mCSPC management: Doublet, triplet, and the role of ARPIs

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

A Urology Times Clinical Forum moderated by Joseph Song, MD, and Jessica Feehan, NP-C, of Georgia Urology, convened a group of practicing urologists to discuss the evolving treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC). The discussion addressed landmark trial data, androgen receptor pathway inhibitor (ARPI) selection, quality-of-life considerations, and the practical challenges of delivering and monitoring combination therapy.

A rapidly changing treatment landscape

The forum opened with a review of how substantially the management of mCSPC has changed over the past decade. Androgen deprivation therapy (ADT) monotherapy is no longer considered an adequate standard of care for most patients with mCSPC. Combination regimens—doublet therapy (ADT plus an ARPI) or, in select patients, triplet therapy (ADT plus an ARPI plus docetaxel)—are now the established approach. Participants noted that single-agent ADT may still be appropriate in carefully selected patients with significant comorbidities, drug-drug interaction concerns, or advanced age and limited functional reserve, and that some asymptomatic patients may be candidates for active surveillance with serial prostate-specific antigen (PSA) and imaging.

For risk stratification, the group referenced the CHAARTED (NCT00309985) criteria, which classify high-volume disease as 4 or more bone metastases (with at least 1 outside the axial skeleton) or the presence of visceral metastases. Patients with high-volume disease are generally candidates for triplet therapy, whereas those with low-volume disease are typically managed with doublet therapy. The LATITUDE trial’s (NCT01715285) stratification schema, which incorporates Gleason score and visceral metastasis, was also discussed as an additional tool for guiding treatment intensification.

Landmark trials establishing combination therapy

Song reviewed several key trials that have defined the current treatment paradigm. The LATITUDE and STAMPEDE trials (NCT00268476), published in 2015, established ADT plus abiraterone acetate (Zytiga) as superior to ADT alone. STAMPEDE was noted for its platform design, which has allowed successive treatment arms to be evaluated against a common control as new agents emerge. The ENZAMET trial (NCT02446405) demonstrated that ADT plus enzalutamide (Xtandi) significantly outperformed ADT plus bicalutamide (Casodex), with a median overall survival improvement of approximately 2.5 years. The ARCHES (NCT02677896) and TITAN trials (NCT02489318) confirmed the benefit of ADT plus enzalutamide and ADT plus apalutamide (Erleada), respectively.

The most recently published doublet therapy trial reviewed was ARANOTE (NCT04736199), which evaluated ADT plus darolutamide (Nubeqa) vs ADT plus placebo. This trial accrued patients from 2021 to 2022, largely from centers in Asia, India, China, and South America—regions where ADT monotherapy remained standard of care at the time of enrollment, given that combination therapy had already been adopted as standard practice in the United States and much of Europe. The primary end point was radiographic progression-free survival, which showed clear divergence between arms within the first year and sustained separation through 3 years of follow-up. Based on ARANOTE data published in 2025, darolutamide received approval for use in the mCSPC setting; it had previously been approved only for metastatic castration-resistant disease or in combination with docetaxel (based on the earlier ARASENS trial [NCT02799602]).

Tolerability, quality of life, and the case for darolutamide

A substantial portion of the discussion centered on adverse event profiles and their clinical relevance. In ARANOTE, treatment-emergent adverse events were similar between the darolutamide-ADT and placebo-ADT arms, with no statistically significant differences in fatigue, cardiovascular events, or drug discontinuation rates. Notably, permanent discontinuation rates were lower in the darolutamide arm than in the placebo arm, which was recognized as clinically meaningful.

Quality-of-life data from ARANOTE, assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) instrument, showed that patients in the darolutamide arm experienced a slower time to deterioration across multiple domains—including functional, emotional, urinary, and social well-being—than those on placebo. The median time to deterioration in total FACT-P score was 16 months in the darolutamide group vs 11 months in the placebo group. Subgroup analyses presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium and the European Society for Medical Oncology Congress showed consistent efficacy across patients with varying numbers of comorbidities, concomitant medications, and age groups (including those older than 75 years), with no meaningful increase in adverse events compared with placebo.

The group also reviewed a pooled individual-patient data meta-analysis that included data from 7 randomized controlled trials, including STAMPEDE, LATITUDE, ENZAMET, and TITAN. This analysis reinforced the benefit of doublet therapy for progression-free survival and overall survival across age groups. A notable finding was that, in the abiraterone arms, prostate cancer–specific survival improved but overall survival benefit diminished, suggesting that competing comorbidities, including cardiovascular events, may offset cancer-related gains in some patients, particularly those with multiple baseline conditions.

Triplet therapy: When to intensify

The forum reviewed evidence for triplet regimens from the ENZAMET, PEACE1 (NCT01957436), and ARASENS trials. All 3 demonstrated statistically significant improvements in overall survival with triplet therapy vs ADT alone or with docetaxel. In ENZAMET and PEACE1, the survival benefit of adding an ARPI or abiraterone was more pronounced in patients with high-volume disease, with limited additional benefit observed in low-volume disease. ARASENS (ADT plus docetaxel plus darolutamide) showed a survival benefit regardless of disease volume. Participants emphasized that triplet therapy is generally reserved for younger patients with visceral metastases or high-volume disease, where the risk-benefit ratio favors more aggressive up-front treatment. An ongoing trial examining triplet therapy in patients with more than 10 metastatic sites was also noted.

ARPI selection: Practical considerations

When asked how they choose among available ARPIs, participants identified several determinants: insurance coverage and drug availability, patient comorbidities, fall and seizure risk, cardiac history, and clinical experience with specific agents. The structural distinction of darolutamide—its polar molecular configuration limits blood-brain barrier penetration—was discussed as a potential contributor to its favorable central nervous system tolerability profile relative to enzalutamide and apalutamide. Cutaneous rash associated with apalutamide—and, to a lesser extent, darolutamide—was raised as a practical concern. Drug-drug interactions, including the interaction between certain ARPIs and statins, were noted as warranting attention, although practice patterns for managing these interactions varied among participants.

For patients with recent myocardial infarction or significant cardiovascular disease, the forum discussed the potential advantage of switching from GnRH agonists to relugolix (Orgovyx), an oral GnRH antagonist associated with lower rates of major adverse cardiac events in available data. Several participants reported holding ADT for 3 to 6 months following acute cardiac events, with reinitiation guided by PSA trajectory rather than a fixed threshold—an approach acknowledged as empirical given the absence of established guidelines.

Emerging strategies

Feehan reviewed several emerging approaches discussed in recent conference presentations. Stereotactic body radiation therapy directed at oligometastatic lesions combined with a short course of ADT and an ARPI, followed by treatment deintensification, was described as a strategy already in use at some practices for castration-sensitive patients with limited metastatic burden. One participant reported sustained PSA response in a family member treated with this approach in 2021.

An FDA-approved multimodal artificial intelligence tool designed to identify patients with nonmetastatic prostate cancer who would benefit from the addition of an ARPI to ADT was also discussed. The algorithm analyzes digitized biopsy slides alongside clinical variables (eg, age, PSA, Gleason score, T stage). In an analysis of STAMPEDE trial participants, the tool correctly identified approximately 25% of patients as benefiting from intensified therapy—potentially sparing the remaining 75% from unnecessary treatment. The group expressed interest in the technology while acknowledging questions about real-world implementation and cost.

The potential role of circulating tumor DNA, available through platforms such as Tempus, was raised as a future monitoring tool, though participants noted that it requires matched tumor tissue for cross-analysis. Ultralow PSA thresholds (< 0.02 ng/mL) were discussed in the context of ARANOTE subgroup data showing that patients who achieved ultralow PSA nadir at any point during treatment had lower rates of radiographic progression and a longer time to castration-resistant disease. In practice, however, several participants cautioned that routine use of ultrasensitive PSA assays can generate unnecessary patient anxiety without clearly informing clinical decisions.

Palliative care, patient support, and adherence

The forum devoted considerable attention to the nonpharmacologic dimensions of mCSPC care. Participants agreed that palliative care consultation—distinct from hospice—is underutilized in this population. Palliative care was described as providing supportive resources for pain management, emotional well-being, and goals-of-care discussions without limiting active oncologic therapy. One participant noted a virtual men’s support group offered at a local health system as an additional resource for patients experiencing social isolation. The FACT-P quality-of-life data from ARANOTE, which showed improvements across social and emotional well-being subscales in the treatment arm, were cited as evidence supporting early and ongoing attention to these domains.

Medication adherence and loss to follow-up were identified as persistent challenges, particularly in high-volume practices. Strategies discussed included scheduling follow-up appointments before patients leave the office, using checkout order sets to prompt staff, and flagging patients who miss visits or are dispensing medications without accompanying clinical encounters. Oxybutynin (5 mg twice daily) was mentioned as a pharmacologic option, with published evidence for managing hot flashes in patients on ADT. Routine bone density monitoring and vitamin D supplementation were also discussed, with participants noting that documentation of musculoskeletal comorbidities generally facilitates insurance coverage for DEXA scanning.

The forum concluded with a discussion of how dramatically outcomes in mCSPC have improved in recent years—with more than half of patients on doublet therapy alive beyond 3 years in contemporary series—and how evolving tools for risk stratification, treatment individualization, and patient monitoring are likely to further refine practice in the years ahead.