Managing ARPI-related fatigue: Balancing tolerability and treatment persistence

In this video, Jeffrey M. Spier, MD, discusses strategies for managing fatigue associated with androgen receptor pathway inhibitor (ARPI) therapy in patients with prostate cancer, including dose reduction, patient monitoring, and approaches to maintaining treatment adherence. Spier is a urologist at Rio Grande Urology in El Paso, Texas.

Fatigue associated with ARPI therapy can substantially affect patients’ daily functioning and quality of life, limiting physical activity and exercise, affecting mood, and reducing enjoyment of daily activities and relationships, according to Spier. He emphasized the importance of assessing how fatigue interferes with each patient’s life and counseling patients about potential adverse effects before initiating treatment. He also notes that fatigue may be more prevalent in clinical practice than reported in clinical trials, highlighting the need for proactive assessment and ongoing management.

For patients who develop persistent fatigue while receiving enzalutamide (Xtandi), Spier recommends evaluating other potential contributors, including anemia, hypothyroidism, depression, and androgen deprivation therapy (ADT), before attributing symptoms to the ARPI. If enzalutamide is the likely cause, he noted that dose reduction may be a viable option, particularly when fatigue interferes with daily activities. He explained that decisions about dose adjustments should incorporate shared decision-making, prostate-specific antigen (PSA) trends, and disease status. He generally continues a reduced dose as long as it remains tolerable and disease control is maintained, with consideration of dose re-escalation if the patient tolerates treatment and clinical circumstances warrant it. Regular follow-up, typically every 3 months, provides opportunities to assess tolerability, monitor PSA levels, and revisit dosing decisions, he added.

Baseline fitness and functional status are also important considerations when managing treatment-related fatigue. Spier exercises particular caution in patients who are frail, have limited exercise capacity, or are at increased risk of falls. He further emphasizes that adverse effects can contribute to poor adherence, treatment interruptions, and discontinuation, making proactive counseling and toxicity management essential to sustaining therapy. Rather than allowing intolerable adverse effects to lead patients to stop treatment altogether, clinicians should discuss manageable alternatives, including dose adjustments, while continuing to monitor disease response, Spier emphasizes.

“Some is better than none would be my philosophy,” Spier says, underscoring the importance of finding a tolerable treatment approach that allows patients to remain on therapy whenever clinically appropriate.