Clinical strategies for treating metastatic castration-sensitive prostate cancer

A recent Urology Times Clinical Forum in Chicago, moderated by Aaron Berger, MD, chief medical officer and director of Clinical Research for Associated Urological Specialists in Illinois, brought together clinicians to discuss evolving strategies for the management of metastatic castration-sensitive prostate cancer (mCSPC). The conversation centered on treatment intensification, patient selection, sequencing of therapies, and real-world considerations associated with the growing use of androgen receptor pathway inhibitors (ARPIs). Across academic and community perspectives, participants emphasized that the modern standard of care for most patients with mCSPC includes androgen deprivation therapy (ADT) combined with an ARPI, with multiple agents now available to support individualized decision-making.

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

Initial evaluation and risk stratification

The discussion began with consensus on the importance of accurate staging and risk stratification at diagnosis. Clinicians highlighted disease volume, metastatic distribution, prostate-specific antigen (PSA) kinetics, Gleason score, symptom burden, and patient comorbidities as key determinants of therapy selection. Although conventional imaging still plays a role in some settings, most participants described PET-based imaging—particularly prostate-specific membrane antigen (PSMA)-PET—as their preferred modality when available. However, variability in insurance coverage continues to influence real-world practice, sometimes requiring sequential imaging approaches.

Once metastatic disease is confirmed, participants emphasized early treatment intensification rather than ADT alone. ADT monotherapy was described as increasingly uncommon and generally reserved for frail patients or those with limited life expectancy who may not tolerate additional therapy.

ARPI-based doublet therapy as the foundation of care

The forum devoted substantial attention to the role of ARPIs in combination with ADT, recognizing this approach as a cornerstone of mCSPC management. Enzalutamide (Xtandi), apalutamide (Erleada), abiraterone acetate (Zytiga), and darolutamide (Nubeqa) were discussed as established options, each supported by robust clinical trial data and increasingly used in routine practice.

Clinicians described enzalutamide as a commonly selected agent due to its broad evidence base across disease states, including mCSPC and earlier biochemical recurrence. Participants noted consistent improvements in progression-free and overall survival across patient subgroups, reinforcing confidence in its long-term efficacy. Fatigue was identified as the most frequently encountered adverse event (AE), though it was generally described as manageable with patient education and supportive care.

Apalutamide was discussed as another well-integrated option in mCSPC, particularly for clinicians familiar with its use in earlier disease settings. Participants highlighted its favorable disease control outcomes and similar survival benefits when combined with ADT. Rash and fatigue were acknowledged as AEs that require monitoring, but most clinicians reported that these issues rarely necessitate discontinuation when proactively managed.

Abiraterone, administered with prednisone, was discussed extensively for its long-standing role in metastatic prostate cancer. Panelists emphasized its effectiveness across a wide range of disease volumes and its appeal in certain patient populations. Monitoring requirements, including liver function tests and electrolyte levels, were noted as important considerations, particularly for patients with cardiovascular risk factors or metabolic comorbidities. Despite these monitoring needs, many clinicians expressed comfort with abiraterone due to extensive real-world experience.

Darolutamide was highlighted for its favorable tolerability profile and minimal central nervous system penetration. Participants noted that this characteristic may be particularly relevant for older patients or those with concerns about cognitive effects or fall risk. Although darolutamide has been most prominently studied in combination with docetaxel in high-volume disease, clinicians described growing comfort using it as part of intensified regimens for appropriate patients.

Selecting among ARPIs in practice

Rather than positioning one ARPI as superior, the group emphasized matching therapy to patient-specific factors. Age, baseline fatigue, cognitive concerns, cardiovascular health, medication burden, and patient preference were all cited as reasons to favor one agent over another. Participants agreed that shared decision-making is critical, particularly when multiple effective options exist with differing safety profiles and administration considerations.

Several clinicians noted that prior exposure to ARPIs in earlier disease states can influence selection at the metastatic stage. Others described institutional preferences or payer considerations that also shape real-world choices.

Triplet therapy and chemotherapy considerations

The conversation also addressed the evolving role of triplet therapy combining ADT, an ARPI, and docetaxel. Although acknowledging the survival benefit demonstrated in select high-risk populations, most clinicians reported a more selective approach to upfront chemotherapy. Triplet therapy was typically reserved for younger, fit patients with high-volume or visceral metastatic disease. For many patients, ARPI-based doublet therapy was viewed as sufficient initial treatment, with chemotherapy reserved for later lines.

Monitoring response and disease progression

PSA monitoring remains central to assessing response, although participants cautioned against relying on PSA alone. Deep PSA responses, particularly achieving undetectable levels, were viewed as favorable prognostic indicators. However, clinicians acknowledged that radiographic progression can occasionally occur despite stable PSA, prompting periodic imaging in selected patients.

When disease progression is identified, clinicians described transitioning to alternative systemic therapies based on prior ARPI exposure, performance status, and molecular profiling results. Sequencing decisions were described as increasingly nuanced as more treatment options become available.

Genetic testing and future planning

Genetic testing has become an integral part of managing metastatic prostate cancer. Panelists reported routine use of germline and somatic testing at the time of metastatic diagnosis, with repeat testing at progression when appropriate. Identifying actionable mutations helps inform later-line therapies, including PARP inhibitors, and supports more personalized care.

Conclusion

The forum underscored that management of mCSPC has shifted decisively toward early, sustained treatment intensification using ARPIs in combination with ADT. Enzalutamide, apalutamide, abiraterone, and darolutamide each play an important role in contemporary practice, offering clinicians multiple effective options to tailor therapy based on patient characteristics and preferences. Rather than a one-size-fits-all approach, optimal care relies on thoughtful selection, proactive toxicity management, and ongoing reassessment as disease biology and patient needs evolve.