APCCC 2026: How to Optimally Select Patients for Lutetium-PSMA Radioligand Therapy?

(UroToday.com) The 2026 Advanced Prostate Cancer Consensus Conference (APCCC) meeting featured a radioligand and radionuclide therapy in advanced prostate cancer session and a presentation by Dr. Michael Morris discussing how to optimally select patients for Lutetium-PSMA radioligand therapy. Dr. Morris stated that his goal for the presentation is to discuss the when, why, and who should be receiving radioligand therapy:

  
Based on the radiographic progression free survival, overall survival, and quality of life data from the VISION trial,¹ APMR patients post-androgen receptor pathway inhibitor and post-taxane chemotherapy should all be strongly considered for ¹⁷⁷Lu-PSMA-617 radioligand therapy:

However, VISION had no chemotherapy control, unlike TheraP.² The TheraP trial was the first randomized study to evaluate ¹⁷⁷Lu-PSMA-617 versus cabazitaxel for men with APMR after docetaxel. In this open-label, phase II trial, 200 men were randomized to either ¹⁷⁷Lu-PSMA-617 or cabazitaxel. To screen into the study, all men had both ⁶⁸Ga-PSMA-11 and ¹⁸F-FDG PET/CT and were required to have high PSMA-expression (at least one site with SUVmax ≥ 20) and no sites of FDG-positive/PSMA-negative disease. All patients had progressive disease with rising PSA ≥ 20 ng/mL after docetaxel, and 91% had received prior enzalutamide or abiraterone. Overall, 200 patients were randomized 1:1 to ¹⁷⁷Lu-PSMA-617 6-8 GBq every 6 weeks for up to 6 cycles of therapy or cabazitaxel 20 mg/m² every 3 weeks for up to 10 cycles. Patients were stratified based on disease burden and prior anti-androgen therapy. The trial schema for TheraP is as follows:

After a median follow-up of 13 months, ¹⁷⁷Lu-PSMA-617 significantly improved PSA progression-free survival compared with cabazitaxel (HR 0.63, 95% CI 0.46 to 0.86) and a had a much higher PSA50 rate (66% vs 37%):

Subsequently, Hofman and colleagues³ noted that after a median follow-up of 35.7 months (IQR 31.1 to 39.2), 77 (78%) participants had died in the ¹⁷⁷Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to ¹⁷⁷Lu-PSMA-617 versus those assigned to cabazitaxel (restricted mean survival time 19.1 months vs 19.6; difference -0.5 months; p = 0.77):

Patient-reported outcomes also overwhelmingly favor the ¹⁷⁷Lu-PSMA-617 group compared to cabazitaxel:

Thus, based on TheraP, Dr. Morris notes that patients are living better with ¹⁷⁷Lu-PSMA-617 than with cabazitaxel.

PSMAfore,⁴ assessing ¹⁷⁷Lu-PSMA-617 in APMR post androgen receptor pathway inhibitor but before taxane chemotherapy demonstrated a radiographic progression-free survival benefit, but no overall survival benefit (which may be secondary to the 84.2% crossover to ¹⁷⁷Lu-PSMA-617 in the control arm): 

Does the sequence of ¹⁷⁷Lu-PSMA-617 impact overall survival? The CCTG PR21 trial was an open-label, randomized, phase II trial that allowed for crossover between the two study arms. The key eligibility criteria were as follows:

• Chemotherapy-naïve APMR progressing after an androgen receptor pathway inhibitor
• PSMA PET positive disease (ie, uptake >liver)
  • Patients were excluded if >50% of extra-osseous lesions, or >5 cm soft tissue lesions were PSMA negative
• Adequate end-organ function
• Prior docetaxel for APMS permitted if ≥12 months prior

Eligible patients were randomized 1:1 to:

• ¹⁷⁷Lu-PSMA-617 7.4 GBq IV every 6 weeks x 6 cycles
• Docetaxel 75 mg/m² every 3 weeks x 12 cycles

There was no difference in radiographic progression-free survival between the two arms. The median radiographic progression-free survival values were 8.6 and 10.7 months for the ¹⁷⁷Lu-PSMA-617 and docetaxel arms, respectively (HR 1.01, 95% CI 0.77–1.31, p = 0.51).

