Optimizing prostate cancer outcomes with 177Lu-PSMA-617 radioligand therapy

Radioligand therapy, which uses prostate-specific membrane antigen (PSMA)–targeted agents to deliver tumour‑focused radiation, has become a key treatment for metastatic castration‑resistant prostate cancer (mCRPC). At an industry‑sponsored meeting, Professor Kim-Nguyen Chi of the University of British Columbia in Vancouver, Canada, discussed how PSMA-targeted radioligand therapy, specifically lutetium 177–PSMA 617 (¹⁷⁷Lu-PSMA-617), is reshaping mCRPC management and optimizes outcomes.

Emergence of PSMA-targeted therapy in mCRPC management
PSMA is highly expressed on most metastatic prostate cancer cells, which enables radioligand therapy to deliver tar­geted radiation while largely sparing nor­mal tissues. In particular, ¹⁷⁷Lu‑PSMA‑617 has been approved in combination with androgen deprivation therapy with or without an androgen receptor pathway inhibitor (ARPI) for treatment of adults with progressive PSMA-positive mCRPC previously treated with an ARPI and taxane-based chemotherapy. [Pluvicto Hong Kong Prescribing Information; N Engl J Med 2021;385:1091-1103]

VISION and PSMAfore
¹⁷⁷Lu-PSMA-617 was approved based on the open-label phase III VISION trial, which included 831 patients with heavily pretreated PSMA-positive mCRPC (ie, ≥1 ARPI and 1–2 taxane regimens). Adding ¹⁷⁷Lu-PSMA-617 to standard care improved radiographic progression-free survival (rPFS; 8.7 vs 3.4 months; haz­ard ratio [HR], 0.40; 99.2 percent confi­dence interval [CI], 0.29–0.57; p<0.001) and overall survival (OS; median, 15.3 vs 11.3 months; HR, 0.62; 95 percent CI, 0.52–0.74; p<0.001), produced greater objective response rates (ORRs) and PSA decline of ≥50 percent (PSA50), and had a manageable safety profile. [N Engl J Med 2021;385:1091-1103]

Another open-label phase III trial, PSMAfore, evaluated earlier use of ¹⁷⁷Lu-PSMA-617 in 468 chemotherapy-naïve patients with PSMA-positive mCRPC, which progressed after one ARPI. Patients received either ¹⁷⁷Lu-PSMA-617 Q6W for up to six cycles or a change of ARPI (ie, abiraterone or enzalutamide), with cross­over permitted after radiographic progres­sion. After a 24-month follow-up period, ¹⁷⁷Lu-PSMA-617 was associated with significantly improved rPFS vs change of ARPI (11.60 vs 5.59 months; HR, 0.49; 95 percent CI, 0.39–0.61). [Lancet 2024;404:1227-1239]

PSA50 and ORRs were significantly higher in the ¹⁷⁷Lu-PSMA-617 arm. Nota­bly, PSMAfore reported a higher proportion of patients achieving complete responses with ¹⁷⁷Lu‑PSMA‑617 than VISION (ie, 21 vs 9.2 percent), suggesting a more favour­able depth of response in the taxane‑naïve setting. In PSMAfore, ¹⁷⁷Lu-PSMA-617 was also associated with fewer grade ≥3 ad­verse events (AEs) vs the ARPI arm (36 vs 48 percent), and no new safety signals were identified. [Lancet 2024;404:1227-1239; N Engl J Med 2021;385:1091-1103]

Earlier use of ¹⁷⁷Lu‑PSMA‑617 in mCRPC treatment
“A prior phase II study showed that switching between abiraterone and en­zalutamide can be reasonable for patients with slowly progressive, asymptomatic mCRPC without visceral disease,” shared Chi. [Lancet Oncol 2019;20:1730-1739] “However, results from VISION and PS­MAfore have established the efficacy of ¹⁷⁷Lu‑PSMA‑617 across late and earlier mCRPC settings, showing improved rPFS, higher response rates and acceptable safety profile vs standard care alone or ARPI switching.” [Lancet 2024;404:1227-1239; N Engl J Med 2021;385:1091-1103]

