A randomized single-blind non-inferiority trial of delayed start with drospirenone-only and ethinyl estradiol-gestodene pills for ovulation inhibition.

We compared the efficacy of 4 mg drospirenone (DRSP) progestin-only pills (POPs) versus combined oral contraceptive pills (COCs) containing 0.02 mg of ethinyl estradiol (EE) and 0.075 mg of gestodene (GS) in ovulation inhibition and inducing unfavorable cervical mucus changes using a delayed-starting approach. This randomized controlled trial involved 36 participants aged 18-45 years. The major outcomes included ovulation inhibition assessed using the Hoogland and Skouby score, and cervical mucus permeability, assessed using the modified World Health Organization score. The results demonstrated ovulation inhibition rates of 77.8% for the EE/GS group and 88.9% for the DRSP group. The risk ratio and absolute risk reduction were 0.50 (95% confidence interval [CI]: 0.10, 2.40) and - 0.11 (95% CI: - 0.35, 0.13), respectively, satisfying the 20% non-inferiority margin threshold. The median time to achieve unfavorable cervical mucus changes was comparable between the DRSP (3 days, interquartile range [IQR]: 6 days) and EE/GS (3.5 days, IQR: 4 days) groups. However, the DRSP group had a higher incidence of unscheduled vaginal bleeding (55.56% vs. 11.11%; p = 0.005). DRSP-only pills, initiated on days 7-9 of the menstrual cycle, were non-inferior to EE/GS pills in ovulation inhibition. However, they exhibited delayed unfavorable cervical mucus changes compared to the standard two-day backup recommendation.Clinical trial registration: Thai Clinical Trials Registry (TCTR20220819001) https://www.thaiclinicaltrials.org/show/TCTR20220819001 .

The rates of septicemia in older adults with prostate cancer treated with abiraterone or enzalutamide: A population-based study.

INTRODUCTION: Prostate cancer (PCa) is the most common non-cutaneous tumor among American men. Androgen receptor signaling inhibitors such as abiraterone and enzalutamide have been approved for similar disease states among patients with advanced PCa. Existing data suggest using steroids is associated with an increased risk of infection. Because abiraterone is usually prescribed with prednisone, we sought to compare the risk of septicemia in patients using abiraterone vs. enzalutamide. MATERIALS AND METHODS: We utilized the SEER-Medicare-linked data and used negative binomial regression models to compare the changes in the rates of septicemia-related hospitalizations six months pre- and post-abiraterone and enzalutamide initiation. RESULTS: We found that the incidence of septicemia-related hospitalizations increased 2.77 fold within six months of initiating abiraterone (incidence rate ratio [IRR]: 2.77, 95% confidence interval [CI]: 2.17-3.53) 1.97 fold within six months of starting enzalutamide (IRR: 1.97, 95% CI: 1.43-2.72). However, the difference in the changes did not reach statistical significance (interaction IRR: 0.71, 95% CI: 0.48-1.06). DISCUSSION: The findings suggest that both abiraterone and enzalutamide are associated with an increased risk of septicemia-related hospitalizations. However, the difference in the increase of septicemia risk following the two treatments did not reach statistical significance. Further studies are warranted to understand the mechanisms at play.

Cardiovascular Toxicity Associated With Androgen Receptor Axis-Targeted Agents in Patients With Prostate Cancer: A Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: Second-generation androgen receptor axis-targeting (ARAT) agents have become a standard treatment for patients with advanced prostate cancer (PC), however much remains unknown about the potential cardiovascular toxicities. PATIENTS AND METHODS: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for randomized controlled trials of patients receiving ARAT agents for PC from inception to March 2023. The odds ratios (ORs) of all-grade and high-grade cardiovascular adverse events (CVAEs) for patients treated with and without ARAT agents were pooled for meta-analysis. Subgroup analyses based on PC type and treatment regimen were conducted. RESULTS: A total of 15 double-blind placebo-controlled phase 3 trials comprising 15,842 patients were included. In addition to hot flush and hypertension of any degree of severity, inclusion of ARAT agents was associated with a significantly higher risk of acute myocardial infarction (OR: 1.96, 95% CI: 1.05-3.68, P = .04), myocardial infarction (OR: 2.44, 95% CI: 1.27-4.66, P = .007) and angina pectoris (OR: 2.00, 95% CI: 1.00-4.02, P = .05). With regard to individual ARAT agents, enzalutamide was associated with a significantly higher risk of acute myocardial infarction (OR: 3.11, 95% CI: 1.17-8.28, P = .02), coronary artery disease (OR: 8.33, 95% CI: 1.54-44.95, P = .01), and high-grade hypertension (OR: 4.94, 95% CI: 1.11-22.06, P = .04), while abiraterone and apalutamide were associated with a significantly higher risk of angina pectoris (OR: 5.48, 95% CI: 1.23-24.33, P = .03) and myocardial infarction (OR: 7.00, 95% CI: 1.60-30.62, P = .01), respectively. CONCLUSION: The inclusion of ARAT agents was associated with a significantly higher risk of several CVAEs. Clinicians should remain vigilant, both in pre-treatment screening and monitoring for clinical symptoms and signs, when considering ARAT agent particularly for patients with pre-existing risk factors.

