abiraterone-acetate and Hypertension

While abiraterone acetate (AA) has demonstrated survival benefit in advanced prostate cancer (APC), meaningful cardiotoxicity is observed. It is unclear whether the magnitude differs based on disease indication and concurrent steroid administration.. We performed a systematic review and meta-analysis of phase II/III RCTs of AA in APC published as of August 11, 2020. Primary outcomes examined were all- and high-grade (grade ≥ 3) hypokalemia and fluid retention, and secondary outcomes included hypertension and cardiac events. We performed random effects meta-analysis comparing intervention (AA + steroid) and control (placebo ± steroid), stratified by treatment indication and whether patients received steroids.. Among 2,739 abstracts, we included 6 relevant studies encompassing 5901 patients. Hypokalemia and fluid retention were observed more frequently among patients receiving AA (odds ratio [OR] 3.10 [95% CI 1.69-5.67] and 1.41 [95% CI 1.19-1.66]). This was modified by whether patients in the control received steroids: trials where control patients did not demonstrated a larger association between AA and hypokalemia (OR 6.88 [95% CI 1.48-2.36] versus OR 1.86 [95% CI 4.97-9.54], P < .0001) and hypertension (OR 2.53 [95% CI 1.91-3.36] vs. OR 1.55 [95% CI 1.17-2.04], P = .1) than those where steroids were administered. We observed heterogeneity due to indication: there were greater effects on hypokalemia (P < 0001), hypertension (P = .03), and cardiac disorders (P = .01) among patients treated for mHSPC than mCRPC.. The magnitude of cardiotoxicity with AA differs based on trial design and disease indication. These data are valuable in treatment decisions and highlight utilization of appropriate data for counseling.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Humans; Hypertension; Hypokalemia; Male; Mineralocorticoids; Prednisone; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Treatment Outcome

Abiraterone acetate is a CYP-17 inhibitor approved for the treatment of prostate cancer. Abiraterone acetate (AA) therapy is associated with toxicities, including hypokalemia, hypertension, liver function test abnormalities and cardiac events. These adverse events are traditionally managed with a standard dose of corticosteroids. However, preliminary data are available on the use of a lower dose of corticosteroids. The aim of this report is to perform a pooled analysis evaluating the risk ratio (RR) of AA-related adverse events of special interest associated with low or standard dose of corticosteroids. A total of 5374 cases from 4 randomized clinical trials were included. Subgroup analysis according to corticosteroids dosage revealed a higher RR of adverse events associated with a dose of 5 mg, compared to 10 mg. In particular, there was a statistically significant higher RR of hypokalemia and ALT/AST increase, and only a modest risk increase for cardiac disorders and hypertension. In conclusion, given the limitations of a literature-based study, in comparison with a meta-analysis based on individual patients' data, our study identified a relatively small increase in RR for hypertension and cardiac disorders and a bigger increase of RR for hypokalemia and ALT/AST toxicity when 5 mg, rather than 10 mg of corticosteroids were administered to manage adverse events of special interest from AA. Further studies with specified end-points are awaited to confirm these results.

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Antineoplastic Agents; Aspartate Aminotransferases; Dose-Response Relationship, Drug; Humans; Hypertension; Hypokalemia; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic

Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, P450 17A1, CYP17A1) catalyzes two major reactions: steroid 17-hydroxylation followed by the 17,20-lyase reactions. The most severe mutations in the cognate CYP17A1 gene abrogate all activities and cause combined 17-hydroxylase/17,20-lyase deficiency (17OHD), a biochemical phenotype that is replicated by treatment with the potent CYP17A1 inhibitor abiraterone acetate. The adrenals of patients with 17OHD synthesize 11-deoxycorticosterone (DOC) and corticosterone but no 19-carbon steroids, similar to the rodent adrenal, and DOC causes hypertension and hypokalemia. Loss of 17,20-lyase activity precludes sex steroid synthesis and leads to sexual infantilism. Rare missense CYP17A1 mutations minimally disrupt 17-hydroxylase activity but cause isolated 17,20-lyase deficiency (ILD), Mutations in the POR gene encoding the required cofactor protein cytochrome P450-oxidoreductase causes a spectrum of disease from ILD to 17OHD combined with 21-hydroxylase and aromatase deficiencies, sometimes including skeletal malformations. Mutations in the CYB5A gene encoding a second cofactor protein cytochrome b

Topics: Abiraterone Acetate; Adrenal Hyperplasia, Congenital; Animals; Antihypertensive Agents; Corticosterone; Cytochromes b5; Desoxycorticosterone; Female; Genotype; Glucocorticoids; Gonadotropins; Humans; Hypertension; Hypospadias; Infertility; Male; Mineralocorticoids; Mutation; Mutation, Missense; Oxidation-Reduction; Steroid 17-alpha-Hydroxylase; Steroid 21-Hydroxylase

