Abstract
Background:
Abiraterone acetate (AA) is used in treatment of patients with metastatic prostate cancer. Despite the survival advantage, AA is associated with hypertension due to mineralocorticoid excess syndrome.
Objective:
We conducted a single-center retrospective analysis to evaluate the real-world incidence and severity of AA-induced hypertension.
Methods:
Electronic health records were used to collect baseline characteristics and prostate cancer history. Patient data, including blood pressure at each 4 (±2)-week interval, were collected for 24 weeks after the initiation of AA therapy. The primary endpoint was the incidence and severity of AA-induced hypertension. The secondary endpoints include effect of different prednisone dosing regimens and prostate cancer types on hypertensive incidence and the impact of clinical pharmacists’ involvement in managing AA-induced hypertension.
Results:
A total of 142 patients who met our inclusion criteria received AA for metastatic prostate cancer, 73 (51.4%) with metastatic castration-resistant prostate cancer (mCRPC), and 69 (48.6%) with metastatic castration-sensitive prostate cancer (mCSPC). Of all, 43.7% experienced all-grade hypertension, and 28.2% experienced grade 3-4 hypertension. There was no difference in incidence of hypertension between patients receiving 5 mg of prednisone daily and those receiving 5 mg of prednisone twice daily. All-grade hypertension occurred in 39.7% of mCRPC and 47.8% of mCSPC patients (P = 0.33). Thirty-two percent of patients were actively managed by a clinical pharmacist and had an overall trend of reduced hypertension severity after 12 weeks.
Conclusion and relevance:
This single-center, retrospective cohort study found that real-world metastatic prostate cancer patients who received AA had substantially higher incidence and severity of hypertension compared with clinical trials regardless of prednisone dose. In patients with mCRPC and mCSPC, the role of prednisone dose in hypertension incidence and severity warrants further investigation. Overall, results indicate the need for closely monitoring hypertension and optimization of anti-hypertensive therapy by multidisciplinary teams in metastatic prostate cancer patients receiving AA.
Introduction
Prostate cancer is the most common cancer in men worldwide and the second leading cause of cancer death in men in the United States, with an estimated 268 490 new cases in 2022. 1 Approximately 80% to 85% of newly diagnosed prostate cancers are localized to the prostate; with the remaining being locally advanced or metastatic.2,3 While most metastatic castration-sensitive prostate cancer (mCSPC) patients initially respond well to androgen deprivation therapy and a low testosterone environment, overtime, the disease will ultimately progress to metastatic castration-resistant prostate cancer (mCRPC).3,4
Abiraterone acetate (AA) with prednisone in combination with androgen deprivation therapy is an approved treatment for mCSPC and mCRPC. 2 Due to its benefits in several different stages of the disease, AA is one of the most common therapies prescribed in advanced prostate cancer cases. Multiple phase 3 randomized clinical trials have shown that treatment with AA and prednisone significantly improved overall survival in patients with both mCRPC and mCSPC.4-7 AA, the prodrug of abiraterone, is a selective inhibitor of cytochrome P450 c17A1 (CYP17), an enzyme required for biosynthesis of androgens.6,8 Although it is effective at treating prostate cancer, AA is associated with a significant risk of hypertension largely related to the inhibition of CYP17, which leads to excess production of mineralocorticoids.9,10 Moreover, inhibition of the CYP17 also leads to decreased glucocorticoid production resulting in a compensatory increase in adrenocorticotropic hormone (ACTH). The undesired excess production of mineralocorticoids causes a clinical presentation that can include hypertension, hypokalemia, and fluid retention.10,11 Prednisone is approved to be administered with AA to reduce mineralocorticoid excess by mimicking normal cortisol production and lowering ACTH levels.9-13 Recommended prednisone doses are 5 mg daily and 5 mg twice daily for patients with mCSPC and mCRPC, respectively. 13 A recent study demonstrated that in patients with mCRPC, prednisone 5 mg twice daily in combination with AA achieved the primary endpoint of no mineralocorticoid excess while prednisone 5 mg daily did not attenuate these adverse effects. 11
Hypertension, especially high grade (grade 3-4), can be detrimental to patient outcomes due to potential dose reduction or interruption, discontinuation of cancer therapy, and death. 12 The onset of AA-induced hypertension occurs within 4 to 24 weeks from initiation.11,14 Although multiple randomized clinical trials have reported an increased incidence and severity of hypertension in patients with metastatic prostate cancer receiving AA and prednisone, data are highly variable.4-7,15 The incidence of all-grade hypertension in landmark clinical trials ranges from 11.1% to 23.8% for mCRPC and 31.5% to 36.7% for mCSPC.4-7,12 In addition, clinical trials tend to underestimate toxicity given inclusion criteria for these studies often do not translate to real-world populations. 16 Therefore, the incidence of AA-induced hypertension is thought to be much higher in practice. This study aimed to analyze the real-world incidence and severity of hypertension in patients with metastatic prostate cancer receiving AA in combination with prednisone and identify potential mitigating factors such as prednisone dose and pharmacist’s involvement in managing hypertension.