Hypersensitivity reaction to Abiraterone, successful desensitization protocol in prostate cancer patient.

INTRODUCTION: In prostate cancer, androgens are key in the growth of both normal prostate and cancer cells. Abiraterone acetate inhibits CYP17, an important target in prostate cancer given its central role in the production of adrenal and tumor-derived androgens. Although abiraterone is generally well tolerated, common adverse effects such as hypertension, hypokalemia, and hepatotoxicity have been reported. CLINICAL CASE: We present the case of an 83-year-old Mexican man with high-volume EC IV prostate cancer resistant to castration, orchiectomy, and bone, liver, and lung metastases. First-line treatment with the CHAARTED scheme was indicated, by patient decision refuse chemotherapy treatment. On the fourth day of starting treatment, he developed pruritic erythematous macular skin lesions and urticaria on the posterior chest that resolved spontaneously. A generalized erythematous and pruritic maculopapular rash appeared 12 days after starting abiraterone, for which she was referred to allergies. MANAGEMENT AND RESULTS: An oral provocation test was performed for two days, presenting localized macular lesions eight hours after the administration of abiraterone. An oral desensitization protocol was carried out for ten days in which no hypersensitivity reactions were observed, thus achieving the successful administration of abiraterone.

A new progestin-only pill (POP): the impact of drospirenone-only pill 4 mg 24 + 4 on coagulation markers and bleeding patterns.

PURPOSE: Progestin-only pills (POPs), compared to combined, are not associated with an increased risk of venous thromboembolism, but are associated with a poor cycle control. The aim of this study was to evaluate the impact of a new POP [4 mg drospirenone (DRSP) for 24 days with a 4-day hormone-free interval] on some coagulation markers (both procoagulant and fibrinolytic) and to describe its impact on bleeding patterns. MATERIALS AND METHODS: This is a prospective trial, based on serum evaluation of following coagulation markers and tests: Factor (F) X, F VIII, F V, INR, aPTT, Protein S and antithrombin III. A 'bleeding diary' was used to categorise women as having (1) unscheduled bleeding, (2) scheduled bleeding and (3) amenorrhoea. Thirty patients were followed for six 28-day intake cycles, with a follow-up at the end of the 3rd and 6th cycles. RESULTS: There was a significant decrease of F X (p = 0.03) (-5.7% at cycle 6). No significant changes have been observed for F VII, F V and INR. A significant increase in aPTT (p = 0.01 at 3 cycles), Protein S (p = 0.0006 at 3 cycles) and antithrombin III (p < 0.0001 at 3 cycles) was recorded. This non-deteriorating coagulation impact was associated with a significant and progressive reduction of days of scheduled and unscheduled bleeding in users between cycles 4 and 6 (from 1.3 ± 0.2 days at cycle 4 to 0.8 ± 0.1 days at cycle 6 and from 2.6 ± 0.4 days at cycle 4 to 0.6 ± 0.2 days at cycle 6, respectively, p < 0.0001). CONCLUSIONS: DRSP 24 + 4 use was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

Contraception with DRSP 24 + 4 was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

The drospirenone (DRSP)-only pill: clinical implications in the daily use.

OBJECTIVES: Progestins used in contraception are either components of combined hormonal contraceptives or are used as a single active ingredient. Progestins are highly effective in long-term contraception and have a very good safety profile with very few contraindications. METHODS: An oestrogen-free ovulation inhibitor POP has been authorised in the USA and the EU. It contains 4 mg of drospirenone (DRSP). The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular- phase levels, preventing oestrogen deficiency. RESULTS: Clinical trials have demonstrated high contraceptive effectiveness, a very low risk of cardiovascular risk events and a favourable bleeding pattern. Due to the long half-life of DRSP (30-34 h), the effectiveness is maintained even in case of a forgotten pill on a single occasion. Studies involving deliberate 4 days in one cycle 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. CONCLUSIONS: This review article will describe the clinical impact in the daily use of the 4 mg DRSP only pill and the resulting data on the effectiveness and safety of this hormonal contraceptive.

