How clinicians navigate ARPI therapy in metastatic prostate cancer

This summary was generated by artificial intelligence and edited by humans for clarity.

During a Urology Times Clinical Forum in Evesham, New Jersey, Gordon A. Brown, DO, FACOS, led an extensive discussion on the rapidly evolving management of metastatic prostate cancer, emphasizing practical decision-making, real-world challenges, and how clinicians are operationalizing the growing body of evidence supporting treatment intensification. The conversation focused heavily on androgen receptor pathway inhibitors (ARPIs)

Defining risk and understanding disease volume

The session opened with a review of how clinicians classify patients with metastatic hormone-sensitive prostate cancer (mHSPC). Participants reaffirmed that high-volume disease continues to be defined by traditional criteria: at least 4 bone lesions (with 1 or more beyond the axial skeleton) or visceral metastases. This classification continues to influence treatment decisions, especially when determining who is most likely to benefit from treatment intensification or the addition of taxane chemotherapy.

Clinicians also noted that symptoms—bone pain, declining function, anemia, and renal compromise—carry significant weight when choosing therapy. The distinction between synchronous and metachronous metastases remains important, although the adoption of prostate-specific membrane antigen (PSMA)–PET imaging has blurred older staging boundaries. Several clinicians acknowledged that conventional “low volume” and “high volume” categories are increasingly difficult to apply when more sensitive imaging reveals disease previously undetectable by CT or bone scan. This imaging shift is creating a new clinical dilemma: deciding when a patient is exhibiting a classic high-risk biochemical recurrence rather than true metastatic disease.

PSMA-PET and the evolution of risk classification

The group explored how the widespread use of PSMA-PET is altering patient stratification. Many patients previously classified with biochemical recurrence would be reclassified as having metastatic disease when staged with PSMA-PET. The higher sensitivity of PSMA-PET often reveals isolated or low-burden PSMA-positive disease despite negative conventional imaging. Participants discussed how these patients may resemble the population studied in trials such as the phase 3 EMBARK study (NCT02319837), where targeted intensification—rather than long-term systemic therapy—appears beneficial.

Because of the growing dependence on PSMA-PET, clinicians acknowledged uncertainty about when imaging progression should trigger a change in therapy, particularly when PSA remains suppressed. The current practical approach is often to treat localized sites with radiotherapy while maintaining the existing systemic regimen.

Treatment intensification: The role of ARPIs

A significant portion of the discussion centered on ARPIs. The group reviewed multiple clinical trials that have shaped modern standards, noting that enzalutamide (Xtandi) remains widely used due to familiarity, broad indications, and predictable clinical performance.

Positioning of enzalutamide

Participants highlighted several points regarding enzalutamide’s use:

• It is viewed as a reliable first-line choice in mHSPC and remains a “workhorse” across practice settings.

• Its efficacy appears consistent regardless of disease volume, Gleason score, or timing of metastases.

• Many clinicians favor enzalutamide because insurance approval is usually straightforward and patient assistance programs are well established.

• PSA suppression to 0.2 ng/mL or less—and especially to ultralow thresholds—is increasingly seen as a meaningful prognostic indicator. Enzalutamide often achieves these deep PSA responses, reinforcing confidence in its selection.

Clinicians also discussed differences between ARPIs. Although some younger, fit patients may be steered toward abiraterone acetate (Zytiga) due to cost advantages or long-term familiarity, enzalutamide remains preferred for patients in whom steroid exposure should be minimized or avoided. The group also cited concerns about potential central nervous system–related effects but agreed that most patients tolerate enzalutamide without significant toxicity.

Choosing between ARPIs: Practical considerations

The group acknowledged that decisions are sometimes influenced by factors unrelated to clinical trial data. These include:

• Drug–drug interactions, especially in older patients with multiple medications

• Patient adherence challenges, especially with food-dependent formulations

• Cost considerations, particularly when generic abiraterone is available

• Local comfort and experience with each agent

Despite these variables, participants agreed that enzalutamide’s ease of use—once-daily dosing without food restrictions—makes it appealing for the majority of patients, particularly those who may have trouble following more complex medication schedules.

Chemotherapy and triplet therapy

The conversation moved to the role of docetaxel in combination with ARPIs. Participants noted that although European practitioners favor docetaxel more frequently, US utilization remains lower. In local practice, docetaxel tends to be reserved for:

• patients with high-volume or visceral metastases;

• younger patients with strong performance status; and

• those with aggressive biology or rapid clinical decline.

Some clinicians expressed a preference for abiraterone when using triplet therapy, although enzalutamide-based triplets remain an option depending on insurance coverage and patient profile.

Overall, the group agreed that triplet therapy should be selectively deployed rather than considered a universal standard.

Tolerability and quality-of-life considerations

Clinicians shared practical observations about the tolerability profiles of various ARPIs. Consistent with general experience, enzalutamide was described as manageable for most patients, although some do experience fatigue. If a patient experiences intolerable fatigue or functional decline, switching to darolutamide (Nubeqa) or abiraterone is a common strategy. However, such switches are infrequent in most practices.

Participants also discussed that many older patients struggle with the exact dosing instructions needed for certain therapies, especially abiraterone. In contrast, the simplicity of enzalutamide dosing reduces the risk of improper use and may help preserve therapeutic benefit.

Evolving concepts: PSA monitoring, genetics, and novel approaches

The forum shifted toward monitoring and next-generation treatment approaches. Ultrasensitive PSA assessments are increasingly used to understand the depth of response, although clinicians acknowledged the lack of definitive guidance on how these tiny fluctuations should influence management.

Genetic testing—both germline and somatic—remains underutilized nationwide, despite its relevance for identifying candidates for emerging therapies such as PARP inhibitors and PTEN-targeted treatments. Participants agreed that guidelines are pushing toward broader genetic testing and that practices must improve their workflows to achieve this.

The group also discussed emerging therapies under investigation, including radionuclide therapy in earlier disease states, novel ARPI combinations, and even experimental strategies such as bipolar androgen therapy. Although these approaches remain exploratory, clinicians were intrigued by their potential future applications.

Conclusions

This event highlighted the continued momentum toward treatment intensification in metastatic prostate cancer and underscored the central role that ARPIs—particularly enzalutamide—play in modern clinical practice.

Participants emphasized that individualized care remains essential. Disease volume, patient age, comorbidities, symptom burden, and treatment adherence capability all influence treatment selection. As imaging and therapeutic options evolve, clinicians will continue adapting their approach, but ARPIs—and especially enzalutamide—are expected to remain foundational tools in managing metastatic prostate cancer.