Materials and Methods
Study Design
This study was designed as a single-center retrospective chart review. It was approved by the University of North Carolina institutional review board. Adult (≥18 years old) patients with a metastatic prostate cancer diagnosis, and who were prescribed AA for cancer treatment from April 4, 2014, to May 31, 2020, were included in the study. Patients were identified from a central electronic database based on prostate cancer diagnosis and prescription history of AA. Patients were excluded if AA was not initiated at the institution, initiation date was prior to April 4, 2014, prostate cancer diagnosis was not metastatic, the patient was lost to oncology follow-up after AA initiation, AA was never initiated, AA was taken for less than 8 weeks, or if AA use was in conjunction with a clinical trial. Patients were followed from the start of treatment and up to 24 weeks after initiation, end of study (May 2020), or death—whichever occurred first.
The electronic health record for each patient was reviewed to identify baseline information, incidence and severity of hypertension after initiation of AA, and antihypertensive medications prescribed. Patient demographics and baseline characteristics at treatment initiation were recorded. The data collected consisted of age, race, ethnicity, baseline vital signs, laboratory values, and comorbidities. In addition, patient cancer history and AA information were collected to include type of metastatic prostate cancer, site of metastasis, Eastern Cooperative Oncology Group (ECOG) performance score, prostate-specific antigen (PSA), Gleason score, abiraterone formulation, prednisone dose, and the number of antihypertensive medications prior to AA therapy. Blood pressure, total number of antihypertensive agents, antihypertensive regimen adjustment, prednisone and abiraterone regimen adjustment, reason for adjustments, and new-onset adverse effects at subsequent oncology office visits were collected in 4 (± 2)-week intervals. Other toxicities associated with mineralocorticoid excess syndrome were assessed including incidence of hypokalemia and edema.
We also aimed to evaluate the impact of pharmacists on BP control in patients with AA-induced hypertension. During the study period, a pharmacist was hired in 2017 and started clinical visits in 2018. Patients were referred to be managed by a pharmacist through provider discretion. There were no specific criteria to determine patient referral. The clinical pharmacist practitioner independently performs monitoring and adverse effect management for patients on active cancer treatment through in-person and telehealth visits. Moreover, the clinical pharmacist practitioner license allows the pharmacist to prescribe medications with an advanced practice practitioner license under a supervising physician.
Study Endpoints
The primary outcome was to evaluate the incidence and severity of AA-induced hypertension. Baseline hypertension was identified based on confirmed diagnosis in patient notes of initial workup or if the patient’s baseline blood pressure, calculated by the average systolic blood pressure (SBP) and diastolic blood pressure (DBP) from 2 to 3 consecutive visits prior to initiation of AA was ≥130/80 mm Hg as defined by 2017 American College of Cardiology/American Heart Association (ACC-AHA) guidelines. 17 For patients without baseline hypertension, AA-induced hypertension is identified by the 2017 ACC-AHA guideline definition (SBP/DBP ≥130/80). 17 However, for patients with baseline hypertension as defined earlier, incidence of AA-induced hypertension is only indicated if medical intervention was initiated due to elevated blood pressure, or if the change in SBP or DBP was ≥20 mm Hg compared to baseline blood pressure. This was done to prevent overreporting of AA-induced hypertension in a retrospective chart review. Once patients were identified with AA-induced hypertension, Common Terminology Criteria for Adverse Events (CTCAE) version 5 grade was used to determine the severity based on the criteria listed below. 18 To monitor changes in severity of AA-induced hypertension, the patient’s CTCAE grade was recorded based on the patient’s blood pressure at each subsequent visits. Per CTCAE, the grades of hypertension include: grade 1, SBP 120 to 139 mm Hg or DBP 80 to 89 mm Hg; grade 2, SBP 140 to 159 mm Hg or DBP 90 to 99 mm Hg if previously within normal limits (WNL); grade 3, SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg; grade 4, life-threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis) or urgent intervention indicated; grade 5, death.