The 4 mg drospirenone-only pill improves the bleeding profile in comparison to 0.075 mg desogestrel and achieves high contraceptive efficacy even with a 24 h missed pill window.

Tolerability and safety of the estetrol/drospirenone combined oral contraceptive: Pooled analysis of two multicenter, open-label phase 3 trials.

OBJECTIVES: To evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials. STUDY DESIGN: The two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings. RESULTS: Of 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment. CONCLUSIONS: E4/DRSP is associated with a favorable tolerability and safety profile. IMPLICATIONS STATEMENT: Pooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks.

A scoping review protocol to elucidate outcomes following abiraterone versus enzalutamide for prostate cancer.

INTRODUCTION: Abiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, and clinical decision making. METHOD AND ANALYSIS: The framework for this methodology was informed by the Joanna Briggs Institute methodology for scoping reviews. Title and abstract screening will be performed by two independent researchers to create an initial study inventory. This will be followed by full-text screening for study inclusion. Population-based studies describing patient outcomes, common toxicities, and associations with patient co-morbidities following abiraterone or enzalutamide therapy will be included. After data is extracted, it will be summarized for presentation. ETHICS AND DISSEMINATION: The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on patient-specific factors informing treatment choice between abiraterone and enzalutamide for castration-resistant prostate cancer. All data are from published openly accessible sources, and therefore, no ethical clearance is necessary. The protocol is also registered at https://doi.org/10.6084/m9.figshare.19149227.

Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women.

OBJECTIVE: To evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen. STUDY DESIGN: We pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes. RESULTS: We included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event. CONCLUSION: E4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns. IMPLICATIONS STATEMENT: Most estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

Estetrol/Drospirenone: A Review in Oral Contraception.

Estetrol/drospirenone is a combined oral contraceptive (COC) with a plant-synthesised foetal oestrogen (estetrol) and a well-established progestin (drospirenone). In preclinical models, estetrol has lower binding affinity for the oestrogen receptor-α (ER-α) in contrast to estradiol and has antagonistic properties against membrane ER-α in several tissues, including the breast, while retaining agonistic activity on receptors located in the nucleus. The low oestrogenicity of estetrol may potentially contribute to reduced thrombotic risk. Estetrol/drospirenone was an effective contraceptive in phase II and III clinical trials, with regular and predictable bleeding cycles maintained in the majority of women. Estetrol/drospirenone was generally well-tolerated with metrorrhagia reported as the most common treatment-related adverse event, which is consistent with other COCs. Cases of migraines with aura (or severe migraines), deep vein thrombosis, hyperkalaemia and depression were rarely reported during the phase III trials. Overall, estetrol/drospirenone is an effective and generally well-tolerated COC, with a potentially reduced risk of thrombosis.

In 2019, an estimated 44% of women aged 15­49 years worldwide used modern contraception methods, and in these women using modern methods, 18% used an oral contraceptive. Estetrol/drospirenone is a combined oral contraceptive (COC) which uses estetrol, a plant-synthesised oestrogen naturally produced by the human foetal liver during pregnancy, in combination with drospirenone, a well-known progestin. Combined, these hormones suppress ovulation, which constitutes their primary mode of action in preventing pregnancy. As estetrol has weaker oestrogen-related effects, it may potentially reduce the risk for blood clots. Estetrol/drospirenone was an effective contraceptive in clinical trials, and most women had regular and predictable bleeding cycles. Metrorrhagia (i.e. abnormal bleeding) was the most commonly reported treatment-related adverse effect; however, this is a common issue with hormonal contraceptives. Cases of severe migraine headaches, deep vein thrombosis, high potassium levels or depression were rarely reported during clinical trials. Estetrol/drospirenone is an effective oral contraceptive, which may offer a contraceptive option with a lower risk for blood clots. However, further research is required to confirm the reduced risk of clotting.

Drospirenone 4 mg in a 24/4 regimen maintains inhibition of ovulation even after a 24-h delay pill intake - Pharmacological aspects and comparison to other progestin-only pills.

