Fatigue is a prevalent and debilitating symptom experienced by prostate cancer patients, influenced by the disease's progression and its treatments. The disease's evolution, especially to metastatic castration-resistant prostate cancer (mCRPC), often exacerbates symptoms, including fatigue. Fatigue can manifest even in early stages with androgen deprivation therapy (ADT) and worsen with chemotherapy or new hormonal agents combined with ADT. Many prostate cancer drugs, including abiraterone, enzalutamide, docetaxel, olaparib, and radium-223, list fatigue as a common adverse event. However, inconsistencies exist between patient- and clinician-reported fatigue, emphasizing the importance of patient-reported outcomes (PROs). Previous research highlights the wide variability in patient-reported fatigue rates across trials, even in similar populations, suggesting that factors like data collection methods, patient selection, and geographic regions can influence these outcomes. Enzalutamide, approved for mHSPC and CRPC, has demonstrated efficacy in various trials. This study uses data from four pivotal phase 3 enzalutamide trials (ARCHES, PROSPER, PREVAIL, and AFFIRM) to assess baseline patient-reported fatigue across different disease stages and the impact of enzalutamide plus ADT versus placebo plus ADT on fatigue.

Existing literature indicates that fatigue is a common symptom in prostate cancer patients, influenced by the disease stage and treatment. Studies have shown that fatigue can occur even in early stages of the disease and worsen with the progression to metastatic castration-resistant prostate cancer (mCRPC). The impact of various treatments, including androgen deprivation therapy (ADT), chemotherapy, and hormonal therapies like abiraterone and enzalutamide, on fatigue has been documented. Discrepancies between patient-reported and clinician-reported fatigue emphasize the importance of using PROs to capture the patient's experience. Previous research has shown variability in patient-reported fatigue rates across trials, even within similar patient populations, highlighting the influence of factors such as data collection methods, patient selection, and geographical location. The studies cited in the paper provide a basis for understanding the prevalence and impact of fatigue in advanced prostate cancer.

This post-hoc exploratory analysis utilized data from four pivotal, phase 3, randomized, placebo-controlled trials comparing enzalutamide 160 mg/day plus ADT to placebo plus ADT. The trials included patients with various prostate cancer stages: mHSPC (ARCHES), high-risk nonmetastatic CRPC (nmCRPC; PROSPER), ADT-naïve patients (PREVAIL), and post-docetaxel mCRPC (AFFIRM). Patient-reported fatigue was assessed using the FACT-P item GP1 ("I have a lack of energy") at baseline, weeks 13 or 17, and every 12 weeks thereafter until disease progression. Longitudinal changes in fatigue scores were analyzed using a restricted maximum likelihood-based mixed-model repeated measures (MMRM) approach, adjusting for baseline characteristics. The analysis included assessments up to the last visit with less than 10% missing data in each treatment group. Baseline characteristics were compared between treatment arms, and the distribution of changes from baseline fatigue scores was analyzed. The authors defined fatigue as a GP1 score of ≥1. Statistical comparisons used two-sided tests. While minimal clinically important differences (MCIDs) exist for FACT-P domains, there was no established MCID for item GP1. The intention-to-treat population was used, and observed data were analyzed without imputation for missing values.

Baseline fatigue rates varied across the four trials, ranging from 58% in PROSPER (nmCRPC) to 85% in AFFIRM (post-docetaxel mCRPC). Patients with later-stage disease and prior treatment lines reported higher baseline fatigue rates. Irrespective of disease stage, both enzalutamide and placebo groups experienced an initial increase in fatigue by weeks 13 or 17, followed by stabilization or improvement. At the last assessment, over 55% of patients in all trials reported fatigue improvement or stabilization compared to baseline. In ARCHES, PROSPER, and PREVAIL, more patients experienced fatigue worsening by ≥1 or ≥2 GP1 units with enzalutamide plus ADT than with placebo plus ADT. Conversely, in AFFIRM, fewer patients in the enzalutamide group experienced fatigue worsening. MMRM analysis showed an initial increase in GP1 score in both arms across all studies by week 13 (or week 17 in PROSPER). This initial increase was less than 1 unit in all arms and trials. The overall adjusted mean increase in score from baseline throughout the study was significantly higher for enzalutamide plus ADT than for placebo plus ADT in ARCHES.

The study demonstrates that fatigue is common across the prostate cancer disease continuum, with higher rates in patients with mCRPC and prior docetaxel treatment. While enzalutamide treatment resulted in an initial increase in fatigue, similar to placebo, the fatigue levels stabilized or improved thereafter in most patients. The increased fatigue observed with enzalutamide in some studies, but not in AFFIRM, may be attributed to the differences in patient populations (e.g., symptom burden). The findings underscore the need for proactive management of fatigue, especially early in treatment. The use of patient-reported outcomes provides valuable insights into the patient experience and highlights the discrepancies between patient and clinician assessments of fatigue. The relatively low rates of fatigue-related treatment discontinuation or dose modifications suggest that fatigue is often manageable with appropriate strategies. The limitations of using a single-item measure to assess the multi-dimensional nature of fatigue should be considered when interpreting the findings.

This large, multi-center, double-blinded study demonstrates that fatigue is a prevalent symptom in prostate cancer patients across various disease stages. While enzalutamide initially increases fatigue in some patients, it generally stabilizes or improves after the initial period. The study highlights the importance of managing patient-reported fatigue, especially early in treatment. Future research should investigate more comprehensive assessments of fatigue and explore strategies to mitigate this adverse event.

The study has several limitations, including the use of a single item to assess fatigue (FACT-P GP1), potential bias due to variations in patient populations across trials, lack of imputation for missing data, and the possibility that the treatment history of patients in earlier trials may not reflect current practice. Additionally, the analysis examined clinical outcomes in treatment groups, with the impact of enzalutamide being potentially biased as patients in the ADT arm may have progressed more quickly. The lack of a defined MCID for GP1 makes interpreting the clinical significance of the findings challenging.