Is Lu-177 (Lutetium-177) ineffective against certain types of prostate cancer?

Lu-177 Therapy Efficacy in Prostate Cancer

Lu-177 PSMA therapy is ineffective in prostate cancer patients with low PSMA expression or those with FDG-positive/PSMA-negative (discordant) disease, with these patients showing a median survival of only 2.5 months after being deemed ineligible for treatment. 1

Efficacy of Lu-177 PSMA Therapy

Lu-177 PSMA (Lutetium-177 prostate-specific membrane antigen) therapy has demonstrated significant efficacy in metastatic castration-resistant prostate cancer (mCRPC) with high PSMA expression:

• The VISION trial showed that Lu-177 PSMA-617 plus standard care significantly prolonged overall survival compared to standard care alone (median 15.3 vs. 11.3 months; HR 0.62) 2
• Lu-177 PSMA therapy achieved PSA declines of ≥50% in 44.9-57% of treated patients 3, 2
• The therapy also significantly improved imaging-based progression-free survival (8.7 vs. 3.4 months; HR 0.40) 2

When Lu-177 Is Ineffective

Despite its overall efficacy, Lu-177 PSMA therapy fails in specific prostate cancer subtypes:

1. Low PSMA Expression Tumors:

   • Patients with low PSMA expression on 68Ga-PSMA-11 PET/CT imaging are typically excluded from Lu-177 therapy 1
   • These patients have extremely poor outcomes with median overall survival of only 2.5 months 1

2. Discordant Disease:

   • FDG-positive/PSMA-negative (discordant) disease represents an aggressive phenotype 1
   • These tumors don't express sufficient PSMA for effective targeting by Lu-177 therapy

3. Post-Cabazitaxel Setting:

   • While Lu-177 can show activity after cabazitaxel, the response is often short-lived with median radiographic progression-free survival of only 4.4 months 4

Patient Selection for Lu-177 Therapy

The ESMO guidelines indicate that Lu-177 PSMA-617 is appropriate for:

• Adult patients with progressive PSMA-positive mCRPC
• Those who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy 5

Proper patient selection requires:

• Confirmation of high PSMA expression through specialized imaging (PSMA PET scans) 6
• Absence of dominant PSMA-negative metastatic lesions 6

Predictors of Poor Response

Several factors predict limited efficacy of Lu-177 PSMA therapy:

• Time to castration resistance <12 months is associated with shorter radiographic progression-free survival 4
• Higher ISUP grade (4-5) tumors may show poorer responses 4
• Baseline PET parameters including PSMA mean SUV and maximum SUV can predict treatment response 4

Clinical Implications

For oncologists considering Lu-177 PSMA therapy:

1. Mandatory PSMA Expression Screening:

   • All patients should undergo 68Ga-PSMA-11 PET/CT to confirm adequate PSMA expression
   • Consider complementary FDG-PET/CT to identify discordant disease

2. Treatment Sequencing:

   • Lu-177 PSMA therapy is typically positioned after failure of androgen receptor pathway inhibitors and taxane-based chemotherapy 5, 6
   • The PACAP study suggests potential benefit from using Lu-177 earlier in the treatment sequence 4

3. Monitoring During Treatment:

   • Regular assessment of hematological parameters before each cycle 6
   • PSA response should be evaluated no earlier than 12 weeks after treatment initiation 6

Lu-177 PSMA therapy represents an important advance in mCRPC treatment, but proper patient selection is critical to avoid futile treatment in those unlikely to benefit.