This review focuses on the pharmacological and inhibition of the ovulation of progestin-only, estrogen-free contraceptive containing drospirenone in a dosage of 4 mg in a regimen 24/4. The USA and European regulatory authorities have approved it. The molecule has anti-gonadotropic, anti-mineralocorticoid, anti-estrogenic, and antiandrogenic properties. This regime improves the bleeding profile, maintains the plasma E2 levels comparable to the menstrual cycle's early follicular phase, avoids hypoestrogenism, and preserves efficacy despite forgetting the tablet intake as drospirenone has a half lifetime of 30-34 hours. Clinical studies have shown good efficacy, very low cardiovascular side effects, and high acceptability and maintenance of ovulation inhibition after scheduled 24-h delays in pill intake. The molecule is compared to other POP like levonorgestrel or desogestrel.

Estetrol and drospirenone: a novel oral contraceptive.

Estetrol (E4) is a natural human estrogen produced during human pregnancy in the fetal liver with a unique mechanism of action that displays tissue-selective activity, and behaves as a natural selective estrogen receptor modulator. E4 acts as an estrogen agonist on the vagina, the uterus and the endometrium, and also shows bone-sparing activity. Its mechanism of action results in neutral impact on endocrine, metabolic and hemostatic parameters, compared with other oral contraceptives. In 2021, Health Canada approved the combination 15 mg E4/3 mg drospirenone (DRSP), the first and only combined oral contraceptive based on the native estrogen E4, which has been synthesized from plant-based sources. Shortly afterwards, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) also approved the combination 14.2 mg E4/3 mg DRSP as a female contraceptive.

Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: A French population-based study on prostate cancer patients.

AIMS: Safety profiles of abiraterone and enzalutamide rely mainly on Phase III clinical trials. Our objective was to estimate the incidence rate ratio (IRR) for certain adverse events leading in real life to hospitalization (atrial fibrillation, acute heart failure, ischaemic heart disease, acute kidney injury [AKI], ischaemic stroke, torsade de pointe/QT interval prolongation, hepatitis and seizure), comparing abiraterone to enzalutamide. We also set out to discuss previously identified safety signals. METHOD: Using the French National Health Insurance System database, all patients newly exposed to abiraterone or enzalutamide between 2013 and 2017 and followed until 31 December 2018 were targeted. IRRs for each event were estimated using a Poisson model in a sub-population of patients without contraindications or precautions for use for either treatment. RESULTS: Among 11 534 new users of abiraterone and enzalutamide, AKI (IRR 1.42, 95% CI: 1.01-2.00), liver monitoring suggestive of hepatic damage (IRR 3.06, 95% CI: 2.66-3.53) and atrial fibrillation (IRR 1.12, 95% CI: 1.05-1.19) were significantly more often observed with abiraterone than with enzalutamide. CONCLUSION: Our study provides knowledge on abiraterone and enzalutamide real-life safety profiles, especially for events leading to hospitalization. Despite several limitations, including the lack of clinical data, the safety signal for AKI under abiraterone is in line with results of an analysis of the French pharmacovigilance database, which requires further specific investigations. Enlightening the clinicians' therapeutic choices for patients treated for prostate cancer, our study should lead to clinicians being cautious in the use of abiraterone.

Overall and bleeding-related discontinuation rates of a new oral contraceptive containing 4 mg drospirenone only in a 24/4 regimen and comparison to 0.075 mg desogestrel.

OBJECTIVES: Progestin-only pills do not increase the risk of venous thromboembolism, stroke, and myocardial infarction but are associated with poor cycle control. A novel estrogen-free pill containing only drospirenone (DRSP) to improve bleeding patterns and tolerability and reduce discontinuation rates has been introduced into the market. The present study aims to describe the improvement in the acceptability of this DRSP-only pill, e.g. regarding the bleeding profile and the reduction in discontinuation rates due to unacceptable bleeding compared to desogestrel (DSG). STUDY DESIGN: Double-blind, double-dummy prospective phase III study in healthy women aged 18-45 years evaluating a total of 858 women with 6691 DRSP and 332 women with 2487 DSG treatment cycles. RESULTS: Overall, 82 (9.6%) women in the DRSP group and 44 (13.3%) women in the DSG group experienced treatment-emergent adverse events (TEAEs) leading to premature termination of the trial meaning that 32% more women in the DRSP group finished the trial in comparison to the DSG group (based on the AUC of Kaplan-Meier's curves). Discontinuation rates due to abnormal bleeding were 3.7% for DRSP and 7.3% for DSG users. This is a 55.7% lower discontinuation rate in the DRSP group compared to the DSG group. CONCLUSIONS: This report describes the improvement in acceptability and bleeding profile of women using the new DRSP-only oral contraceptive compared to DSG, providing a better quality of life and adherence to the contraceptive method as demonstrated by lower discontinuation rates of women using the estrogen-free DRSP-only pill.