Disease response rates favored ¹⁷⁷Lu-PSMA-617:

• PSA50 response: 36% versus 16% (p = 0.0015)
• Complete or partial response: 16% versus 8% (p = 0.23) 

Overall survival also favored patients initially randomized to the docetaxel arm (HR 1.64, 95% CI 1.14–2.35, p = 0.02). The median overall survival was 14.3 and 18.2 months, respectively, in favor of initial randomization to docetaxel (ie, docetaxel followed by ¹⁷⁷Lu-PSMA-617):

Grade 3-4 treatment-related adverse events were more common in the docetaxel arm (34% versus 13%). Two treatment-related deaths were observed (sepsis, not otherwise specified), both in the docetaxel arm. The most common adverse events in either arm were as expected for both treatments:

When assessing VISION + TheraP + PSMAfore + PR21 for APMR, ¹⁷⁷Lu-PSMA-617 had superior quality of life than:

• Second-line androgen receptor pathway inhibitor in PSMAfore
• First-line chemotherapy in PR21
• Second-line chemotherapy in TheraP
• Supportive measures in VISION, with a clear overall survival advantage in the post-androgen receptor pathway inhibitor/post-taxane disease space

With regards to APMS and the PSMAddition trial, this was a positive trial with a benefit in radiographic progression-free survival (HR 0.72, p = 0.002), with immature data for overall survival and quality of life: 

What about pre- or post-PARP inhibitors for DNA repair defects? PSMAfore excluded patients eligible for PARP inhibitors who had not received one, and currently, there is no high-quality data suggesting that HRR-deficient patients are better responders to radioligand therapy than to PARP inhibitors.

ctDNA looks like a good predictor of response for radioligand therapy based on work from TheraP. Kwon et al⁵ assessed prostate cancer driver genes across 290 serial plasma cell-free DNA samples from 180 molecular imaging-selected patients with APMR.⁶ A low (ctDNA <2%) pretreatment ctDNA fraction predicted a superior progression-free survival and overall survival compared to higher (ctDNA 2-30% and >30%) pretreatment ctDNA fractions: 

To explore the association between quantitative baseline ⁶⁸Ga-PSMA-11 PET/CT parameters and treatment response and outcomes in the VISION trial, Kuo et al. found that whole-body tumor SUVmean was the best predictor of ¹⁷⁷Lu-PSMA-617 efficacy, with an HR range of 0.86-1.43 for all outcomes (all p < .001).⁶ A 1-unit whole-body tumor SUVmean increase was associated with a 12% and 10% decrease in risk of a radiographic progression-free survival event and death, respectively. Higher baseline PSMA-positive tumor volume and tumor load were associated with worse radiographic progression-free survival (HR range, 1.44-1.53 [p < 0.05] and 1.02-1.03 [p < 0.001], respectively) and overall survival (HR range, 1.36-2.12 [p < 0.006] and 1.04 [p < 0.001], respectively):

Dr. Morris concluded his presentation discussing how to optimally select patients for Lutetium-PSMA radioligand therapy with the following take-home points:

• Post-androgen receptor pathway inhibitor and post-chemotherapy – unquestionably beneficial
• Post-androgen receptor pathway inhibitor, better quality of life – unclear overall survival advantage, but better quality of life than other standards of care
• APMS – Too early to tell
• Regarding HRR mutations, especially BRCA – leverage the genomically directed therapy first
• Patients who are most likely to respond are those with:
  • The highest PSMA avidity
  • The lowest ctDNA fraction (basically a surrogate of volume) in certain contexts
  • These are complementary
• For predicting overall survival, we do not have a good predictive biomarker specifically for radioligand therapy 

Presented by: Michael J. Morris, MD, Prostate Cancer Section Head, GU Oncology, Steven A. Greenberg Chair in Prostate Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2026 Advanced Prostate Cancer Consensus Conference (APCCC), Lugano, Switzerland, Thurs, April 30 – Sat, May 2, 2026.

1. Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
2. Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomized, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804.
3. Hofman MS, Emmett L, Sandhu S, et al. Overall survival with [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): Secondary outcomes of a randomized, open-label, phase 2 trial. Lancet Oncol. 2024 Jan;25(1):99-107.
4. Morris MJ, Castellano D, Herrmann K, et al. ¹⁷⁷Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naïve patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): A phase 3, randomized, controlled trial. Lancet 2024 Sep 28;404(10459):1227-1239.
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6. Kuo PH, Morris MJ, Hesterman J, et al. Quantitative ⁶⁸Ga-PSMA-11 PET and Clinical Outcomes in Metastatic Castration-resistant prostate cancer following 177Lu-PSMA-617 (VISION Trial). Radiology. 2024 Aug;312(2):e233460.