What is the role of Pluvicto (Lutetium-177 psma) in treating prostate cancer?

Role of Pluvicto (Lutetium-177 PSMA-617) in Prostate Cancer

Pluvicto is indicated for adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have already received both an androgen receptor pathway inhibitor and taxane-based chemotherapy, where it provides a 4-month overall survival benefit and should be prioritized over cabazitaxel in this setting. 1, 2

Specific Patient Selection Criteria

PSMA Expression Requirements:

• Patients must have PSMA-positive disease confirmed by PET-PSMA imaging (using LOCAMETZ or another approved PSMA-11 imaging agent) 1
• Tumors must express PSMA without PSMA non-expressing lesions 2, 3
• This imaging requirement is critical as only PSMA-expressing tumors will respond to the radioligand therapy 4

Prior Treatment Requirements:

• Must have received at least one androgen receptor pathway inhibitor (abiraterone, apalutamide, darolutamide, or enzalutamide) 1, 2
• Must have received one or two prior taxane-based chemotherapy regimens (typically docetaxel) 1, 4
• The FDA label specifically requires both categories of prior treatment before Pluvicto eligibility 1

Treatment Protocol and Dosing

Standard Dosing Regimen:

• 7.4 GBq (200 mCi) intravenously every 6 weeks 1
• Up to 6 doses total, or until disease progression or unacceptable toxicity 1
• Treatment intervals can be extended from 6 weeks up to 10 weeks if needed for adverse reaction management 1

Dose Modifications:

• Single dose reduction to 5.9 GBq (160 mCi) permitted for Grade ≥3 myelosuppression after recovery to Grade 1 or baseline 1
• No dose re-escalation allowed after reduction 1
• Permanent discontinuation required if treatment delay exceeds 4 weeks or if second dose reduction would be needed 1

Clinical Efficacy Data

Survival Benefits from VISION Trial:

• Median overall survival: 15.3 months with Pluvicto plus standard care versus 11.3 months with standard care alone (HR 0.62,95% CI 0.52-0.74, P<0.001) 4, 5
• This represents a 4-month absolute survival gain 2
• Median imaging-based progression-free survival: 8.7 months versus 3.4 months (HR 0.40,99.2% CI 0.29-0.57, P<0.001) 4

Response Rates:

• PSA response rate of 66% in patients previously treated with docetaxel 2, 3
• Objective response rate of 35% in real-world settings after cabazitaxel 6
• 44-55% of patients experience PSA decline ≥50% 6, 3

Guideline Recommendations and Evidence Quality

ESMO Guidelines (2023):

• 177Lu-PSMA-617 receives Level I, Grade A recommendation 2
• ESMO-MCBS v1.1 score of 4 (highest benefit score) 2
• Recommended for patients fit enough to receive treatment after both androgen receptor axis inhibitor and docetaxel 2

NCCN Guidelines (2023):

• Recommended for mCRPC patients with PSMA-positive disease who have received prior docetaxel 2
• TheraP trial data supports use even after limited docetaxel cycles 2, 3
• Prioritized over sequential novel hormone therapy after initial androgen receptor pathway inhibitor 2

Treatment Sequencing Considerations

Preferred Position in Treatment Algorithm:

• Pluvicto should be used after both an androgen receptor pathway inhibitor and docetaxel, but before cabazitaxel when possible 2
• The TheraP trial showed superior PSA response with Lu-177-PSMA-617 (66%) versus cabazitaxel (37%) with fewer grade 3-4 adverse events (33% vs 53%) 2, 3
• Cross-resistance between abiraterone and enzalutamide makes sequential novel hormone therapy suboptimal compared to Pluvicto 2

Activity After Cabazitaxel:

• Pluvicto retains activity after cabazitaxel with median radiographic PFS of 4.4 months and median OS of 8.9 months 6
• However, activity is more limited in this heavily pretreated population compared to earlier use 6
• Duration of previous cabazitaxel treatment does not impact Pluvicto outcomes 6

Safety Profile and Monitoring

Most Common Adverse Reactions (≥20%):

• Fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation 5, 1
• Grade 3 or higher adverse events occur in 52.7% versus 38% with standard care alone 4, 2

Laboratory Abnormalities (≥30%):

• Decreased lymphocytes, hemoglobin, leukocytes, platelets, calcium, and sodium 5, 1
• Myelosuppression is cumulative with additional cycles 3

Required Monitoring:

• Blood counts, renal function, and hepatic function before each treatment cycle 3, 1
• For Grade 2 myelosuppression: withhold until improvement to Grade 1 or baseline 1
• For Grade ≥3 myelosuppression: withhold until improvement, then reduce dose by 20% 1

Critical Pitfalls to Avoid

PSMA Imaging Requirement:

• Do not use Pluvicto without confirmed PSMA-positive disease on PET imaging 1, 2
• Presence of PSMA non-expressing lesions is a contraindication 2, 3

Combination Therapy Caution:

• Do not combine Pluvicto with radium-223, as the ERA-223 trial showed increased fracture risk with combined radioligand therapy 2
• Ensure bone-targeted agents (bisphosphonates or denosumab) are started before Pluvicto based on radium-223 experience 2

Treatment Delay Management:

• If adverse reactions cause treatment delay >4 weeks, permanently discontinue rather than continuing to wait 1
• Only one dose reduction is permitted; second dose reduction indication requires permanent discontinuation 1

Predictors of Response

Favorable Prognostic Factors:

• PSA decline ≥50% during therapy predicts longer radiographic PFS, time to PSA progression, and overall survival 6
• Time to castration resistance ≥12 months associated with longer radiographic PFS 6

Unfavorable Prognostic Factors:

• ISUP grade 4-5 disease shows trend toward shorter radiographic PFS 6
• Higher baseline PSMA mean SUV and maximum SUV on PET imaging trend toward shorter outcomes 6
• Visceral metastases present in 21% of treated patients but outcomes data limited 6

Radiation Safety Requirements

Handling Precautions:

• Use waterproof gloves and effective radiation shielding when handling 1
• Must be used by or under control of healthcare providers qualified by specific training in radiopharmaceutical handling 1
• Follow radioprotection precautions according to national and local regulations 3

Multidisciplinary Approach:

• Collaboration between medical oncology, nuclear medicine, and radiation safety is essential for optimal utilization 3