How to optimize treatment strategies for mHSPC by integrating pivotal data?

Alongside patient characteristics, disease volume and risk as well as presence of synchronous metastases should be key factors influencing choice of treatment strategy for metastatic hormone-sensitive prostate cancer (mHSPC), according to pivotal trial data reviewed by Professor Jacob See-Tong Pang of the Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Linkou District, New Taipei City, Taiwan, at Uro-Oncology Asia 2025 meeting.

 

Prostate cancer cases and deaths set to rise in Asia

With age-standardized incidence of 29.4 and mortality of 7.3 per 100,000, according to GLOBOCAN 2022 data, prostate cancer is the second most common cancer and the fifth leading cause of cancer death among men globally. While prostate cancer incidence and mortality rates were the lowest (12.4 and 3.8 per 100,000, respectively) in Asia in 2022, the region is set to overtake Europe in terms of the estimated number of new cases by 2034 and already has the highest number of prostate cancer–related deaths in the world. [CA Cancer J Clin 2024;74:229-263]

 

“Ageing population and better awareness of prostate cancer, even in the absence of national screening programmes, are the driving factors behind the increasing incidence,” explained Pang. “The rising incidence of metastatic prostate cancer is of high priority because of the incurable nature of advanced disease associated with inevitable resistance to therapy and the overall survival [OS] rate of only 30 percent at 5 years in patients with an initial diagnosis of mHSPC.” [JAMA Network Open 2022;5e222246; ESMO Open 2023;8:101194]

 

Choosing therapy based on disease and patient characteristics 

Current clinical guidelines regard androgen receptor pathway inhibitor (ARPI)–based regimens, including doublet (ARPI plus androgen deprivation therapy [ADT]) and triplet (ARPI plus docetaxel plus ADT) combinations, as the SoC for eligible mHSPC patients. [J Urol 2023;209:1082-1090; National Comprehensive Cancer Network Clinical Practice Guidelines (NCCN), Prostate Cancer, version 1.2025; Eur Urol 2024;86:164-182] However, it is not entirely clear which regimens are superior in individual clinical situations.

 

Doublet therapy

Docetaxel improves survival when combined with ADT vs ADT monotherapy. Although the GETUG-AFU study was negative for OS improvement, the CHAARTED and STAMPEDE (arm C) studies demonstrated longer OS with the addition of docetaxel. While in CHAARTED the improvement was more pronounced in high-volume disease, volume did not affect OS benefit in STAMPEDE. “Several meta-analyses have since shown that the benefit of docetaxel is greater in synchronous, high-volume disease”, noted Pang. [Actas Urol Esp 2024;9:623-631] “Also, in Taiwan, we tend to reserve chemotherapy for younger, fitter patients.”

 

Unlike doublet therapy with ADT plus docetaxel, the combination of ADT with an ARPI is currently part of international recommendations for mHSPC. [NCCN Practice Guidelines, Prostate Cancer, version 1.2025] Arm G of the STAMPEDE study demonstrated OS benefit with the addition of abiraterone and prednisolone to ADT vs ADT alone. [N Engl J Med 2017;377:338-351] OS benefit was also shown in the LATITUDE trial of abiraterone and prednisone plus ADT vs ADT alone, which only included patients with synchronous, high-risk metastases (defined as two of the three following factors: Gleason score ≥8, ≥3 bone lesions, and presence of visceral metastasis). [N Engl J Med 2017;377:352-360] Apalutamide and enzalutamide also showed OS benefit in low- and high-volume disease in the TITAN and ARCHES trials, respectively. [J Clin Oncol 2022;40:1616-1622; J Clin Oncol 2021;39:2294-2303]

 

“Combining ARPI and ADT significantly improves OS in mHSPC compared with ADT alone regardless of disease volume,” stressed Pang.

 

The latest data for ADT plus ARPI doublet therapy come from the ARANOTE trial, which showed that the addition of darolutamide to ADT significantly improved radiological PFS vs ADT alone, with consistent benefits across subgroups, including high- and low-volume disease. [J Clin Oncol 2024;42:4271-4281] “Darolutamide also demonstrated benefit across all secondary endpoints, including time to metastatic castration-resistant disease, time to pain progression and time to prostate-specific antigen progression, with a favourable safety profile, meaning it should become an additional SoC for mHSPC. Although the OS data are not yet mature, we will probably see results similar to the other novel hormone agents,” added Pang.

 

Triplet therapy

PEACE-1 and ARASENS are the two trials to date to demonstrate superiority of ARPI (abiraterone and darolutamide, respectively) plus ADT plus docetaxel triplet therapy over ADT plus docetaxel doublet, with ARASENS being the only study originally designed to investigate whether adding an ARPI to ADT plus docetaxel would improve OS vs doublet therapy.

 

In PEACE-1, triplet therapy improved OS vs docetaxel and ADT, with a greater benefit in high-volume disease. A subanalysis of PEACE-1 evaluated the effect of triplet therapy in patients aged ≥70 years vs younger patients and showed that older patients derived less benefit in terms of radiographic PFS and OS. [J Clin Oncol 2023;41:3595-3607]