Personalized systemic approaches for treatment of mHSPC

Leaders in urologic oncology convened in Oklahoma City to discuss evolving strategies in the management of metastatic hormone-sensitive prostate cancer (mHSPC). Under the moderation of Michael Cookson, MD, MMHC, FACS, participants explored the increasing role of treatment intensification, the practical use of androgen receptor (AR) inhibitors such as darolutamide (Nubeqa), and the nuances of patient selection in both doublet and triple therapy approaches.

Shifting Standards in Hormone-Sensitive Disease

The discussion began with a reflection on how dramatically the treatment landscape has changed in recent years. Once managed primarily with androgen deprivation therapy (ADT) alone, mHSPC is now treated with a range of combination approaches supported by strong clinical data.

Although pivotal trials such as CHAARTED, LATITUDE, and ARASENS have established combination therapy as standard of care, clinicians acknowledged that real-world adoption remains uneven. Factors such as patient comorbidities, access, and institutional familiarity continue to shape treatment decisions. Several participants noted that a significant portion of men in community settings still receive ADT alone despite clear evidence supporting intensification.

Assessing disease burden and tailoring treatment intensity

The panel discussed how they stratify patients by disease volume and overall health status when determining therapy. For de novo metastatic patients with high-volume disease, most agreed that combination therapy with ADT and either chemotherapy or an AR inhibitor provides the best outcomes.
Conversely, for patients with low-volume or recurrent disease after prior local therapy, the group leaned toward intensification with an oral AR inhibitor, often without chemotherapy.

Cookson emphasized the growing importance of individualization—recognizing that not every patient is a candidate for triplet therapy, but that almost all benefit from intensification beyond ADT alone.

Evolving role of darolutamide

Much of the discussion centered on darolutamide, a next-generation AR inhibitor that has gained traction for its tolerability and expanding indications. Clinicians highlighted that darolutamide’s development, including the ARASENS trial, demonstrated a survival advantage when combined with ADT and docetaxel in patients with mHSPC.

Participants noted that darolutamide is now used both within the triplet regimen and as part of doublet therapy with ADT alone, reflecting a more individualized approach to disease management. Several described darolutamide as a favorable option for patients who are either not ideal candidates for chemotherapy or who have experienced side effects with other AR inhibitors.

One participant observed that the drug’s limited central nervous system penetration likely contributes to its favorable adverse event profile, especially in comparison to older agents such as enzalutamide (Xtandi). Fatigue, cognitive effects, and falls were reported to be less frequent, making darolutamide particularly appealing for older or more frail men.

Real-world application and sequencing strategies

As treatment options multiply, sequencing and timing have become more complex. Panelists shared differing opinions about when to introduce darolutamide and how to manage transitions from other AR inhibitors. Several clinicians described switching patients to darolutamide after intolerance to other agents, particularly in those experiencing fatigue or mental clouding.

Others emphasized initiating darolutamide earlier, as part of first-line therapy, to optimize long-term disease control. A consistent theme was the need for shared decision-making with patients, weighing oncologic benefit against quality-of-life considerations.

From a logistical standpoint, participants cited access and formulary approval as occasional barriers, though most noted that insurance authorization has improved as darolutamide’s role has expanded. A few centers had implemented streamlined approval pathways for AR inhibitors to reduce treatment delays.

Selecting between doublet and triple therapy

The panel discussed the practical decision points between darolutamide-based doublet therapy and the triplet regimen that includes docetaxel. Many clinicians favored doublet therapy for patients with comorbidities, limited performance status, or a strong desire to avoid chemotherapy.

For younger, fit men with high-volume disease, most agreed that the triplet regimen offers the greatest chance for deep and durable response. However, participants also acknowledged that even in these cases, not all patients tolerate chemotherapy well, and darolutamide monotherapy in combination with ADT can remain a viable and evidence-based choice.

Several clinicians referenced the ongoing shift in how disease volume and tempo influence these decisions. For instance, in patients with low-volume but high-grade disease, or those who experience rapid PSA doubling, adding darolutamide earlier was considered reasonable. Others highlighted that genomic testing and molecular profiling may soon help identify those most likely to benefit from therapy intensification.

Managing toxicity and preserving quality of life

Across the discussion, participants underscored the importance of maintaining quality of life as treatment options expand. The relatively low rates of fatigue, hypertension, and cognitive adverse events seen with darolutamide were consistently cited as major advantages.

Clinicians shared their real-world observations that patients tend to tolerate darolutamide longer without dose interruptions. This, they noted, can translate into more consistent disease suppression and fewer therapy-related disruptions to daily life.

Practical management strategies included periodic laboratory monitoring, attention to cardiovascular risk factors, and collaboration with primary care physicians for patients on long-term ADT and AR inhibition. The panel agreed that proactive communication about side effects helps ensure adherence and patient confidence in treatment.

Emerging data and future directions

The conversation also touched on future directions in therapy sequencing and biomarker-driven care. Participants expressed interest in emerging data exploring early use of AR inhibitors across disease stages and potential de-escalation strategies for patients achieving deep responses.

Cookson concluded by noting that ongoing studies will likely refine the role of darolutamide in both hormone-sensitive and castration-resistant settings. As combination strategies continue to evolve, balancing efficacy with tolerability will remain the cornerstone of care.

Conclusion

The Oklahoma City discussion underscored that management of mHSPC is no longer defined by a single standard approach. Instead, clinicians are integrating agents such as darolutamide into nuanced, patient-specific regimens that reflect both evidence and experience.

Darolutamide’s favorable tolerability profile and proven efficacy in combination therapy have made it an increasingly important part of that discussion—offering clinicians flexibility to tailor treatment intensity without sacrificing outcomes.