Metastatic castration-resistant prostate cancer (mCRPC) is a disease that primarily affects older men. Abiraterone acetate (AA), a selective androgen biosynthesis inhibitor, in combination with low-dose prednisone (P) improved overall survival (OS) in a randomised trial in mCRPC progressing after docetaxel versus placebo (PL) plus P.. To examine the efficacy and safety of AA plus P versus PL plus P in subgroups of elderly (aged ≥ 75 yr) (n=331) and younger patients (<75 yr) (n=863).. We conducted a post hoc analysis of a randomised double-blind PL-controlled study in mCRPC patients progressing after docetaxel chemotherapy.. Patients were randomised 2:1 to AA (1000 mg) plus low-dose P (5mg twice daily) (n=797) or PL plus P (n=398).. Primary end point was OS. Secondary end points were time to prostate-specific antigen (PSA) progression (TTPP), radiographic progression-free survival (rPFS), and PSA response rate. Treatment differences were compared using the stratified log-rank test. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). The key limitation was the post hoc analysis.. Elderly patients treated with AA plus P showed improved OS (HR: 0.64; 95% CI, 0.478-0.853; p=0.0022), TTPP (HR: 0.76; 95% CI, 0.503-1.155; p=0.1995), and rPFS (HR: 0.66; 95% CI, 0.506-0.859; p=0.0019), and higher PSA response rate with relative risk (HR: 4.15; 95% CI, 2.2-8.0]; p ≤ 0.0001) compared with patients treated with PL plus P. Grade 3/4 adverse events occurred in 62% of elderly patients and in 60% of patients aged <75 yr treated with AA plus P. Incidences of hypertension and hypokalaemia, although increased in the AA plus P arm, were similar in both age subgroups and readily managed.. AA improves OS and is well tolerated in both elderly patients and younger patients with mCRPC following docetaxel, hence providing an important treatment option for elderly patients who may not tolerate alternative therapies with greater toxicity.. ClinicalTrials.gov, identifier NCT00638690.

Topics: Abiraterone Acetate; Adult; Age Factors; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Double-Blind Method; Fatigue; Humans; Hypertension; Hypokalemia; Male; Middle Aged; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Survival Rate; Taxoids

This research work was aimed at evaluating the incidence and risk factors of adverse events (AEs) occurring in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials. These associations were assessed regarding the survival outcomes.. The study included 191 patients aged ≥18 years of confirmed metastatic castration-resistant prostate cancer (mCRPC) between March 2017 and April 2022. AE incidences were descriptively summarized from the whole cohort. Baseline characteristics, safety (treatment-emergent AEs and severe AEs), and efficacy [progression-free survival (PFS)] were analyzed. Multi-variable Cox proportional hazards models were employed to assess the factors linked with PFS.. AA is effective and tolerated in asymptomatic or slightly symptomatic mCRPC in "real-life" setting. The survival outcomes are influenced by multiple organ metastasis, hypertension, and radiotherapy.

Topics: Abiraterone Acetate; Adolescent; Adult; Humans; Hypertension; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Abiraterone improves survival in metastatic castration-resistant prostate cancer (mCRPC) but may result in the development or worsening of comorbid conditions. We assessed the course of these conditions in patients receiving abiraterone in clinical practice and compared outcomes with those in clinical trials.. Medical records of patients with mCRPC who started abiraterone at an academic institution between 2012 and 2015 were reviewed for emergency department (ED) visits, hospitalizations, and the development and/or worsening of key comorbid conditions while on abiraterone. Patient characteristics and adverse events were compared with those from clinical trials.. In a cohort of 174 patients, 28% experienced either the development or worsening of a comorbid disease; 8% required an ED visit or hospitalization owing to known adverse effects of abiraterone. Increasing age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17), higher prostate-specific antigen at initiation of treatment (OR, 1.68; 95% CI, 1.18-2.47), preexisting uncontrolled hypertension (OR, 7.61; 95% CI, 1.22-38.70), congestive heart failure (OR, 7.61; 95% CI, 1.22-38.70), and cardiac arrhythmias (OR, 4.73; 95% CI, 1.39-15.12) were associated with increased odds of an ED visit or hospitalization owing to known adverse effects of abiraterone. The rate of discontinuation (6%) was similar to 1 phase III trial that demonstrated the drug's efficacy in chemotherapy-naive patients.. Few patients discontinued abiraterone owing to toxicity; however, the fact that over one-quarter of patients experienced the development or worsening of cardiovascular and metabolic diseases warrants development of team-based approaches to the management of these comorbid conditions.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Cardiovascular Diseases; Emergency Service, Hospital; Hospitalization; Humans; Hypertension; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant