Management of metastatic hormone-sensitive prostate cancer (mHSPC) has transformed from androgen deprivation therapy (ADT) alone to the addition of chemotherapy and androgen receptor pathway inhibitors (ARPIs) to create more efficacious treatment regimens. At an industry-sponsored meeting organized by the Hong Kong Society of Uro-Oncology, Professor Axel Merseburger of the Department of Urology, University of Lübeck in Germany, and Ms Helen Chan, Principal Pharmacist of the Chinese University of Hong Kong Medical Centre in Hong Kong, explored how ARPI-associated advances can further optimize outcomes, not only by improving survival, but also by maintaining health-related quality of life (HRQoL) and minimizing adverse events (AEs) and critical drug–drug interactions (DDIs).
Evolving mHSPC approaches: From ADT to doublet and triplet regimens
“For years, clinicians navigated choices between chemotherapy and ARPIs,” said Merseburger. “More recently, landmark data have validated triplet regimens, namely, ADT plus docetaxel and an ARPI, as standard intensification strategy for patients with good performance status or aggressive disease biology.” [Lancet 2022;399:1695-1707; N Engl J Med 2022;386:1132-1142]
PEACE-1 confirmed that ADT plus docetaxel and abiraterone (an androgen biosynthesis inhibitor administered with prednisone) improved survival vs ADT plus docetaxel, with longer radiological progression-free survival (rPFS; hazard ratio [HR], 0.50; 99.9 percent confidence interval [CI], 0.34–0.71; p<0.0001) and overall survival (OS; HR, 0.75; 95.1 percent CI, 0.59–0.95; p=0.017) vs ADT plus docetaxel. [Lancet 2022;399:1695-1707]
Meanwhile, ARASENS demonstrated that adding the second-generation ARPI, darolutamide, to ADT plus docetaxel significantly reduced the risk of death by 32.5 percent vs ADT plus docetaxel alone (HR, 0.68; 95 percent CI, 0.57–0.80; p<0.001). [N Engl J Med 2022;386:1132-1142]
“In Germany, we employ a collaborative approach, including switching between urologists and medical oncologists to deliver chemotherapy as needed, underscoring the importance of MDT and flexible care pathways,” he said. “A shared, informed decision-making process that incorporates patients’ preferences, functional status, and HRQoL concerns remains essential for choosing between these regimens.”
ARANOTE: Expanding evidence for darolutamide in doublet therapy
“ARANOTE is a global, phase III, double-blind trial designed to provide evidence for darolutamide plus ADT as a chemotherapy-free option for patients with mHSPC,” explained Merseburger. “Patients were randomly assigned to receive either darolutamide 600 mg BID plus ADT [n=446] or placebo plus ADT [n=223].” [J Clin Oncol 2024;42:4271-4281]
The trial achieved its primary endpoint, with the addition of darolutamide to ADT being associated with a significant 46 percent reduction in risk of radiological progression or death (HR, 0.54; 95 percent CI, 0.41–0.71; p<0.0001). (Figure 1) Of note, AE rates were similar between the two groups, and there were fewer study drug discontinuations due to AEs among patients who received darolutamide vs placebo (6.1 vs 9.0 percent).
Positive QoL impact with darolutamide
“ARANOTE excluded docetaxel, offering an alternative for patients unsuitable for chemotherapy,” said Merseburger. “This provides flexibility for clinicians and patients – now we have the choice of darolutamide with or without docetaxel.” [J Clin Oncol 2024;42:4271-4281]
Beyond prolonged survival, maintaining social, family and functional well-being, managing urinary symptoms and delaying pain progression are important goals for patients with mHSPC. In this regard, ARANOTE also demonstrated that darolutamide was associated with significant, clinically meaningful improvements in HRQoL, as measured by patient-reported outcome measures. [J Clin Oncol 2024;42:4271-4281; Morgans AK, et al, ASCO 2025, abstract 5004]
Median time to pain progression (ie, time from randomization to confirmed increase of ≥2 points in the Brief Pain Inventory-Short Form worst pain score over the nadir or initiation of opioid treatment for ≥7 days), a key secondary endpoint of ARANOTE, was not reached in the darolutamide arm vs 29.9 months in the placebo arm (HR, 0.72; 95 percent CI, 0.54–0.96). [J Clin Oncol 2024;42:4271- 4281; Morgans AK, et al, ASCO 2025, abstract 5004]
For HRQoL assessment, ARANOTE employed the Functional Assessment of Cancer Therapy–Prostate (FACT-P) total score. Results showed that darolutamide extended the prespecified exploratory endpoint of median time to first deterioration in FACT-P total score of ≥10 points by 5.1 months vs placebo (16.6 vs 11.5 months; HR, 0.76; 95 percent CI, 0.61–0.93). This was strongly
driven by longer time to deterioration in the subscales of social/family well-being (HR, 0.79; 95 percent CI, 0.64–0.98), functional well-being (HR, 0.78; 95 percent, 0.63–0.96), and urinary symptoms (HR, 0.78; 95 percent CI, 0.61–0.99). (Figure 2) [Morgans AK, et al, ASCO 2025, abstract 5004]
Importantly, patients who received darolutamide and achieved ultra-low or low PSA levels (<0.02 ng/mL or 0.02– <0.2 ng/mL ) at any time demonstrated longer time to pain progression and prolonged HRQoL maintenance vs those with PSA levels ≥0.2 ng/mL. These post hoc ARANOTE analyses show that deeper PSA responses are consistently associated with more favourable clinical outcomes, including improved rPFS, OS, time to castration-resistant disease, and PSA progression, with the greatest benefit observed among patients achieving ultra-low PSA levels. [Morgans AK, et al, ASCO 2025, abstract 5004; Eur Urol Oncol 2025;8:1321-1332]
“Clinically, these findings highlight low/ ultra-low PSA as a marker of sustained disease control, while persistently higher PSA identifies patients with poorer prognosis who may require closer monitoring and more intensive treatment [eg, triplet therapy],” suggested Merseburger.
