Metastatic hormone-sensitive prostate cancer (mHSPC) was historically treated with ADT alone, but several agents first proven in castrate-resistant disease now improve survival when added to ADT up front. The modern standard is treatment intensification — ADT plus at least one of an AR-pathway inhibitor (abiraterone, enzalutamide, apalutamide, or darolutamide), docetaxel chemotherapy, or, for low-volume disease, radiation to the prostate. Disease volume guides the choice.
Defining Disease Volume
Two definitions recur and are easily confused:
- CHAARTED high-volume — visceral metastases, or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis.
- LATITUDE high-risk — ≥2 of: visceral metastasis, ≥3 bone lesions, Gleason ≥8.
ADT Plus an AR-Pathway Inhibitor
| Agent (added to ADT) | Trials | Key result |
|---|---|---|
| Abiraterone + prednisone | LATITUDE (Fizazi 2017, n=1,199 high-risk), STAMPEDE (James 2017, n=1,917) | OS improved (LATITUDE HR 0.62, median not reached vs 34.7 mo); rPFS 33.0 vs 14.8 mo (HR 0.47); STAMPEDE improved overall and failure-free survival |
| Enzalutamide | ENZAMET (Davis 2019, n=1,125), ARCHES (Armstrong 2019, n=1,150) | OS improved (HR 0.67; 3-yr 80% vs 72%), more fatigue and seizures; rPFS HR 0.39 in both high- and low-volume disease |
| Apalutamide | TITAN (Chi 2019, n=525) | Improved radiographic progression-free and overall survival |
| Darolutamide | ARASENS (Smith 2022, n=1,306) | Added to ADT + docetaxel ("triplet therapy"), improved overall survival |
ADT Plus Docetaxel
Docetaxel is a taxane that inhibits microtubule assembly, arresting the cell cycle. Key toxicities are neutropenia (febrile neutropenia is the commonest serious event), anaemia, thrombocytopenia, neuropathy, alopecia, fluid retention, dyspnoea, and gastrointestinal upset.
- CHAARTED (Sweeney 2015; 790 men) — ADT ± docetaxel improved median OS by 13.6 months (57.6 vs 44.0 mo, HR 0.61) overall, but on stratified analysis the benefit was significant only in high-volume disease.
- STAMPEDE (James 2016; 2,692 men, including non-metastatic disease) — adding docetaxel (75 mg/m² for six 3-weekly cycles with prednisolone 10 mg daily) to standard ADT improved OS by ~10 months (81 vs 71 mo, HR 0.78), along with failure-free and cancer-specific survival; zoledronic acid added no survival benefit.
The 2019 NCCN guideline recommends ADT + docetaxel for M1 castration-naïve disease, reserving ADT monotherapy for asymptomatic metastatic men with a life expectancy ≤5 years.
Radiation to the Primary
STAMPEDE (Parker 2018; 1,061 newly diagnosed metastatic men with no prior radical treatment) randomized prostate radiotherapy versus standard of care. There was no overall survival benefit overall (HR 0.92, 95% CI 0.80–1.06), but radiotherapy improved failure-free survival (HR 0.76) and — critically — improved OS in the low-metastatic-burden subgroup (HR 0.68, 95% CI 0.52–0.90) but not the high-burden subgroup (HR 1.07). This established prostate radiotherapy as standard for low-volume metastatic disease.
Self-Test
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Describe the CHAARTED trial and its definition of high-volume disease. 790 men with metastatic castration-sensitive disease randomized to ADT ± docetaxel; chemotherapy improved median overall survival by about 14 months, with benefit confined to high-volume disease on stratified analysis. High-volume = visceral metastases, or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis.
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What are the treatment options for metastatic hormone-sensitive disease, and which trials support them? ADT plus one of: abiraterone (LATITUDE, STAMPEDE), enzalutamide (ENZAMET, ARCHES), apalutamide (TITAN), darolutamide added to docetaxel (ARASENS), or docetaxel (CHAARTED, STAMPEDE); add prostate radiotherapy for low-volume disease (STAMPEDE 2018).