Intensifying treatment in mCSPC: Balancing efficacy and tolerability

During a recent Urology Times Clinical Forum discussion in San Antonio, Texas, urologists gathered to examine evolving strategies for managing metastatic castration-sensitive prostate cancer (mCSPC). The conversation, moderated by Daniel R. Saltzstein, MD, of Urology San Antonio, centered on sequencing systemic therapies, balancing treatment intensity with patient tolerability, and integrating emerging evidence from pivotal trials.

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

Shifting paradigms in mCSPC management

The discussion began with consensus that the treatment paradigm for mCSPC has shifted decisively toward earlier and more intensive systemic therapy. Participants emphasized that androgen deprivation therapy (ADT) alone is no longer sufficient for most patients, with data supporting combination regimens to improve survival outcomes. Although ADT remains the foundation of care, the addition of next-generation androgen receptor (AR) inhibitors or chemotherapy has become standard in eligible patients.

The group reflected on how key studies, such as CHAARTED and STAMPEDE, established the importance of intensifying therapy in patients with high-volume disease, whereas more recent trials continue to refine optimal sequencing and combination approaches. Even so, treatment selection remains individualized, with decisions shaped by factors including disease burden, comorbidities, patient preferences, and logistical barriers such as insurance coverage.

Participants noted that although adoption of combination regimens has grown, a substantial proportion of patients with metastatic disease still receive only ADT. Contributing factors include cost, limited awareness, and hesitation among both clinicians and patients to escalate therapy in older or frail individuals.

Sequencing and patient selection

The group discussed how disease volume and distribution influence therapeutic strategy. For high-volume or symptomatic disease, clinicians favored systemic intensification, typically combining ADT with either an AR-targeted agent or docetaxel. For low-volume or indolent presentations, some participants considered starting with doublet therapy while deferring chemotherapy to preserve quality of life.

Case-based discussions underscored the nuances of these decisions. For example, a patient with bone metastases and mild symptoms might benefit from an oral AR inhibitor rather than docetaxel, given the need for long-term disease control with manageable toxicity. In contrast, patients presenting with rapidly progressive or visceral disease may be candidates for triplet therapy incorporating both docetaxel and an AR inhibitor.

Participants highlighted that multidisciplinary collaboration between urologists, oncologists, and primary care physicians is crucial for coordinating these complex treatment pathways, particularly in community settings where resources may vary.

Role of darolutamide in modern practice

A major focus of the discussion was the growing role of darolutamide (Nubeqa) in the management of mCSPC. Clinicians discussed findings from the ARASENS and ARANOTE trials, which demonstrated robust efficacy and tolerability across a broad range of patients.

Darolutamide’s pharmacologic profile was described as a key differentiator among AR inhibitors. Its limited penetration of the blood-brain barrier results in fewer central nervous system (CNS) adverse events, such as fatigue, cognitive changes, and falls, which are more commonly associated with other agents in the class. This feature, coupled with minimal drug–drug interactions, makes darolutamide a particularly attractive option for older patients and those with comorbidities or complex medication regimens.

The group noted that darolutamide’s safety profile has led many clinicians to favor it in patients who might otherwise be ineligible for or intolerant of other AR inhibitors. Participants cited improved patient adherence and satisfaction in real-world use, attributing this in part to the reduced risk of CNS-related adverse events that can compromise quality of life and functional independence.

Darolutamide’s use in both doublet therapy (in combination with ADT) and triplet therapy (with ADT and docetaxel) was discussed extensively. The ARASENS trial established the triplet combination as a standard option for high-volume mCSPC, while the ARANOTE data supported ADT plus darolutamide as an effective alternative for patients not suited for chemotherapy. Panelists emphasized that the availability of these complementary regimens enables clinicians to tailor therapy intensity to patient condition and treatment goals.

Comparative considerations and tolerability

Comparisons among AR inhibitors—darolutamide, apalutamide (Erleada), enzalutamide (Xtandi), and abiraterone acetate (Zytiga)—featured prominently in the conversation. Although efficacy across agents appears broadly similar, panelists agreed that tolerability, drug interactions, and practical factors often guide final selection.

Apalutamide and enzalutamide were associated with a higher incidence of fatigue, hypertension, and cognitive effects, whereas abiraterone requires concomitant prednisone and frequent monitoring of liver enzymes and potassium levels. In contrast, darolutamide’s limited CNS penetration and favorable adverse event profile make it appealing for older or comorbid patients.

Participants highlighted that these distinctions are meaningful in day-to-day practice, as many patients with metastatic disease are older and have cardiovascular, metabolic, or cognitive comorbidities. Minimizing treatment-related toxicity was viewed as essential to maintaining quality of life and adherence over prolonged therapy durations.

Patient cases and real-world decision-making

Several case discussions illustrated how clinicians apply trial data to practice. One example involved a patient in his early 70s with bone-only disease and well-controlled cardiovascular comorbidities. The group agreed that ADT combined with darolutamide would provide optimal disease control with minimal toxicity risk.

Another case focused on a younger patient with high-volume visceral disease and good performance status, for whom triplet therapy with ADT, darolutamide, and docetaxel was favored. Clinicians emphasized the importance of shared decision-making, ensuring that patients understand the potential trade-offs between intensified treatment and adverse event burden.

The conversation also addressed logistical challenges such as insurance approvals and drug tier placement, which can influence regimen choice as much as clinical factors. Participants noted ongoing efforts to improve patient access to newer agents through institutional pathways and patient assistance programs.

Managing adverse events and maintaining quality of life

Across all therapies, adverse event monitoring and proactive management were emphasized as critical to sustained treatment success. Fatigue, hypertension, and mild gastrointestinal effects remain among the most common AEs associated with AR inhibitors. Clinicians recommended early identification and intervention, including medication adjustment or supportive measures.

Darolutamide was noted for its lower incidence of CNS and fatigue-related events, which may contribute to better treatment continuity and patient-reported outcomes. Participants stressed that ongoing communication, multidisciplinary support, and clear patient education are key to managing side effects and optimizing adherence.

Looking ahead

The panel concluded by discussing ongoing research and the future direction of mCSPC treatment. Several clinicians anticipated broader use of AR inhibitors in earlier disease settings and in combination with novel agents, as emerging data continue to show survival and quality-of-life benefits.

Participants also acknowledged that despite strong evidence for combination therapy, underutilization persists nationwide. They called for continued education, streamlined access pathways, and collaborative care models to ensure patients benefit fully from therapeutic advances.

Conclusion

The San Antonio discussion underscored that systemic therapy for mCSPC is increasingly centered on individualized combination strategies. Darolutamide has emerged as a preferred option for many clinicians, offering potent disease control with a favorable safety and tolerability profile. As real-world experience and clinical data continue to expand, integrating these therapies thoughtfully—based on patient characteristics, comorbidities, and personal goals—remains key to achieving durable outcomes in this evolving disease landscape.