maximum of 2 y following the nadir or between the nadir and the end of continuous ADT were included in the regression model.
^ Nadir was defined as the lowest PSA value following both a prostate cancer diagnosis and either continuous ADT, a bilateral orchiectomy, or castration levels of testosterone. If patients experienced continuous ADT, castrate levels of testosterone, and/or a bilateral orchiectomy, the nadir was defined based on the following hierarchy: (1) bilateral orchiectomy, (2) continuous ADT, and (3) castrate levels of testosterone.
The proportion of patients with PSA assessments during the follow-up period are illustrated in Supplementary Figure 2. Within 3 months of the index date, PSA measurements were observed among 151 (78.2%), 25 (75.8%), and 114 (82.6%) patients in the overall, Black, and non-Black cohorts, respectively. Within 6 months of the index date, PSA measurements were observed among 176 (91.2%), 29 (87.9%), and 126 (91.3%) patients in the overall, Black, and non-Black cohorts, respectively. Across all 3 patient cohorts, the mean number of PSA tests during the follow-up period was 3.8 (Supplementary Fig. 3). Mean PSA levels (ng/mL) during the follow-up were 4.3, 3.2, and 4.0 among patients in the overall, Black, and non-Black cohorts, respectively. During the first 12 months of the follow-up period, a PSA response was observed among 86.0%, 93.1%, and 85.9% of patients in the overall, Black, and non-Black cohorts, respectively (Fig. 1). During the entire follow-up period, bone metastasis was observed among 6 patients (3.1%), 1 patient (3.0%), and 5 patients (3.6%) in the overall, Black, and non-Black cohorts, respectively.
Figure 1PSA Response Rates during the Observation Period1,2,3 PSA = prostate-specific antigen. Notes: (1) Observation period was defined as the time from the index date to end of data availability (October 4, 2019), switch to another first- or next-generation androgen signaling inhibitor (if prior to metastatic involvement), or death, whichever is earliest. Follow-up PSA tests exclude those evaluated at the index date. (2) PSA response was defined as a decline of 50% or more from the last PSA identified in the 12-mo baseline period (including index date). (3) Denominator included only those patients with both a baseline and follow-up PSA value. (Color version available online.)
Treatment patterns were assessed over a mean of 333 days, 352 days, and 326 days among the overall, Black, and non-Black cohorts, respectively (Table 2). During the follow-up period, the mean duration of apalutamide treatment was 259 days, 282 days, 251 days, among the overall, Black, and non-Black cohorts, respectively, with a treatment gap (ie, duration of time treatment was not taken) of >90 days. The mean MPR was 93.6%, 90.1%, and 94.5%, among the overall, Black, and non-Black cohorts, respectively. A total of 167 (86.5%), 26 (78.8%), and 122 (88.4%) patients in the overall, Black, and non-Black cohorts, respectively, had an MPR ≥80%. Among patients with ≥6 months of follow-up, the PDC evaluated at 6 months was 83.3%, 81.4%, and 84.2%, among the overall (n = 153), Black (n = 27), and non-Black cohorts (n = 108), respectively. Among patients with ≥12 months of follow-up, the PDC evaluated at 12 months was 75.3%, 76.9%, and 74.8%, among the overall (n = 102), Black (n = 19), and non-Black cohorts (n = 70), respectively.
Treatment duration was defined as the time from the date of the first index medication prescription filled to the last day of supply before a gap greater than the indicated number of days.
The MPR was defined as the sum of the days of supply of the index medication divided by the number of days between the first filled prescription and the last filled prescription plus the days of supply of the last filled prescription.
PDC was defined as the sum of non-overlapping days of supply divided by fixed time periods of 6 and 12 mo.
