What are the current treatment options and clinical trials for metastatic prostate cancer?

Current Treatment Options and Clinical Trials for Metastatic Prostate Cancer

The most significant recent advancement for metastatic prostate cancer treatment is Lutetium-177 PSMA-617 (177Lu-PSMA-617), which demonstrated significant overall survival improvement (15.3 vs 11.3 months) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after taxane-based chemotherapy and androgen receptor pathway inhibitors. 1

Treatment Algorithm for Metastatic Prostate Cancer

First-Line Treatment for Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

For patients newly diagnosed with metastatic prostate cancer:

• For fit patients with high-volume disease (multiple bone metastases or visceral metastases):

  • ADT + docetaxel + abiraterone + prednisone (triplet therapy) [I, B; ESMO-MCBS score: 4] 1
  • ADT + docetaxel + darolutamide [I, B; ESMO-MCBS score: 4] 1

• For all mHSPC patients (including low-volume disease):

  • ADT + novel hormone agent (NHA):
    • ADT + abiraterone + prednisone [I, A; ESMO-MCBS score: 4] 1
    • ADT + apalutamide [I, A; ESMO-MCBS score: 4] 1
    • ADT + enzalutamide [I, A; ESMO-MCBS score: 4] 1

• For vulnerable patients who cannot tolerate treatment intensification:

  • ADT alone [III, C] 1

Treatment for Metastatic Castration-Resistant Prostate Cancer (mCRPC)

After progression on initial therapy:

1. For patients with BRCA1/2 alterations:

   • Olaparib after novel androgen receptor axis inhibitors (with or without prior taxane) [I, B; ESMO-MCBS score: 3] 1

2. For patients who have received a novel androgen receptor axis inhibitor and docetaxel:

   • 177Lu-PSMA-617 for patients with PSMA-expressing tumors (without PSMA non-expressing lesions) [I, A; ESMO-MCBS score: 4] 1
   • Cabazitaxel [I, A; ESMO-MCBS score: 3] 1

Recent Clinical Trial Evidence

VISION Trial (177Lu-PSMA-617)

The VISION trial demonstrated that 177Lu-PSMA-617 plus standard of care significantly improved:

• Overall survival: 15.3 vs 11.3 months (HR 0.62,95% CI 0.52-0.74, p < 0.001) 1
• Radiographic progression-free survival: 8.7 vs 3.4 months (HR 0.40,99.2% CI 0.29-0.57, p < 0.001) 1

PROfound Trial (Olaparib)

For patients with mCRPC with BRCA1/2 or ATM alterations who progressed on prior androgen receptor axis inhibitor:

• Overall survival: 19.1 vs 14.7 months (HR 0.69,95% CI 0.50-0.97, p = 0.0175) 1
• Benefit was predominantly observed in patients with BRCA alterations 1

CARD Trial (Cabazitaxel)

For patients with mCRPC pretreated with docetaxel and progression within 12 months on a novel androgen receptor axis inhibitor:

• Overall survival: 13.6 vs 11.0 months compared with abiraterone or enzalutamide 1, 2

Important Considerations for Treatment Selection

1. Patient Fitness Assessment:

   • Performance status
   • Comorbidities
   • Prior treatment tolerance
   • Age (not necessarily a limiting factor with good health status) 2

2. Disease Characteristics:

   • Tumor volume (high vs. low)
   • Presence of visceral metastases
   • PSMA expression (for 177Lu-PSMA-617 therapy) 2
   • Genomic alterations (particularly BRCA1/2 for olaparib) 1

3. Treatment Toxicity Considerations:

   • 177Lu-PSMA-617: Higher grade 3-4 adverse events (52.7% vs 38%) 2
   • Abiraterone: Risk of hypokalemia, fluid retention, cardiovascular events, hepatotoxicity 3
   • Docetaxel: Risk of neutropenia, hypersensitivity reactions, fluid retention 4

Common Pitfalls to Avoid

1. Undertreatment of fit patients: Using ADT alone in fit patients with mHSPC when combination therapy shows clear survival benefit 1

2. Inadequate genomic testing: Failing to test for BRCA1/2 alterations which could identify candidates for olaparib 1

3. Overlooking PSMA expression: Not evaluating PSMA expression before considering 177Lu-PSMA-617 therapy 1, 2

4. Inappropriate sequencing: Using second-generation antiandrogens after progression on first-generation antiandrogens without considering alternative mechanisms of action 1

5. Inadequate monitoring: Not monitoring for treatment-specific toxicities such as mineralocorticoid excess with abiraterone or neutropenia with docetaxel 3, 4

While there is no definitive cure for metastatic prostate cancer yet, the treatment landscape has evolved significantly with multiple options that can extend survival and maintain quality of life. The selection of therapy should be based on disease characteristics, patient factors, and prior treatment history to optimize outcomes.