Management of metastatic hormone-sensitive prostate cancer (mHSPC) continues to evolve as clinicians refine the use of androgen deprivation therapy (ADT) and/or chemotherapy in combination with androgen receptor pathway inhibitors (ARPIs) in routine clinical practice. At an advisory board meeting organized by the Hong Kong Society of Uro-Oncology, Professor Axel Merseburger of the University of Lübeck in Germany and Dr Darren Poon of the Hong Kong Sanatorium & Hospital discussed updated strategies and shared case studies to illustrate use of optimal ARPI-based regimens in patients with mHSPC.
mHSPC: Evolving treatment strategies with ARPIs
“Since the introduction of docetaxel and ARPIs to PC treatment paradigm, there have been substantial improvements in survival while maintaining quality of life [QoL] outcomes, especially in patients with mHSPC,” said Merseburger. [N Engl J Med 2015;373:737-746; N Engl J Med 2017;377:352-360; Clin Oncol 2021;39:2294-2303; N Engl J Med 2019;381:121-131]
Treatment intensification with triplet therapy
“Landmark clinical data from the phase III PEACE-1 and ARASENS trials validated triplet regimens consisting of ADT plus docetaxel and an ARPI as the standard intensification strategy for patients with good performance status [PS],” Merseburger explained. [Lancet 2022;399:1695-1707; N Engl J Med 2022;386:1132-1142]
In PEACE-1, ADT plus docetaxel and abiraterone prolonged radiological progression-free survival (rPFS; hazard ratio [HR], 0.50; 99.9 percent confidence interval [CI], 0.34–0.71; p<0.0001) and 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 (HR, 0.68; 95 percent CI, 0.57–0.80; p<0.001). Benefits in favour of the triplet regimen remained consistent across key secondary endpoints and prespecified subgroups. Adverse event (AE) rates were also similar between the two groups, and most occurred during treatment with docetaxel. [N Engl J Med 2022;386:1132-1142]
ARASAFE: Adjusting docetaxel dose to improve tolerability
The phase III ARASAFE trial investigated whether triplet therapy with darolutamide, ADT, and Q2W docetaxel at 50 mg/m² (D50) could achieve similar efficacy while reducing the incidence of severe (grade 3–5) AEs vs the standard 75 mg/m² Q3W regimen (D75) in patients with mHSPC. [Grimm MO, et al, ESMO 2025, abstract LBA92]
The results favoured D50, with significant reductions in grade 3–5 AEs (61.2 vs 78.9 percent; p=0.0024) and grade 3–4 neutropenia or death (24.0 vs 64.1 percent; p<0.00001) vs D75. There were marked reductions in the median PSA levels in both groups at 26 weeks after the final participant received the first docetaxel dose. In particular, the D50 regimen had lower incidences of all-grade and grade 3–5 treatment-emergent neutropenia (56.2 and 20.7 percent, respectively), leukopenia (62.0 and 9.1 percent, respectively), and febrile neutropenia (1.7 percent for both) than the D75 regimen (75.0 and 55.5 percent; 69.5 and 25.0 percent; 5.5 percent for both).
“These findings suggest the potential of Q2W docetaxel plus darolutamide and ADT as a new standard of care [SoC] in mHSPC,” said Merseburger. (Case 1)
Case 1: Managing triplet therapy toxicity in a patient with high-volume mHSPC with a strong skeletal component
In August 2022, a 61-year-old male presented with persistent back pain. He had no urinary symptoms, comorbidities or other complaints. His baseline Eastern Cooperative Oncology Group (ECOG) PS was 0, PSA level was slightly elevated at 5 ng/mL, and the result of prostate biopsy was negative. No additional assessments were done, and his pain medications were adjusted.
At follow-up in May 2023, he had ongoing back pain, PSA of 7.24 ng/mL, ECOG PS of 0, and digital rectal exam (DRE) indicated enlarged prostate. Prostate-specific membrane antigen (PSMA) PET-CT scan revealed de novo metastatic PC with PSMA-avid bilateral pelvic lymph node (LN) and diffuse osteolytic skeletal metastases. Additional assessments confirmed high-risk (Gleason 5+5), high-volume mHSPC.