Doublet vs triplet therapy in mHSPC: Clinical decision-making and PSA dynamics
“Selecting between doublet [ADT plus ARPI] and triplet [ADT plus ARPI plus docetaxel] therapy requires nuanced evaluation,” he added. “Based on the results of ARASENS and ARANOTE, we should tailor treatment regimens according to disease burden and patient fitness.” [N Engl J Med 2022;386:1132-1142; J Clin Oncol 2024;42:4271-4281]
“Given ARASENS findings, triplet therapy is favoured for high-risk, de novo metastatic disease, especially in younger patients with visceral involvement, high PSA, or aggressive features, where rapid disease control is imperative,” he continued. [N Engl J Med 2022;386:1132-1142] “Meanwhile, doublet therapy with ARPIs such as darolutamide remains appropriate for those with lower-volume, metachronous or recurrent mHSPC, and for patients with significant comorbidity or advanced age, especially if PSA reduction is robust [eg, reaching undetectable or ultra-low levels within 3 months of initiating treatment].” (Figure 3) [J Clin Oncol 2024;42:4271- 4281; BJU Int 2024;134:982-991; Eur Urol Oncol 2025;8:1321-1332; Ong M, et al, ASCO 2025, abstract 5002]
“If the patient’s PSA level fails to drop to <0.2 ng/mL after 3 months of doublet therapy, I would consider escalating to a triplet regimen, because persistently detectable PSA signals a poorer prognosis and increases the risk of progression to castration-resistant disease,” added Merseburger. [BJU Int 2024;134:982- 991]
ARPI safety and DDIs: A critical consideration
PC frequently affects older men, many of whom have several coexisting medical conditions managed with multiple medications. [ESMO Open 2024;9:103736]
“Approximately 67 percent of patients on ARPIs have at least one cardiovascular comorbidity,” shared Chan. [JAMA Oncol 2024;10:874-884] “Given the high prevalence of comorbidities such as cardiovascular disease, diabetes mellitus, hypertension and chronic pulmonary disease in elderly men with PC, careful consideration of DDIs is essential when selecting an ARPI.” [ESMO Open 2024;9:103736]
Each ARPI demonstrates unique interaction patterns with common comedications used to manage these comorbidities, stemming from differences in their impact on key cytochrome P450 (CYP) enzymes, such as CYP2D6 inhibition with abiraterone and CYP3A4 induction with enzalutamide and apalutamide. Recognizing and understanding these distinctions is critical to minimizing complications, ensuring optimal therapeutic efficacy, and maintaining patient safety in routine practice. [ESMO Open 2024;9:103736; J Oncol Pharm Pract 2024;30:1057-1072; JCO Oncol Pract 2024;20:1231-1242]
“We must never underestimate DDIs,” stressed Merseburger. “For instance, select ARPIs may reduce the concentration of selective serotonin reuptake inhibitors, as we unfortunately discovered after a patient on ARPI therapy committed suicide while on antidepressants.” [ESMO Open 2024;9:103736]
The Table summarizes key ARPI-specific AEs and relevant DDIs to support evidence-based clinical decision-making and safe prescribing in complex PC cases.
“Darolutamide, which is structurally distinct from other ARPIs, particularly stands out for its minimal CYP-mediated and clinical DDIs, arguably making it an attractive ARPI for patients onww multiple agents for comorbidities,” suggested Chan. “In contrast, enzalutamide and apalutamide, as potent CYP3A4 inducers, can substantially lower the efficacy of several critical drugs [eg, anticoagulants, certain antibiotics, antiplatelets, proton pump inhibitors, antiepileptics], and may even increase the risk for severe complications such as recurrent thrombosis or heart failure.” (Table) [ESMO Open 2024;9:103736]
“Select ARPIs are known to easily cross the blood-brain barrier, increasing the risk of central nervous system [CNS]–related AEs,” she added. “However, darolutamide demonstrates negligible CNS penetration and reduced CNS side effects, which is particularly advantageous for elderly patients and those with neurological comorbidities.” (Table)
Abiraterone is generally considered to have a favourable DDI profile vs apalutamide and enzalutamide. (Table) However, its required co-administration with prednisone/ prednisolone increases the risk of mineralocorticoid toxicity. These nuances reinforce the importance of personalized ARPI selection in this patient population. [ESMO Open 2024;9:103736; Zytiga Hong Kong Prescribing Information]
Conclusions
mHSPC management is now defined by multidisciplinary collaboration and individualized therapy, leveraging the advantages of ARPIs such as darolutamide to improve both survival and HRQoL. Darolutamide’s favourable tolerability, minimal DDI profile, and robust HRQoL benefits make it a valid option for the increasingly older and multimorbid mHSPC population. Optimal treatment selection involves balancing therapeutic efficacy, toxicity, patient’s preference, and the realities of polypharmacy, ensuring the highest standards in PC care.
This special report is supported by an education grant from the industry.
