What are the recommended treatment options for metastatic prostate cancer?

Treatment of Metastatic Prostate Cancer

For metastatic hormone-sensitive prostate cancer, combination therapy with ADT plus an androgen receptor-targeted agent (abiraterone, apalutamide, enzalutamide, or darolutamide) is the standard of care, with triplet therapy (ADT + docetaxel + androgen receptor agent) recommended for fit patients with high-volume disease. 1

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

First-Line Treatment Options

The treatment landscape has shifted dramatically away from ADT monotherapy, which should only be used in vulnerable patients who cannot tolerate treatment intensification 1.

Triplet Therapy (Preferred for Fit Patients with High-Volume Disease):

• ADT + docetaxel + abiraterone + prednisone is recommended for fit men with de novo mHSPC, especially those with multiple bone metastases (>3) or visceral metastases 1
• ADT + docetaxel + darolutamide is also recommended as first-line treatment for mHSPC, including patients with de novo disease and those who progressed after local therapy 1
• Both triplet regimens have ESMO-MCBS v1.1 scores of 4, indicating substantial clinical benefit 1

Doublet Therapy (ADT + Novel Hormone Agent):

For patients where chemotherapy is not appropriate or preferred, the following combinations are strongly recommended 1:

• ADT + abiraterone (1,000 mg) + prednisone (5 mg daily): Strong recommendation for high-risk disease per LATITUDE criteria; moderate recommendation for low-risk disease per STAMPEDE 1
• ADT + apalutamide (240 mg daily): Strong recommendation for all mHSPC patients, including de novo and post-local therapy 1
• ADT + enzalutamide (160 mg daily): Strong recommendation with demonstrated short-term survival benefits across all patient subgroups 1
• ADT + darolutamide: Recommended option with ESMO-MCBS score of 4 1

All novel hormone agent combinations have high-quality evidence and strong recommendations, with ESMO-MCBS v1.1 scores of 4 1. The choice between triplet and doublet therapy has not been directly compared in head-to-head trials 1.

Key Treatment Considerations

Risk Stratification:

• High-risk disease is defined by LATITUDE criteria (at least 2 of: Gleason ≥8, ≥3 bone lesions, visceral metastases) 1
• High-volume disease includes multiple bone metastases (>3) or visceral metastases, favoring triplet therapy 1

Abiraterone vs. Other Agents:

• Abiraterone requires concurrent prednisone/prednisolone 5 mg daily 1
• Cost considerations: enzalutamide discussions should include lack of long-term data and higher costs compared to abiraterone 1
• For patients with de novo mHSPC, abiraterone improved median OS from 36.5 to 53.3 months (HR 0.66) compared to ADT alone 2

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Treatment Sequencing After Progression

For Patients with BRCA1/2 Alterations:

• Olaparib should be considered after progression on androgen receptor axis inhibitors (with or without prior taxane) 1
• In the PROfound trial, olaparib improved OS (HR 0.69; median 19.1 vs 14.7 months), with benefit predominantly in BRCA-altered patients 1
• ESMO-MCBS v1.1 score: 3 1

For Patients Who Have Received Both Novel Androgen Receptor Axis Inhibitor and Docetaxel:

The following treatments should be used in fit patients 1:

1. 177Lu-PSMA-617 radioligand therapy in men with PSMA-expressing cancer on PET without PSMA non-expressing lesions:

   • Improved radiographic PFS (HR 0.40; median 8.7 vs 3.4 months) 1
   • Improved OS (HR 0.62; median 15.3 vs 11.3 months) 1
   • ESMO-MCBS v1.1 score: 4 (highest benefit rating) 1

2. Cabazitaxel chemotherapy:

   • ESMO-MCBS v1.1 score: 3 1
   • Improved OS (median 13.6 vs 11.0 months) compared to abiraterone/enzalutamide in patients who progressed within 12 months on prior androgen receptor axis inhibitor 1

PARP Inhibitor Considerations

• Response varies by specific gene alterations, with greatest benefit for BRCA1/2, CDK12, and PALB2 mutations 3
• Talazoparib + enzalutamide combination showed longer radiological PFS and better OS regardless of DNA repair gene mutational status 3
• Several PARP inhibitors approved as monotherapy or in combination with ARPIs when chemotherapy is not clinically indicated 3

Common Pitfalls to Avoid

• Do not use ADT monotherapy in patients who can tolerate treatment intensification—this is outdated and associated with inferior survival 1
• Do not delay treatment intensification in mHSPC—early combination therapy provides the greatest survival benefit 1
• Do not use enzalutamide after progression on another androgen receptor axis inhibitor without considering cross-resistance—177Lu-PSMA-617 or cabazitaxel are preferred in this setting 1
• Do not overlook genetic testing for homologous recombination repair gene alterations, as this identifies candidates for PARP inhibitor therapy 1, 3
• Do not use 177Lu-PSMA-617 without confirming PSMA expression on PET imaging and absence of PSMA non-expressing lesions 1