Signal detection of drospirenone-containing oral contraceptives: a disproportionality analysis using the Korea Adverse Event Reporting System Database, 2008-2017.

OBJECTIVES: To detect the signals for drospirenone-containing oral contraceptives (DCOCs) and describe the reporting pattern of adverse events (AEs) caused by DCOCs compared with levonorgestrel/desogestrel/gestodene-containing (second/third generation) oral contraceptives. DESIGN: A descriptive analysis of claims data. SETTING: The Korea Institute of Drug Safety & Risk Management-Korea Adverse Event Reporting System Database from 1 February 2008 to 31 December 2017. OUTCOME MEASURES: Signals for DCOCs were identified using three data mining indices. The characteristics, death cases, and the annual pattern of AE reports were compared between DCOCs and second/third generation oral contraceptives. RESULTS: Of the 242 DCOC-related AEs, 54 signals were detected and 10 were identified as new signals that were not included in Korea, US and UK label. The newly detected signals include deep vein thrombophlebitis and frequent urination. Serious AEs were more likely to be reported with DCOCs (7.85%) than with second/third generation oral contraceptives (2.92%). Five deaths after use of DCOCs were reported with vascular AEs, such as pulmonary embolism and thrombosis, whereas one death after use of second/third generation oral contraceptives was reported with the cardiac arrest. CONCLUSIONS: We identified 10 new signals related to DCOCs that were not included in the current label. Additionally, we found higher reports of the deaths and vascular AEs associated with DCOCs than with second/third generation oral contraceptives, which warrants careful monitoring to ensure the safe use of DCOCs.

Association of Chemotherapy, Enzalutamide, Abiraterone, and Radium 223 With Cognitive Function in Older Men With Metastatic Castration-Resistant Prostate Cancer.

Importance: Older adults are at greater risk of cognitive decline with various oncologic therapies. Some commonly used therapies for advanced prostate cancer, such as enzalutamide, have been linked to cognitive impairment, but published data are scarce, come from single-group studies, or focus on self-reported cognition. Objective: To longitudinally examine the association between cognitive function and docetaxel (chemotherapy), abiraterone, enzalutamide, and radium Ra 223 dichloride (radium 223) in older men with metastatic castration-resistant prostate cancer. Design, Setting, and Participants: A multicenter, prospective, observational cohort study was conducted across 4 academic cancer centers in Ontario, Canada. A consecutive sample of 155 men age 65 years or older with metastatic castration-resistant prostate cancer starting any treatment with docetaxel, abiraterone acetate, enzalutamide, or radium Ra 223 dichloride (radium 223) were enrolled between July 1, 2015, and December 31, 2019. Exposures: First-line chemotherapy (docetaxel), abiraterone, enzalutamide, or radium 223. Main Outcomes and Measures: Cognitive function was measured at baseline and end of treatment using the Montreal Cognitive Assessment, the Trail Making Test part A, and the Trail Making Test part B to assess global cognition, attention, and executive function, respectively. Absolute changes in scores over time were analyzed using univariate and multivariable linear regression, and the percentages of individuals with a decline of 1.5 SDs in each domain were calculated. Results: A total of 155 men starting treatment with docetaxel (n = 51) (mean [SD] age, 73.5 [6.2] years; 34 [66.7%] with some postsecondary education), abiraterone (n = 29) (mean [SD] age, 76.2 [7.2] years; 18 [62.1%] with some postsecondary education), enzalutamide (n = 54) (mean [SD] age, 75.7 [7.4] years; 33 [61.1%] with some postsecondary education), and radium 223 (n = 21) (mean [SD] age, 76.4 [7.2] years; 17 [81.0%] with some postsecondary education) were included. Most patients had stable cognition or slight improvements during treatment. A cognitive decline of 1.5 SDs or more was observed in 0% to 6.5% of patients on each measure of cognitive function (eg, 3 of 46 patients [6.5%; 95% CI, 2.2%-17.5%] in the group receiving chemotherapy [docetaxel] had a decline of 1.5 SDs for Trails A and Trails B). Although patients taking enzalutamide had numerically larger declines than those taking abiraterone, differences were small and clinically unimportant. Conclusions and Relevance: These findings suggest that most older men do not experience significant cognitive decline in attention, executive function, and global cognition while undergoing treatment for advanced prostate cancer regardless of the treatment used.