Can targeted radiation, such as Lutetium-177 (Lutetium-177) PSMA (Prostate-Specific Membrane Antigen), stop the spread of abiraterone (Abiraterone acetate)-resistant prostate cancer?

Lutetium-177 PSMA Radioligand Therapy for Abiraterone-Resistant Prostate Cancer

Yes, targeted radiation with Lutetium-177 PSMA-617 (Lu-177-PSMA-617) significantly stops disease progression and extends survival in abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC), provided patients have PSMA-positive disease on imaging. 1

Evidence for Disease Control

Lu-177-PSMA-617 demonstrates robust efficacy in controlling disease spread after abiraterone failure:

• Progression-free survival improves dramatically from 3.4 months with standard care alone to 8.7 months when Lu-177-PSMA-617 is added (HR 0.40,99.2% CI 0.29-0.57, P<0.001) 1, 2
• Overall survival extends from 11.3 months to 15.3 months (HR 0.62,95% CI 0.52-0.74, P<0.001) 1, 2
• PSA response rates (≥50% decline) occur in 56-66% of patients, indicating substantial tumor burden reduction 3, 4

These survival benefits represent meaningful disease control in a population that has exhausted androgen receptor pathway inhibitors like abiraterone.

Patient Selection Algorithm

Step 1: Confirm Eligibility Criteria 1

• Metastatic castration-resistant prostate cancer with documented progression
• Prior treatment with at least one androgen receptor pathway inhibitor (abiraterone or enzalutamide)
• Prior treatment with at least one taxane-based chemotherapy (docetaxel)
• ECOG performance status ≤2

Step 2: Obtain PSMA PET Imaging 1

• Order Ga-68 PSMA-11, F-18 piflufolastat, or F-18 flotufolastat PET/CT
• Confirm at least one PSMA-positive metastatic lesion
• Critical exclusion: No dominant PSMA-negative lesions (defined as bone lesions with soft tissue ≥1.0 cm, lymph nodes ≥2.5 cm short axis, or solid organ metastases ≥1.0 cm that lack PSMA uptake) 1

Step 3: Verify Organ Function 1, 5

• Check complete blood count (adequate bone marrow reserve)
• Assess renal function (creatinine clearance)
• Evaluate hepatic function (liver enzymes, bilirubin)

Treatment Protocol

Standard Regimen 1, 6, 5

• Administer 7.4 GBq (200 mCi) intravenously every 6 weeks
• Plan for 4-6 cycles total
• Continue treatment unless progression or unacceptable toxicity occurs

Mandatory Concurrent Therapy 1

• All patients must receive bone-protecting agents (denosumab or zoledronic acid) to reduce fracture risk, based on PEACE III trial data showing fracture rates of 2.8% with bone protection versus 45.9% without when combining radioligand therapy with hormonal agents 1

Monitoring Requirements 1, 5

• Check blood counts, renal function, and hepatic function before each cycle
• Measure PSA levels before each treatment
• Perform clinical assessment for symptoms and adverse events
• Follow radioprotection precautions per local regulations

Safety Profile

The toxicity profile is manageable and does not adversely affect quality of life 2:

• Grade 3-4 adverse events occur in 52.7% versus 38% with standard care alone 2
• Most common side effects: dry mouth (87%, grade 1), transient nausea (50%, grade 1-2), fatigue (50%, grade 1-2) 3
• Hematologic toxicity: thrombocytopenia (13% grade 3-4), anemia, lymphopenia 1, 3
• Quality of life measures show improvement or no deterioration despite treatment 2

Clinical Context and Guideline Support

NCCN Category 1 Recommendation 1 The NCCN designates Lu-177-PSMA-617 as a Category 1 (highest level), "useful in certain circumstances" treatment option for patients meeting the eligibility criteria outlined above.

Strong AUA/SUO Recommendation 1 The American Urological Association provides a Strong Recommendation (Evidence Level Grade B) for offering Lu-177-PSMA-617 to progressive mCRPC patients with prior docetaxel and androgen pathway inhibitor exposure who have positive PSMA PET imaging.

ASCO Endorsement 1 ASCO supports the use of multiple PSMA radiotracers (Ga-68 PSMA-11, F-18 piflufolastat, F-18 flotufolastat) for determining treatment eligibility, recognizing their equivalency.

Important Caveats

Limited Docetaxel Exposure 6 Patients who received limited docetaxel cycles due to intolerance or early progression remain eligible. The TheraP trial demonstrated Lu-177-PSMA-617 achieved superior PSA response rates (66%) compared to cabazitaxel (37%) in this population, regardless of the number of prior docetaxel cycles 6.

Visceral Metastases 1 Unlike Radium-223 (which is contraindicated with visceral disease), Lu-177-PSMA-617 can treat patients with visceral metastases provided they are PSMA-positive 1, 2.

Combination Therapy Caution 1 Do not combine Lu-177-PSMA-617 with chemotherapy outside clinical trials due to additive myelosuppression risk. Androgen deprivation therapy continuation is permitted 1.

Multidisciplinary Coordination 1 Optimal utilization requires collaboration between medical oncology, nuclear medicine, and radiation oncology for patient selection, treatment delivery, and monitoring 1.