A Guide to Managing Toxicities Across Four Androgen Receptor Pathway Inhibitors in Prostate Cancer

Understanding ARPI-Related Toxicities in Prostate Cancer

In this episode of the Tox Check series on the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Alicia Morgans, MD, MPH, of Dana-Farber Cancer Institute, and Christopher Pieczonka, MD, of U.S. Urology Partners, about the use of ARPIs for the management of prostate cancer. In this disease space, there are four FDA-approved ARPIs: abiraterone, apalutamide, darolutamide, and enzalutamide.

These drugs, when used with androgen deprivation therapy (ADT), have long been considered a mainstay for treatment. However, they are associated with side effects, including cognitive changes and cardiac events, which must be considered when recommending a course of therapy to allow patients to remain on a drug safely for a longer period of time.

Key Side Effects With Abiraterone

Abiraterone is associated with several toxicities, with a common concern being fluid retention in patients with mineralocorticoid excess, according to Dr. Pieczonka. While peripheral edema in the legs is easy to see, Dr. Pieczonka said the drug is also associated with increased risk of congestive heart failure.

Another concern is blood abnormalities, such as transaminase elevation, hepatotoxicity, and hypokalemia—a condition that often goes undetected. “If a patient in our practice is on abiraterone, most of the reason we have them come in is to rule out life-threatening hypokalemia,” Dr. Pieczonka said.

To avoid that scenario, Dr. Pieczonka recommended checking the comprehensive metabolic panel every 2 weeks for the first 3 months, then monthly.

In some cases, physicians may use abiraterone at a lower dose of 250 mg with a low-fat meal rather than the standard 1000-mg dose taken on an empty stomach. This approach may be considered for some patients, including when cost is a concern. “We have options. So we can try other things, but it’s not my typical go-to unless there are financial reasons,” Dr. Morgans said.

However, using the lower dose does not necessarily reduce toxicity even though blood levels appear to be similar, she noted.

Apalutamide: Addressing Rash, Falls, and Endocrine Toxicities 

Apalutamide gained attention at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, where findings from the phase 3 PROTEUS clinical trial demonstrated its efficacy as part of a perioperative treatment regimen. When used in combination with ADT before and after surgery, it was shown to significantly improve outcomes in high-risk localized or locally advanced prostate cancer, Dr. Rohit Gosain said.

However, use of apalutamide is also associated with increased risk of falls and fatigue. Rash is also a concern, typically appearing around 2 months after administration and affecting up to 29% of patients, Dr. Pieczonka explained. Rash identification and counseling are key, he added, since it can lead to scarring or Stevens-Johnson syndrome. 

Although there are data supporting dose reduction, Dr. Pieczonka advised stopping the medication completely in the event of a rash. 

Other toxicities for physicians to consider include fatigue and hypothyroidism, which presents in about 8% of patients, according to Dr. Pieczonka. 

Darolutamide’s Role in Preserving Cognitive Function 

With darolutamide, Dr. Morgans advised monitoring liver function, particularly because it is taken twice a day.  “It’s important that patients remember to take that second dose in order to get adequate exposure to the medication and get full treatment and the full effect,” Dr. Morgans said. 

An important benefit of the drug was uncovered at ASCO 2026, where results of the phase 2 ARACOG trial were presented by Dr. Morgans, who served as the study’s lead author. She and colleagues found that darolutamide caused significantly less cognitive decline compared with enzalutamide in patients with advanced prostate cancer based on computer-based assessments. The findings could have significant implications, according to Dr. Morgans. “If I have a patient who already has mild cognitive decline, if I have a patient at high risk, or if I have a patient who says ‘My job is dependent on maintaining mental acuity,’ then darolutamide is often a drug I’ll reach for,” she said. 

“I was quite impressed [with the results of the ARACOG study],” Dr. Pieczonka said. “That might be practice-changing for us here in the clinic. It certainly is eye-opening for me about the potential for patients who might have more neurocognitive side effects on enzalutamide switching to darolutamide.”

Fall and Fracture Risk With Enzalutamide

For patients taking enzalutamide, there is risk of falls, seizure, and fatigue. The most serious concern is the risk of  falls leading to fracture and causing harm to the patient, Dr. Pieczonka said. 

Side effect awareness is critical. Dr. Pieczonka suggested counseling patients on cane use if they were on the verge of needing one and asking about the home environment. Nurse practitioners are also advised to schedule a visit with the patient one month into enzalutamide therapy for the patient to undergo cognitive testing.

Dr. Morgans agreed, urging physicians to screen for mobility and memory challenges. “It’s important to remember that all the side effects of ADT are also going to impact patients taking ARPIs,” she said. “We do have the ability to make inroads.”

At the same time, it’s important to remember that while the data can help inform treatment strategies, each patient is different. “You have to do what you think is best for the patients using the entire cadre of information,” Dr. Pieczonka said.