MPR
MPR, %, mean ± SD [median]
93.6 ± 11.7 [100]
90.1 ± 13.8 [96.8]
94.5 ± 11.0 [100]
MPR ≥80%, n (%)
167 (86.5)
26 (78.8)
122 (88.4)
PDC at 6 months
Patients with ≥6 mo of observation, n (%)
153 (79.3)
27 (81.8)
108 (78.3)
PDC, %, mean ± SD [median]
83.3 ± 21.0 [95.6]
81.4 ± 21.6 [95.6]
84.2 ± 21.0 [95.6]
PDC ≥80%, n (%)
107 (69.9)
17 (63.0)
79 (73.1)
PDC at 12 months
Patients with ≥12 mo of observation, n (%)
102 (52.8)
19 (57.6)
70 (50.7)
PDC, %, mean ± SD [median]
75.3 ± 25.8 [87.2]
76.9 ± 25.3 [89.7]
74.8 ± 26.4 [85.3]
PDC ≥80%, n (%)
64 (62.7)
12 (63.2)
43 (61.4)
MPR, medication possession ratio; PDC, proportion of days covered; SD, standard deviation.
Treatment duration was defined as the time from the date of the first index medication prescription filled to the last day of supply before a gap greater than the indicated number of days.
† The MPR was defined as the sum of the days of supply of the index medication divided by the number of days between the first filled prescription and the last filled prescription plus the days of supply of the last filled prescription.
‡ PDC was defined as the sum of non-overlapping days of supply divided by fixed time periods of 6 and 12 mo.
The rates of persistence are summarized in Figure 2. At 6 months, the persistence rates for patients with no gaps of >90 days were 88.9%, 92.6%, and 87.0%, among the overall (n = 153), Black (n = 27), and non-Black cohorts (n = 108), respectively. At 12 months, the persistence rates of patients with no gaps of >90 days were 69.6%, 78.9%, and 65.7%, among the overall (n = 102), Black (n = 19), and non-Black cohorts (n = 70), respectively.
Figure 2Persistence Rates during the Observation Period1 Note: (1) Persistence was defined as the proportion of patients with no gap >45 or >90 d for the index treatment evaluated over fixed time periods of 6 mo and 12 mo. (Color version available online.)
Due to the heterogeneity among real-world patient populations relative to clinical trials, there is a need to understand whether the results from a clinical trial setting reflect outcomes in real-world practice, particularly among Black patients, a demographic with a particularly high risk for the development of PC and also a demographic underrepresented in clinical trials.
In this study, PSA response, treatment patterns, and adherence were summarized among patients overall and also stratified according to race (ie, Black and non-Black) in subgroup analyses. In general, results showed that patients with nmCRPC who initiated apalutamide had high adherence to the medication. The high treatment adherence observed in this study translated into a favorable PSA response. Results were similar among patients in the overall cohort as well as patients in the Black and non-Black cohorts.
The PSA response observed across the patient cohorts in the present study is consistent with the findings from the SPARTAN trial.
In that study, efficacy outcomes among patients with nmCRPC who initiated apalutamide with continuous ADT were compared to patients administered ADT alone. Exploratory analyses that included assessments of PSA levels 12 weeks following randomization showed that PSA levels declined by 89.7% among patients treated with apalutamide. Black patients in the SPARTAN trial represented 6.0% of all patients treated with apalutamide with continuous ADT, however their responses were not reported. In light of prior research indicating a differential response among Black versus non-Black patients,
and the absence of reported response among Black patients in the SPARTAN trial, the numerically higher response among Black versus non-Black patients (93.1% vs 85.9%) provides important insight for health care stakeholders.
This study is one of the first real-world studies to describe adherence rates for apalutamide among patients with either nmCRPC or metastatic castration-sensitive prostate cancer (mCSPC), a recently expanded indication for apalutamide.
Medication adherence, treatment patterns, and dose reduction in patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate or enzalutamide.
the results of this analysis are consistent with a previous study conducted among commercially-insured patients with mCRPC who were treated with enzalutamide or abiraterone acetate, 2 next-generation androgen signaling inhibitors.
Medication adherence, treatment patterns, and dose reduction in patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate or enzalutamide.
In that study, patients – particularly those initiated on abiraterone acetate – had a rate of adherence that was assessed as an MPR of approximately 90%.
Medication adherence, treatment patterns, and dose reduction in patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate or enzalutamide.
Medication adherence, treatment patterns, and dose reduction in patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate or enzalutamide.