¹⁷⁷Lu‑PSMA‑617 before ARPI switching
PSMAfore’s exploratory post hoc analysis showed that ¹⁷⁷Lu-PSMA-617 prolonged rPFS vs ARPI change irrespec­tive of pre-randomization ARPI. ¹⁷⁷Lu-PS­MA-617 improved rPFS vs ARPI change among patients who received pre-ran­domization abiraterone (pre-abiraterone: HR, 0.47; 95 percent CI, 0.33–0.66) or en­zalutamide (pre-enzalutamide: HR, 0.35; 95 percent CI, 0.24–0.52). PSA50 re­sponse and ORRs also favoured ¹⁷⁷Lu-PS­MA-617 regardless of pre-randomization ARPI. [Wei XX, et al, AUA 2024, abstract P2-04; J Urol 2024;211(5S2):e2]

“Of note, complete response rates for ¹⁷⁷Lu-PSMA-617 in patients who re­ceived pre-randomization abiraterone or enzalutamide were 25.0 and 20.0 percent, respectively,” noted Chi. (Figure 1) “These are quite profound results, as we’re not used to seeing such high response rates in patients with mCRPC who have pro­gressed on ARPIs.”

These findings support considering ¹⁷⁷Lu-PSMA-617 before ARPI switching as a new standard treatment approach for patients with taxane-naïve mCRPC.

¹⁷⁷Lu‑PSMA‑617 before chemotherapy
“Docetaxel remains a benchmark therapy in mCRPC, with a median OS of approximately 19 months that has been remarkably consistent from the phase III TAX 327 trial more than 20 years ago through last year’s phase III KEYNOTE‑921 trial,” stressed Chi. [N Engl J Med 2004;351:1502-1512; J Clin Oncol 2025;43:1638-1649] “Yet, contem­porary population‑based data from Can­ada showed that only about 25 percent of men who died from prostate cancer ever received docetaxel, despite having a single-payer universal healthcare system. This possibly reflects toxicity concerns, ad­vanced age and comorbidities, with many patients likely reluctant to undergo chemo­therapy.” [Roberts HN, et al, ESMO 2025, abstract 2526eP]

“PSMAfore enrolled mainly asymp­tomatic, taxane‑naïve patients who were ineligible for or able to defer chemother­apy. Moreover, docetaxel is typically re­served for more symptomatic patients with visceral disease,” he continued. [Lan­cet 2024;404:1227-1239] “We initiated the randomized, multicentre, open-label phase II PLUDO trial to directly com­pare ¹⁷⁷Lu‑PSMA‑617 vs docetaxel in chemotherapy-naïve but -eligible patients with PSMA-PET–positive mCRPC pro­gressing after receiving an ARPI.” [Chi KN, et al, ESMO 2025, abstract LBA89; NCT04663997]

In PLUDO (n=199), patients received either ¹⁷⁷Lu‑PSMA‑617 at 7.4 GBq Q6W for a maximum of 6 cycles, or docetaxel at 75 mg/m² Q3W for a maximum of 12 cycles with cross-over at progression.

“PLUDO deliberately used a less strin­gent PSMA-PET criteria than VISION or PSMAfore to have a more inclusive pop­ulation, which could have biased the out­comes against the ¹⁷⁷Lu‑PSMA‑617 arm,” Chi said. [N Engl J Med 2021;385:1091-1103; Lancet 2024;404:1227-1239; Chi KN, et al, ESMO 2025, abstract LBA89] “Nevertheless, primary endpoint results showed that rPFS was comparable be­tween the two arms [8.6 vs 10.7 months; HR, 1.01; 90 percent CI, 0.77–1.31; p=0.51].” [Chi KN, et al, ESMO 2025, ab­stract LBA89]

Importantly, disease responses fa­voured the ¹⁷⁷Lu‑PSMA‑617 arm, with PSA50 and complete or partial response rates approximately double those of docetaxel. (Figure 2)

