What are the novel agents for treating prostate cancer?

Novel Agents for Prostate Cancer

The most impactful novel agents for prostate cancer include androgen receptor pathway inhibitors (apalutamide, enzalutamide, darolutamide, abiraterone), PARP inhibitors (olaparib for BRCA-mutated disease), radiopharmaceuticals (177Lu-PSMA-617), and chemotherapy agents (docetaxel, cabazitaxel), with treatment selection determined by disease stage, prior therapies, and molecular characteristics. 1

Novel Hormone Agents (Androgen Receptor Pathway Inhibitors)

These represent the most significant therapeutic advance across multiple disease states:

For Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Triplet therapy with ADT + docetaxel + darolutamide is the most effective first-line regimen, achieving a 23-month overall survival gain (OS HR: 0.68) 2. This combination is particularly recommended for fit patients with de novo metastatic disease, especially those with multiple bone metastases (>3) or visceral metastases 1.

Alternative triplet therapy options include:

• ADT + docetaxel + abiraterone + prednisone (ESMO-MCBS score: 4) 1
• ADT + docetaxel + apalutamide (median OS gain: 16.4 months, OS HR: 0.75) 1

For patients unable to tolerate triplet therapy, doublet regimens with novel hormone agents plus ADT are effective:

• ADT + abiraterone + prednisone (median OS: 53.3 months vs 36.5 months with ADT alone, HR: 0.66) 3
• ADT + apalutamide (ESMO-MCBS score: 4) 1
• ADT + enzalutamide (4-year OS gain: 14%, OS HR: 0.66-0.67) 1

For Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

Three agents significantly delay metastasis and improve survival in high-risk nmCRPC:

• Apalutamide + ADT: Median metastasis-free survival (MFS) gain of 24.3 months (MFS HR: 0.28), with 14-month OS gain (OS HR: 0.78) 1
• Enzalutamide + ADT: MFS gain of 21.9 months (MFS HR: 0.29), with 10.7-month OS gain (OS HR: 0.73) 1
• Darolutamide + ADT: MFS gain of 22.0 months (MFS HR: 0.41), with 6% 3-year OS gain (OS HR: 0.69) 1

For Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Enzalutamide demonstrates superior efficacy among novel hormone agents in chemotherapy-naïve mCRPC, with a 4.8-month OS gain (HR: 0.71) compared to placebo 1, 4. Abiraterone + prednisone is the second-most effective option (OS HR: 0.78) 4.

In post-docetaxel mCRPC, both agents provide survival benefits:

• Enzalutamide: 4.8-month OS gain (HR: 0.73) with improved quality of life 1
• Abiraterone + prednisone: 4.6-month OS gain (HR: 0.74) 1

Targeted Therapies: PARP Inhibitors

Olaparib is the first FDA-approved targeted therapy for prostate cancer, specifically for patients with mCRPC harboring BRCA1/2 or other homologous recombination repair (HRR) gene mutations 1.

Key efficacy data:

• In BRCA1/2-mutated mCRPC after prior novel hormone agent: OS improvement from 14.7 to 19.1 months (HR: 0.69), with benefit predominantly in BRCA-altered patients 1
• PFS gain of 3.8 months (HR: 0.25-0.47) 1

Critical caveat: Olaparib should only be used after progression on androgen receptor pathway inhibitors in patients with confirmed BRCA1/2 alterations, as the benefit is limited to this molecular subset 1, 2.

Radiopharmaceuticals

177Lu-PSMA-617 represents a breakthrough for heavily pretreated mCRPC, approved for patients with PSMA-positive disease who have received both a novel androgen receptor axis inhibitor and taxane chemotherapy 1.

Efficacy outcomes:

• OS gain of 4.0 months (HR: 0.62,95% CI 0.52-0.74) 1
• Radiographic PFS improvement from 3.4 to 8.7 months (HR: 0.40) 1

Important selection criteria: Requires PSMA expression on PET imaging without PSMA non-expressing lesions 1. Higher toxicity profile with 52.7% grade 3+ adverse events versus 38% with standard care 1.

Chemotherapy Agents

Docetaxel

Docetaxel remains foundational across multiple disease states 5:

• In mHSPC: Combined with ADT and novel hormone agents in triplet therapy (see above) 1, 2
• In mCRPC (chemotherapy-naïve): 2.9-month OS gain as monotherapy (HR: 0.79) with improved quality of life 1
• FDA-approved dose: 75 mg/m² IV every 3 weeks for prostate cancer 5

Critical warning: The 100 mg/m² dose in previously treated patients is associated with increased hematologic toxicity, infection, and treatment-related mortality 5.

Cabazitaxel

Cabazitaxel is the preferred chemotherapy after docetaxel failure, particularly when patients progress within 12 months of novel hormone agent therapy 1.

Efficacy in post-docetaxel mCRPC:

• Versus mitoxantrone: 2.4-month OS gain (HR: 0.70) 1
• Versus abiraterone/enzalutamide (CARD trial): 2.6-month OS gain (HR: 0.64), with 4.3-month PFS gain (HR: 0.54) 1

Treatment Sequencing Algorithm

For Newly Diagnosed mHSPC:

1. Fit patients with high-volume disease: ADT + docetaxel + darolutamide (or abiraterone) 1, 2
2. Patients unable to tolerate triplet therapy: ADT + novel hormone agent (abiraterone, apalutamide, or enzalutamide) 1
3. Vulnerable patients: ADT alone only if cannot tolerate treatment intensification 1

For nmCRPC at High Risk of Metastasis:

• Any of the three agents (apalutamide, enzalutamide, or darolutamide) + ADT, with apalutamide showing the longest MFS gain 1

For mCRPC Progression:

1. First-line (chemotherapy-naïve): Enzalutamide or abiraterone + prednisone 1, 4
2. After novel hormone agent + docetaxel:
   • If BRCA1/2 mutation present: Olaparib 1
   • If PSMA-positive on PET: 177Lu-PSMA-617 1
   • Otherwise: Cabazitaxel 1

Common Pitfalls and Caveats

Cross-resistance between novel hormone agents is significant: Sequential use of abiraterone after enzalutamide (or vice versa) shows limited benefit, with only 36% achieving any PSA decline and median PFS of 3.4 months 6. Avoid sequential novel hormone agents in the same disease state 6.

Molecular testing is essential: BRCA1/2 and HRR gene mutation testing should be performed in all mCRPC patients to identify candidates for olaparib 1, 2. PSMA PET imaging is required before 177Lu-PSMA-617 1.

Hepatotoxicity monitoring is critical: Docetaxel is contraindicated in patients with bilirubin >ULN or AST/ALT >1.5× ULN with alkaline phosphatase >2.5× ULN 5. Monitor liver function before each cycle 5.

Quality of life considerations vary: Enzalutamide improved QOL in post-docetaxel mCRPC 1, while apalutamide, darolutamide, and enzalutamide in nmCRPC showed no QOL benefit or only exploratory endpoints 1. This should factor into shared decision-making 2.

Clinical trial participation should be strongly encouraged given the rapidly evolving treatment landscape and need to identify optimal sequences 2.