Treatment and response
He initially received bicalutamide for 4 weeks in May 2023. Following ARASENS data, treatment was intensified in June 2023 with a triplet regimen of standard-dose darolutamide, leuprorelin acetate and docetaxel, plus radiotherapy to thoracic vertebrae T8 and T10. [N Engl J Med 2022;386:1132-1142]
After two chemotherapy cycles, on 26 July 2023, he reported extreme fatigue, and blood tests showed grade 1 anaemia and grade 4 neutropenia. Docetaxel was adjusted from 75 mg/m2 Q3W to 50 mg/m2 Q2W for the remaining four cycles to address haematologic toxicity, and darolutamide was reduced to 300 mg BID. The AEs gradually resolved, and he resumed darolutamide 600 mg BID in November 2023 after completing chemotherapy.
Despite dose reductions, the patient’s PSA declined rapidly, and his back pain resolved. (Figure 1) Follow-up PSMA PET-CT showed marked metabolic response, nodal regression and increasing sclerosis of osseous lesions. He remained on ADT plus darolutamide 600 mg BID. His last PSA was 0.02 ng/mL in December 2024.
Key points
• Bicalutamide monotherapy is no longer the SoC in mHSPC. For
de novo high-volume, high-risk disease, such as this patient’s, triplet therapy
with ADT, ARPI and docetaxel is preferred. [Oncol Rev 2013;7:e6; Int
J Urol 2025;32:239-250; NCCN Clinical Practice Guidelines in Oncology,
Prostate Cancer, version 5.2026; N Engl J Med 2022;386:1132-1142]
• This case aligns with ARASAFE safety findings, which showed
that docetaxel 50 mg/m2 Q2W improves tolerability in patients with mHSPC,
despite the cumulative exposure to docetaxel being greater with D50 than with
D75 – without compromising treatment response. (Table) [Grimm MO, et al, ESMO
2025, abstract LBA92]
Age-related considerations
“Since most men with PC are diagnosed over the age of 65 years, age is often a concern in those receiving triplet therapy, particularly with respect to docetaxel,” noted Merseburger. [
Am Soc Clin Oncol Educ Book 2023;43:e390396]
A subgroup analysis of ARASENS evaluated outcomes with darolutamide, ADT and docetaxel among mHSPC patients aged <75 and ≥75 years. Results showed benefit of the darolutamide-containing triplet regimen irrespective of age, with consistent improvements in OS, time to metastatic castration-resistant PC, and time to initiation of subsequent therapy. Triplet therapy was also well tolerated in both age subgroups. [Carles J, et al, ASCO GU 2025, abstract 143] (Case 2)
Case 2: Triplet therapy in an elderly patient with low-burden, high-risk mHSPC
In May 2024, a 73-year-old male presented with unspecified urinary symptoms. His father and brother had history of PC.
His baseline ECOG PS was 1. DRE was abnormal and PSA was 95 ng/mL. Prostate biopsy confirmed multifocal PC (Gleason 4+5). CT scan revealed enlarged pelvic and retroperitoneal LNs without visceral metastases. Bone scan showed three spinal lesions suspicious for metastases. He was assessed to have low-burden, high-risk mHSPC.
Treatment and response
As the patient was relatively fit, intensive triplet therapy with darolutamide (600 mg BID; first dose in May 2024), ADT with subcutaneous leuprorelin acetate (22.5 mg Q3M; first dose in June 2024), and docetaxel (75 mg/m2 Q3W for six cycles; first cycle in June 2024) was started. He also received prostate radiotherapy in June 2024.
Treatment was well tolerated, with only mild fatigue and grade 1 anaemia. PSA declined rapidly to undetectable levels (ie, <0.1 ng/ mL) within 6 months after triplet therapy initiation, with concomitant resolution of urinary symptoms. (Figure 2) At the latest follow-up, he maintained an ECOG PS of 1 and continued to receive ADT and darolutamide, with PSA levels remaining undetectable.