Secondary outcomes included comparison of the incidence of hypertension between different prostate cancer types (mCRPC vs mCSPC) and the effect of different prednisone dosing regimens (5 mg daily vs 5 mg twice daily) on the incidence of hypertension. The 5 mg twice daily dosing included both 5 mg twice daily and 10 mg once daily regimens. For the purpose of this study, the presence of hypokalemia was defined as a potassium level below the lower limit of normal and/or requiring potassium supplementation. In addition, the presence of edema reported in the clinic notes was collected at each assessment interval.
To evaluate pharmacist involvement and impact on blood pressure outcomes, pharmacist involvement was identified if a patient was actively managed by a pharmacist through telehealth follow-ups or in-person clinic visits after the initiation of AA. Pharmacist impact on blood pressure was collected by comparing SBP and DBP weekly between a group of patients who were actively managed by the pharmacist and the group that was not.
Statistical Analysis
Microsoft Excel (Redmond, WA) was utilized for descriptive data analyses. Nominal data were reported as numbers and percentages. Descriptive statistics were used to determine the incidence and severity of hypertension in patients receiving AA treatment and to analyze changes in blood pressure in patients with and without pharmacist involvement. Chi-square test, with P values <0.05 considered significant, was used to compare the proportion of patients with mCRPC and mCSPC receiving different prednisone doses, to identify the effect of different prostate cancer types on incidence of hypertension, and difference between prednisone 5 mg daily and prednisone 5 mg twice daily in causing hypertension.
Results
Baseline Characteristics
Among 272 patients with prostate cancer and treatment history of AA, 142 patients met the inclusion criteria. There were 73 patients with mCRPC and 69 with mCSPC. Reasons for exclusion are shown in Figure 1. The median age of patients was 72 years (range 56-85 years), and the majority were non-Hispanic/Latino (95.8%). Of all, 59.2% were Caucasian and 33.1% were African American. Of the patients included, 125 (88%) patients had hypertension at baseline; of these, 37 (26%) had stage 1 hypertension, and 69 (48.6%) had stage 2 hypertension. Patients with both mCRPC and mCSPC had a high baseline incidence of hypertension, 84.9% and 89.9%, respectively. Six patients with poorly controlled hypertension at baseline were initiated on additional hypertensive medications prior to AA initiation. Additional characteristics are depicted in Table 1. Table 2 categorizes patient prostate cancer history, abiraterone formulation, prednisone dose, androgen-deprivation method, and antihypertensive agents at baseline. Prior to AA initiation, 38 (26.8%) patients did not use any antihypertensive agents, 81 (57%) patients were receiving 1 or 2 agents, and 23 (16.2%) patients were receiving 3 or more agents. The most common antihypertensive agents were angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs; 43.7%) and dihydropyridine calcium channel blockers (DHP CCBs; 26.8%). As seen in Table 3, patients with mCRPC were more likely to receive prednisone 5 mg twice daily while patients with mCSPC were more likely to receive prednisone 5 mg daily.
Study eligibility criteria and inclusion. This diagram depicts the total number of patients included in the study and in each group (mCRPC and mCSPC). It also depicts the number of excluded patients based on exclusion criteria.
Baseline Characteristics.
Abbreviations: AdjBW, adjusted body weight; CAD, coronary artery disease; CrCl, creatinine clearance; IQR, interquartile range; MI, myocardial infarction; SD, standard deviations; TIA, transient ischemic attack.
Prostate Cancer and Abiraterone History.
Abbreviations: AA, abiraterone acetate; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; DHP CCB, dihydropyridine calcium channel blocker; ECOG, Eastern Cooperative Oncology Group; HTN, hypertension; LHRH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen.
Prednisone Doses Received and Incidence of Abiraterone-Induced Hypertension—No. (%).
Abbreviations: mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer.