As high rates of adherence are associated with improved clinical outcomes, the ability to capture adherence rates among patients administered newer therapies, particularly stratified by race, has the potential to serve as a benchmark of progress in the clinical management of PC. More recently, an open-source claims-based analysis among patients with advanced PC initiating any next-generation androgen signaling inhibitor reported adherence rates of 58% at 6 months, measured by PDC and found that Black race has been associated with a 17% reduction in adherence relative to white patients
independent of other socio-demographic characteristics. As a result, a greater understanding of the circumstances related to instances of lower adherence in specific groups at risk of non-adherence are warranted to better inform health care stakeholders.
To the best of our knowledge, this is also the first study to characterize treatment response of apalutamide among Black patients with nmCRPC. Although previous research has identified disparities among Black patients with regard to diagnosis and treatment response to localized prostate cancer interventions (ie, radiotherapy),
no information related to nmCRPC, specifically, has been reported. A retrospective study that examined race-specific differences in treatment response between Black patients and white patients treated with abiraterone acetate found that Black patients had favorable responses compared to white patients.
Although the results from the present analysis is consistent with the favorable treatment responses among Black patients, that study was conducted among a small population of patients with mCRPC which is different from the study population of patients with nmCRPC in the current study.
In light of the underrepresentation of Black patients in clinical research, additional studies exploring treatment-specific differences among Black versus non-Black patients are needed.
Limitations
This study should be considered within the context of certain limitations. First, this study was based on descriptions of a small population of 193 patients, of whom 33 were Black, which limits firm conclusions as it relates to representation of the real-world population. Moreover, due to the nature of the sample size obtained, it was not possible to determine whether the sample size was the result of utilization rates of apalutamide in the general population or for Black patients specifically. To offset the limitation resulting from the small sample size, only patients who were treated in urology clinics with dispensation information were characterized and as a result, this is expected to improve the validity of the treatment patterns assessed. Even though patients treated in urology clinics with and without dispensing information had similar characteristics, some differences were observed in terms of baseline testosterone level, which may limit generalizability of the study. Second, because patients were required to have ≥2 prescription fills, the adherence and persistence estimates may be overestimated, as this measure did not include patients who discontinue treatment after their first prescription fill. Third, during the follow-up period, heterogeneity in the timing of the PSA response measurement was unavoidable as PSA measurements were not performed at precisely the same time between patients. Fourth, as with most retrospective EMR-based studies, analyses are subject to inherent limitations related to coding inaccuracies, unknown generalizability to other PC patient populations who access care outside the network, and the inability to confirm that the filled prescriptions were taken as prescribed. Fifth, given that data from PPS analytics represents a closed network of community-based oncology clinics, care received outside of this setting is not captured in the data source. Finally, the study period examined was short (February 2018-October 2019) with some patients having a smaller length of study, additional studies examining a longer follow-up are needed.
CONCLUSIONS
This real-world study found that patients with nmCRPC who initiated apalutamide had a PSA response that was robust and consistent with clinical trials. Importantly, Black and non-Black patients had a similar PSA response and demonstrated high adherence to apalutamide. In light of the limited available evidence regarding the treatment response and treatment patterns among Black patients, this descriptive study provides important preliminary insight regarding outcomes in this understudied patient population.
630P Apalutamide for non-metastatic castration resistant prostate cancer (nmCRPC): a comparison of real-life experience from an international named patient program (NPP) vs the prior phase III clinical study (Abstract).
Medication adherence, treatment patterns, and dose reduction in patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate or enzalutamide.
Financial Disclosure:B. Lowentritt, G. Brown, K. Kernen, P. Sieber, and N. Shore have received financial support from Janssen Scientific Affairs, LLC. D. Pilon, G. Germain, C. Rossi, and P. Lefebvre are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC. L. Ellis is an employee of Janssen Scientific Affairs, LLC. Medical writing assistance was provided by Gloria DeWalt, an employee of Analysis Group, Inc.; financial support for this assistance was provided by Janssen Scientific Affairs, LLC.
Funding Source:This work was supported by Janssen Scientific Affairs, LLC. The study sponsor was involved in the study design, composition and editing of the article.
Prior ADT use was assessed at any prior to the index date, including time before the start of the baseline period.
00245-X&id=gr1.jpg){kind=link}
00245-X&id=gr2.jpg){kind=link}