Clinical perspectives on ARPIs in metastatic prostate cancer

During a Urology Times^@Clinical Forum held in Nashville, Tennessee, moderator David Morris, MD, FACS, led a multidisciplinary group of clinicians in a wide-ranging discussion on the evolving management of metastatic prostate cancer. The conversation reflected how quickly the treatment landscape is shifting, particularly as urologists and medical oncologists navigate increasingly complex imaging findings and a broadening menu of systemic therapies. What follows is a summary of this program.

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

Changing patterns of presentation and the impact of modern imaging

Clinicians agreed that the majority of metastatic cases now enter the system through outpatient evaluation rather than hospital admissions. Patients frequently present with elevated prostate-specific antigen (PSA) levels or incidental imaging abnormalities identified during unrelated evaluations. Some attendees described receiving referrals from non-urologic physicians who had pursued advanced imaging or biopsies before a prostate biopsy was even performed.

This shift has heightened the importance of effective evaluation and coordination at the urology level, particularly when prostate-specific membrane antigen (PSMA)-PET imaging reveals only minimal disease. Participants noted that PSMA-PET has created a growing population of patients with “borderline” metastatic findings—cases in which only 1 or 2 small metastases are detected. These findings are difficult to align with historical concepts of low- vs high-volume disease, which were defined using conventional imaging. The clinicians agreed that evidence guiding treatment in this emerging category remains incomplete, and the ambiguity significantly affects therapeutic decision-making.

Multidisciplinary coordination and timing of oncology referral

The group discussed wide variation in when and how patients transition from urology to medical oncology. In some practices, systemic therapy is initiated primarily by oncologists; in others, urologists frequently begin treatment themselves—particularly when oncology access is limited or scheduling delays would set back timely therapy.

Participants emphasized that coordination is often less structured than it should be. Communication lapses sometimes lead to duplicated testing or confusion over who is responsible for initiating treatment. The clinicians agreed that clearer pathways, even if informal, are essential for efficient care—especially as treatment regimens become more complex.

Transitioning from monotherapy to combination treatment

As treatment standards evolve, monotherapy with androgen deprivation therapy (ADT) alone has become less common. Most clinicians described shifting toward combination therapy, whether as a doublet (ADT plus an androgen receptor pathway inhibitor [ARPI]) or, in selected cases, as a triplet that incorporates chemotherapy.

The physicians emphasized tailoring treatment intensity to disease burden and patient fitness. High-volume or symptomatic disease typically prompts more aggressive therapy, whereas low-volume disease with minimal symptoms often sparks debate about the best degree of intensification. The Nashville discussion reflected ongoing uncertainty in the field, especially for patients with only 1 or 2 metastatic sites on PET imaging. Many felt that the available data do not clearly define how aggressively such cases should be treated.

The expanding role of enzalutamide

A major focus of the discussion involved the practical advantages and considerations associated with enzalutamide (Xtandi), an ARPI that many participants use frequently in mCSPC.

Clinicians described several reasons why enzalutamide remains a widely chosen option:

1. Broad familiarity and real-world comfort: Many attendees noted that enzalutamide has become highly integrated into their workflows. Staff are familiar with its dosing, monitoring, and potential adverse events, making it straightforward to implement.

2. Convenient administration: The oral, once-daily dosing was viewed as an advantage for many patients. Physicians noted that simplifying treatment routines can ease adherence, particularly for older adults managing multiple medications.

3. Suitability across a wide clinical spectrum: Participants explained that they often consider enzalutamide for both low- and high-volume metastatic disease. They especially valued its versatility when developing plans for patients who are not candidates for chemotherapy or when immediate systemic intensification is required.

4. Increased reliance in community practice: Some urologists shared that in regions where medical oncology appointments are difficult to obtain quickly, they themselves initiate ADT plus enzalutamide to avoid delaying treatment. The group agreed that this pattern is becoming more common, and that familiarity with enzalutamide’s workflow features—monitoring requirements, scheduling, and counseling—helps support this approach.

5. Considerations related to tolerability: Participants discussed adverse events associated with the ARPI class. Fatigue was described as one of the more frequent issues with enzalutamide, prompting clinicians to incorporate patient lifestyle factors into counseling. Even so, many emphasized that they successfully use enzalutamide in older adults when careful monitoring is in place.

Local therapy and the oligometastatic question

The clinicians also examined the ongoing question of whether and how to use local therapy—particularly radiation—in cases of oligometastatic disease. With PSMA-PET revealing smaller and fewer metastases than were historically seen, the group acknowledged that the evidence base guiding radiotherapy decisions is increasingly misaligned with modern staging.

Several physicians described uncertainty about which patients benefit most from prostate-directed radiation or metastasis-directed radiation in combination with ARPI-based systemic therapy. Determining the appropriate duration of intensification, particularly in men with very limited metastatic burden, was also identified as a recurring clinical dilemma.

Case discussions: Applying evidence to practice

Throughout the forum, participants worked through real-world case scenarios that reflected the practical challenges of treating metastatic disease.

One scenario involved a patient presenting with a very high PSA but limited metastatic disease on PSMA-PET. The clinicians debated how intensively to treat such a patient, given the ambiguity in mapping PET findings to historical trial definitions. Most favored initiating combination systemic therapy promptly, with several noting that enzalutamide would be a reasonable choice for its ease of initiation and manageable monitoring requirements.

Another case involved a patient with extensive comorbidities and lower performance status. Here, clinicians evaluated how to balance the need for cancer control against the risk of treatment-related exhaustion or decline. Some would still recommend combination therapy, whereas others suggested moderating treatment intensity so that therapy remains tolerable. Several explained that enzalutamide can be used successfully in such patients with proper monitoring for fatigue and other systemic effects.

Follow-up, monitoring, and tailoring treatment over time

The forum also addressed how to monitor treatment response, manage adverse events, and adjust therapy as the disease evolves. Participants emphasized:

• the importance of periodic imaging, though frequency varies widely in practice

• attention to patient-reported symptoms, especially fatigue or cognitive changes

• coordination between urology and oncology to ensure consistent follow-up

• flexibility in modifying therapy based on disease progression or tolerance

Several clinicians explained that in patients doing well on ADT plus enzalutamide, they continue the regimen indefinitely while monitoring PSA kinetics, side effects, and quality of life.

Moving toward practical, patient-centered intensification

The Nashville discussion reflected a consensus that treatment for metastatic prostate cancer is becoming more complex—but also more effective. The group agreed that systemic therapy intensification should be discussed with virtually all metastatic patients, with adjustments based on comorbidities, disease volume, and patient goals.

Although the field continues to refine optimal intensification strategies, the clinicians expressed confidence that ARPIs—particularly enzalutamide—will remain central components of mCSPC management. Their familiarity with the agent, broad applicability across disease states, and straightforward dosing contribute to its strong real-world role.

Overall, the clinicians highlighted the need for more clarity in the PSMA-PET era, better pathways for multidisciplinary coordination, and continued attention to practical issues that influence treatment selection. The Nashville forum captured the realities of applying evolving evidence to everyday practice, emphasizing individualized care, modern systemic therapy, and collaboration across specialties as the foundation of contemporary metastatic prostate cancer management.