Incidence and Severity of AA-Induced Hypertension
Over the 24-week study period following AA, all-grade AA-induced hypertension and grade 3-4 hypertension occurred in 62 (43.7%) and 40 (28.2%) of all patients, respectively (Table 3). All-grade AA-induced hypertension occurred in 29 (39.7%) mCRPC and 33 (47.8%) mCSPC patients (P = 0.33) and grade 3-4 hypertension occurred in 18 (24.7%) mCRPC and 22 (31.9%) mCSPC patients (P = 0.44). As seen in Figure 2, all-grade hypertension occurred most frequently between week 12 and 20. At week 12, 16, and 20, 37 of 90 (41.1%) patients, 33 of 79 (41.2%) patients, and 27 of 66 (40.9%) patients experienced all-grade hypertension, respectively. Grade 3-4 hypertension occurred most frequently during week 8 and 12 following AA initiation in 12 (12%) and 12 (13.3%) patients, respectively. Among 62 patients with AA-induced hypertension, AA was held in 9 patients due to elevated blood pressure and restarted at a reduced dose, and 1 patient discontinued AA treatment due to hypertension. In addition, 8 of 17 (47%) patients without hypertension at baseline developed new hypertension after initiation of AA. The effect of prednisone dosing was evaluated, and 30 of 64 (46.9%) patients receiving prednisone 5 mg daily and 32 of 76 (42.1%) patients receiving prednisone 5 mg twice daily with AA experienced all-grade hypertension. There was no significant difference in hypertension between patients receiving prednisone 5 mg versus 5 mg twice daily (P = 0.57).
Incidence and severity of HTN. This figure represents the percentage of patients with hypertension and associated CTCAE grade at each follow-up interval. N represents the number of patients with oncology follow-up during the 4 ± 2-week intervals.
Incidence of other AA-induced toxicities including hypokalemia and peripheral edema occurred in 11 (7.8%) and 6 (4.2%) patients, respectively. Five patients who experienced hypokalemia and 2 patients who experienced edema also experienced all-grade hypertension. In addition, 2 patients developed heart failure in our cohort while receiving AA.
Pharmacist Involvement in Managing Blood Pressure
Pharmacist involvement was documented in 46 (32.4%) patients receiving AA treatment. Pharmacist visits included both telehealth visits and in-person clinic visits. Mean SBP and DBP in patients with and without pharmacist involvement at each follow-up interval are shown in Figures 3 and 4, respectively. Change in mean SBP and DBP at each follow-up interval compared to baseline, number of antihypertensive agents added, and number of doses increased are shown in Table 4. Comparing patients who were actively managed by a clinical pharmacist to those who were not managed by a pharmacist, the greatest changes in mean SBP from baseline were observed between week 12 and 16 (−5.72 ± 1.8 mm Hg vs 2.51 ± 1.87 mm Hg) and between week 20 and 24 (−6.34 ± 1.72 mm Hg vs −0.03 ± 1.88 mm Hg). During the 24-week study period, 14 (30.4%) antihypertensive agent modifications occurred in 46 patients managed by pharmacist, and 23 (24%) modifications occurred in 96 patients with no pharmacist involvement. Of 23 antihypertensive agents initiated, 11 (47.8%) were ACE inhibitor/ARBs, and 7 (30.4%) were DHP CCB.
Systolic blood pressure with and without pharmacist involvement at each follow-up interval.
Diastolic blood pressure in patients with and without pharmacist involvement at each follow-up interval.
Pharmacist Involvement in Blood Pressure Management.
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blockers; DBP, diastolic blood pressure; SBP, systolic blood pressure; SEM, standard error of mean.
Discussion
In patients receiving AA, increased mineralocorticoid levels from CYP17 inhibition are directly associated with hypertension.8-10 Although hypertension has been reported as an adverse effect of AA in clinical trials, incidence and severity may be higher in real-world settings due to heterogenous patient baseline characteristics and more broad inclusion of patients for therapy outside of clinical trials. In the COU-AA-301 and COU-AA-302 trials, 8% and 13% of patients, respectively, in the placebo arm experienced all-grade hypertension, indicating that patients enrolled in clinical trials with abiraterone have been highly selected to exclude patients with any degree of uncontrolled hypertension.5,6 Unlike clinical trials, patients in our study demonstrated a high incidence of hypertension (87.3%) prior to AA initiation. More specifically, 48.6% of patients had stage 2 hypertension prior to initiation of AA and would have been ineligible for abiraterone clinical trials. A recent meta-analysis demonstrated a summary incidence of 21.9% for all-grade hypertension and 4.6% for grade 3-4 hypertension in patients receiving AA across multiple major clinical trials using CTCAE version 3. 12 In contrast, our study reflected a substantially higher incidence and severity of hypertension in real-world patients, an incidence rate of 43.7% for all-grade hypertension and 28.2% for grade 3-4 hypertension. The higher incidence and severity of hypertension may be associated with strict inclusion criteria from clinical trials and broader range of comorbidities in the real-world population. In addition, a more diverse population was included in this analysis; a third of the patients were African American, which has been a historically underrepresented population in large randomized controlled trials. 19
In addition, a recent phase 2 trial by Attard et al 11 demonstrated that 47% and 21% of patients who received prednisone 5 mg once daily and 5 mg twice daily experienced grade 2 or greater hypertension, respectively. In comparison, our study demonstrated no difference in the incidence of hypertension between the two prednisone dosing regimens, likely due to a small sample size and the retrospective nature of our study. Importantly, despite no difference in baseline incidence of hypertension between patients with mCRPC and mCSPC, the incidence of all-grade and grade 3-4 hypertension was notably higher in patients with mCSPC. While this difference was not significantly different, it is clinically meaningful and may be explained by the significantly larger proportion of patients with mCSPC receiving lower prednisone doses. Further research is needed to validate the ideal dose of glucocorticoid in real-world patients receiving AA.
