What treatment options are available for a patient with oligorecurrent prostate cancer, considering enrollment in the LUNAR (Lutetium (Lutetium-177) PSMA (Prostate-Specific Membrane Antigen) Neoadjuvant to Ablative Radiotherapy) clinical trial?

Treatment Options for Oligorecurrent Prostate Cancer: LUNAR Trial Enrollment Considerations

For patients with oligorecurrent hormone-sensitive prostate cancer, enrollment in the LUNAR trial offers a promising investigational approach combining 177Lu-PSMA radioligand therapy with stereotactic ablative radiotherapy (SABR), which has demonstrated superior progression-free survival (17.6 months vs 7.4 months) compared to SABR alone in recently published results. 1

Primary Treatment Approach: SABR Metastasis-Directed Therapy

Clinicians may perform SABR metastasis-directed therapy (MDT) for patients with regional or metastatic oligorecurrence following primary salvage therapy, though must carefully weigh toxicity risks against potential benefits. 2

Evidence Supporting SABR MDT:

• The STOMP trial demonstrated improved ADT-free survival with MDT (21 months vs 13 months; HR 0.60,95% CI 0.40-0.90) in patients with up to 3 metastases on choline PET 2
• The ORIOLE trial enrolled 54 patients with up to 3 metastases on conventional imaging, providing additional randomized evidence for MDT 2
• The POPSTAR trial showed >90% local progression-free survival at 2 years with single-fraction SBRT, with only 14% grade 2 and 3% grade 3 toxicity 2, 3

Recommended SABR Dosing:

• 24 Gy in 1 fraction demonstrated superior complete pain response in phase II/III trials 3
• 20 Gy in 1 fraction represents an alternative evidence-based regimen with excellent local control and acceptable toxicity 3

LUNAR Trial: Investigational Combination Approach

Trial Design and Eligibility:

The LUNAR trial randomizes patients 1:1 to receive either:

• Control arm: SBRT to all disease sites
• Experimental arm: Two cycles of neoadjuvant 177Lu-PNT2002 (6.8 GBq) 6-8 weeks apart, followed by interval PSMA PET/CT and dose-adapted SBRT 4

Key Inclusion Criteria:

• 1-5 lesions identified on PSMA PET/CT with central review by board-certified nuclear medicine physician 4
• Oligorecurrent metastatic hormone-sensitive prostate cancer (not castrate-resistant) 4
• No androgen deprivation therapy within 6 months of enrollment 4
• Excludes de novo oligometastatic disease 4

Published LUNAR Trial Results:

The addition of 177Lu-PNT2002 to SBRT significantly improved progression-free survival (17.6 months vs 7.4 months; HR 0.37,95% CI 0.22-0.61, P<0.0001) without increased toxicity in 87 evaluable patients. 1

• Grade 3 adverse events limited to lymphopenia: 4.8% in SBRT group vs 6.7% in combination group 1
• Median follow-up of 22 months 1
• PSA response rate of 55% (95% CI 36-72%) observed with combination therapy 5

Alternative Systemic Approaches (Not Applicable for LUNAR Eligibility)

177Lu-PSMA Monotherapy for Castration-Resistant Disease:

For patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on docetaxel and androgen pathway inhibitors, Lu-177-PSMA-617 is strongly recommended as monotherapy, extending overall survival from 11.3 to 15.3 months (HR 0.62,95% CI 0.52-0.74, P<0.001). 6

This represents a Category 1 recommendation with standard dosing of 7.4 GBq (200 mCi) intravenously every 6 weeks for 4-6 cycles 6. However, this applies only to castration-resistant disease, not the hormone-sensitive oligorecurrent population eligible for LUNAR 6.

Continuation of Androgen Pathway Inhibitors:

When using Lu-177-PSMA-617 in mCRPC, abiraterone should be continued during radioligand therapy at standard dosing (1,000 mg daily plus prednisone 5 mg twice daily), based on VISION trial data showing maintained survival benefit. 6

Patient Selection Algorithm for Treatment Decision

Step 1: Confirm Oligorecurrent Status

• Obtain PSMA PET imaging (Ga-68 PSMA-11, F-18 piflufolastat, or F-18 flotufolastat) to identify 1-5 metastatic lesions 6, 4
• Ensure no widespread polymetastatic disease that would exclude MDT approaches 3

Step 2: Assess Hormone Sensitivity

• If hormone-sensitive (no ADT within 6 months): Consider LUNAR trial enrollment or standard SABR MDT 4
• If castration-resistant with prior docetaxel/ARPI exposure: Standard Lu-177-PSMA-617 monotherapy per FDA approval 6

Step 3: Evaluate Prior Treatments

• No recent ADT and ≤5 lesions: LUNAR trial represents optimal investigational option given 17.6-month median PFS 1
• Standard SABR alone: Reasonable alternative with 7.4-month median PFS and established safety profile 1

Step 4: Consider Bone Protection

Mandatory concurrent bone-protecting agents (denosumab or zoledronic acid) should be initiated before any Lu-177-PSMA therapy to reduce fracture risk, based on PEACE III trial data showing fracture rates of 2.8% with bone protection versus 45.9% without. 6

Critical Pitfalls to Avoid

Inappropriate Patient Selection:

• Do not offer SABR MDT to patients with widespread polymetastatic disease or uncontrolled primary tumors 3
• Conventional imaging may miss additional metastases; PSMA-PET is strongly preferred for accurate staging 3

Timing Considerations:

• LUNAR trial specifically excludes patients who received ADT within 6 months, distinguishing it from castration-resistant protocols 4
• Do not confuse eligibility criteria for hormone-sensitive oligorecurrent disease (LUNAR) with mCRPC indications for standard Lu-177-PSMA-617 6, 4

Monitoring Requirements:

• Regular monitoring during Lu-177 treatment requires PSA levels before each cycle, complete blood count, renal and hepatic function assessment 6
• PSMA PET/CT should be acquired systematically at PSA progression and/or 12 months after SBRT 1

Quality of Life and Toxicity Profile

The LUNAR combination approach demonstrated no increase in grade 3+ toxicity compared to SABR alone, with only lymphopenia as the sole grade 3 adverse event in both arms. 1

Earlier phase 2 data with Lu-177-PSMA monotherapy showed:

• 87% experienced grade 1 dry mouth 7
• 50% had grade 1-2 transient nausea and fatigue 7
• Clinically meaningful improvements in pain severity and global health scores at all timepoints 7