Key points
A triplet regimen combining ADT, ARPI and docetaxel is now the standard intensification strategy for patients with high-volume, high-risk disease. [N Engl J Med 2022;386:1132-1142; NCCN Clinical Practice Guidelines in Oncology, Prostate Cancer, version 5.2026]
• Triplet therapy is also appropriate for fit patients with aggressive disease biology, irrespective of chronological age. [Lancet 2022;399:1695-1707; N Engl J Med 2022;386:1132-1142; Carles J, et al, ASCO GU 2025, abstract 143] Clinical fitness is not defined by age alone and should not be the sole criterion when considering treatment intensification in mHSPC, especially in de novo metastatic presentations, since these patients have a poorer prognosis than those with metachronous disease. [Eur J Cancer 2019;116:116-136; Prostate 2018;78:889-895]
• In this patient’s case, treatment intensification with darolutamide plus ADT and docetaxel, despite his advanced age, is supported by the age-related subgroup analysis of ARASENS, which showed consistent OS and disease-control benefits with acceptable tolerability across age groups (<75 and ≥75 years). These findings highlight that appropriately selected older patients can receive docetaxel-containing triplet therapy. [Carles J, et al, ASCO GU 2025, abstract 143]
Maintaining and improving QoL with ARPIs
“A doublet therapy strategy may offer improved health-related QoL [HRQoL] outcomes in appropriate patients [ie, those with low symptom burden],” suggested Merseburger. [J Clin Oncol 2019;37:2974-2986; J Clin Oncol 2024;42:4271-4281]
Several phase III trials in mHSPC (eg, TITAN and ARCHES) have previously reported preservation or maintenance of HRQoL after adding an ARPI to ADT. [Lancet Oncol 2019;20:1518-1530; Eur Urol 2020;78:603-614]
“On the other hand, the phase III ARANOTE trial showed HRQoL results that favoured darolutamide plus ADT, offering a chemotherapy-free option for patients with mHSPC,” said Merseburger. [J Clin Oncol 2024;42:4271-4281; Morgans AK, et al, ASCO 2025, abstract 5004]
In ARANOTE, the addition of darolutamide to ADT was associated with a 46 percent reduction in risk of radiological progression or death (HR, 0.54; 95 percent CI 0.41–0.71; p<0.0001), while AE rates were similar between darolutamide and placebo. [J Clin Oncol 2024;42:4271-4281]
Notably, darolutamide is the first and only ARPI offering clinically meaningful delays in deterioration of patient-relevant HRQoL outcomes in mHSPC. In ARANOTE, darolutamide demonstrated significant, clinically meaningful improvements in HRQoL, extending the prespecified exploratory endpoint of median time to first deterioration in Functional Assessment of Cancer Therapy–Prostate (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). (Figure 3) This was mainly 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). [Morgans AK, et al, ASCO 2025, abstract 5004]
ARPIs’ different safety profiles
“Second-generation ARPIs share broadly comparable efficacy. However, important differences in structure and pharmacology mean that evaluation on the basis of metastasis-free survival or OS endpoints alone is incomplete and risks an ‘apples to bananas’ comparison, especially when safety and comorbidities drive real-world treatment choices,” noted Poon. [Nat Rev Urol 2019;16:335-336]
Metabolism and drug interactions
ARPIs are metabolized differently and, as a result, have different drug– drug interaction profiles. Darolutamide is preferrable in multimorbid patients as, unlike enzalutamide and apalutamide, it is a weak inducer of CYP3A4 and does not meaningfully reduce exposure to agents such as anticoagulants, anti-biotics, antiplatelets, and antiepileptics. As a result, darolutamide is unlikely to precipitate life-threatening events such as recurrent thrombosis or heart failure. [Nat Rev Urol 2019;16:335-336; ESMO Open 2024;9:103736]
Blood–brain barrier and CNS effects
Enzalutamide and apalutamide readily cross the blood–brain barrier, which aligns with a higher incidence of central nervous system (CNS)–related AEs. In contrast, due to its flexible polar-substituted pyrazole structure, darolutamide shows negligible CNS penetration and, correspondingly, minimal CNS toxicity, which is an advantage for older patients or those with neurological comorbidities. [ESMO Open 2024;9:103736; Onco Targets Ther 2019;12:8769-8777; Target Oncol 2020;15:791-799]
Summary
ARPI regimens have redefined mHSPC management by enabling effective treatment intensification with ADT and docetaxel while maintaining HRQoL. In particular, triplet therapy with ADT, docetaxel and darolutamide improves survival outcomes across age subgroups, whereas doublet chemotherapy‑free strategies offer favourable tolerability as well as improved HRQoL for select low-symptom patients. Treatment choice should consider efficacy, toxicity, comorbidities and polypharmacy to optimize long-term PC care.
This special report is supported by an education grant from the industry.