To maximize AA’s benefits in providing increased overall survival rates in metastatic prostate cancer patients, adverse effects must be effectively managed. Our results strongly indicate the need for careful consideration of cardiovascular risk factors and close monitoring of blood pressure to prevent and treat hypertension associated with AA therapy and to avoid dose de-escalation or discontinuation. Moreover, for patients with baseline hypertension, adjusting the patient’s current regimen prior to the initiation of AA therapy should be considered to prevent high-grade hypertension. Future prospective studies with a real-world patient populations are needed to confirm the findings of this study. In addition, studies are needed to evaluate prescribing trends and the effectiveness of different antihypertensive regimens to treat effects of excess mineralocorticoid production in this patient population.
The onset of AA-induced hypertension is within 4 to 24 weeks from initiation. Although the population of patients managed by pharmacist is smaller due to the lack of a dedicated clinical pharmacist in the clinic before 2018, our analysis of pharmacist involvement in managing hypertension demonstrated a trend in reduced hypertension severity after 12 weeks. Improvement in blood pressure management occurred despite fewer modifications to their antihypertensive regimen, suggesting greater effectiveness in hypertension management with the incorporation of a clinical pharmacist practitioner on a multidisciplinary team. In addition to medication modifications, the clinical pharmacist practitioner provided interventions, including patient education on medication adherence and lifestyle modification, and facilitated medication access processes. Overall, our data suggest the benefits of telehealth and in-person clinic visits with a clinical pharmacist during the first 6 months of therapy when the incidence of AA-induced hypertension was most significant.
There are several limitations to this study. First, missing data are inherent to the retrospective study design. The number of patients at each 4-week follow-up visit interval declined over time because of the lack of enforceable follow-up time as well as the nature of their end-stage disease. Furthermore, many patients did not have documented follow-up oncology visits for 1 to 3 months from initiation which could lead to an inaccurate depiction of the relationship between time after the initiation of AA and the incidence and severity of hypertension. In addition, blood pressure at each visit was only recorded once for most patients, which can lead to misclassification of baseline hypertension and an overestimation of hypertensive incidence due to the lack of objective observations, white-coat hypertension, among other related reasons. Another limitation is the inherent difficulty of retrospectively categorizing the severity of hypertension by CTCAE grade especially since most of the patients had baseline hypertension. The study design also limits our ability to account for the patient’s condition at each visit and to determine the reason for antihypertensive regimen modifications. Other limitations include single-center study limiting, sample size leading to higher variability and bias, and generalizability of patient baseline and characteristics to other geographical areas. Finally, this retrospective study includes reporting bias because the data were reviewed and processed by a single investigator.
Conclusion and Relevance
This study observed a higher incidence and severity of hypertension in real-world metastatic prostate cancer patients receiving AA than historical clinical trials, indicating the need for further consideration of cardiovascular risks and safety when managing this population. In patients with mCRPC and mCSPC, the role for prednisone dose in hypertension incidence and severity warrants further investigation. Finally, multidisciplinary management involving a pharmacist is recommended to assure timely and optimal management of hypertension.
Footnotes
Author Contributions
K.P.M., B.M., and J.E.R. contributed to study conceptualization. B.L. performed data collection. B.L. and K.P.M. performed formal analysis. B.L. carried out investigation. K.P.M. and B.L. framed study methodology. K.P.M., B.M., and J.E.R. supervised the study processes. All authors contributed to writing the manuscript.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