Tolerability also favoured radioligand therapy, with only one patient discontinu­ing treatment in the ¹⁷⁷Lu‑PSMA‑617 arm vs 15 patients in the docetaxel arm due to treatment-related AEs. Grade 3/4 treatment‑related AEs occurred more frequently in the docetaxel vs ¹⁷⁷Lu‑PS­MA‑617 arm (34 vs 13 percent), with two treatment‑related deaths reported only in the chemotherapy arm. [Chi KN, et al, ESMO 2025, abstract LBA89]

“These results support using ¹⁷⁷Lu-PSMA-617 before docetaxel due to the observed similar rPFS, improved disease response, and better tolerabil­ity,” suggested Chi. “Using ¹⁷⁷Lu-PS­MA-617 first will help preserve patients’ performance status and marrow re­serve, which will also prepare them for subsequent lines of therapy, including docetaxel, thereby maximizing the life­time benefit of succeeding treatments.”

“While median OS results favoured the docetaxel‑first sequence [18.2 vs 14.3 months], this was likely driven by fewer patients crossing over from ¹⁷⁷Lu‑PSMA‑617 to docetaxel than vice versa [n=38 vs 56], which may suggest reluctance to accept later che­motherapy rather than intrinsic inferi­ority of the radioligand‑first approach,” suggested Chi.

“This crossover imbalance reinforc­es the importance of chemotherapy as a valid later-line therapy in patients with mCRPC for optimizing OS ben­efits,” said Chi. “Nevertheless, earlier ¹⁷⁷Lu‑PSMA‑617 use offers similar dis­ease control with better tolerability than docetaxel. Treatment decisions should therefore ultimately be balanced by pa­tient factors and preferences, as well as management goals.”

Current mCRPC therapies and ¹⁷⁷Lu‑PSMA‑617 after ARPI progression
“Practice-informed analyses and pivotal clinical trials support use of ¹⁷⁷Lu‑PSMA‑617 as the favoured treatment for patients with mCRPC progressing after an ARPI, before an ARPI switch or taxane-based chemotherapy,” suggested Chi. “There are limited data comparing ¹⁷⁷Lu‑PSMA‑617 vs other therapies, but certain considerations based on clinical experience, available evidence, and cur­rent treatment recommendations may help in the decision-making process.” (Figure 3)

¹⁷⁷Lu‑PSMA‑617 and patient selection
“Based on subgroup analyses of the pivotal trials discussed, all patient subgroups appear to benefit from ¹⁷⁷Lu‑PSMA‑617 therapy,” noted Chi.

“Across VISION and PSMAfore, patients with liver or other visceral me­tastases derived rPFS benefit from ¹⁷⁷Lu‑PSMA‑617, with rPFS outcomes comparable to or greater than those with­out visceral disease,” he continued. [N Engl J Med 2021;385:1091-1103; Lancet 2024;404:1227-1239] “Similarly, PLUDO demonstrated no differential effect vs docetaxel in this subgroup, suggesting that chemotherapy doesn’t necessarily work any better than radioligand thera­py.” [Chi KN, et al, ESMO 2025, abstract LBA89]

“Quantitative PET analyses suggest that higher PSMA standard uptake values [SUVs] may predict better outcomes with ¹⁷⁷Lu-PSMA-617 vs taxane therapy,” Chi explained. [Lancet Oncol 2022;23:1389-1397] “In VISION, patients with higher baseline mean SUV [SUV_mean] did derive the greatest rPFS and OS benefits from ¹⁷⁷Lu-PSMA-617 plus standard care, but benefits were still observed at lower SUV_mean levels.” [Radiology 2024;312:e233460]

Similarly, PSMAfore reported that higher SUV_mean was associated with better outcomes with ¹⁷⁷Lu-PSMA-617 therapy, although no optimal thresh­olds were identified. [Herrmann K, et al, ESMO 2025, abstract 2390P] In PLUDO, higher baseline SUV_mean was associated with better rPFS in both the ¹⁷⁷Lu‑PSMA‑617 and docetaxel arms; however, there was no clear preferen­tial benefit from radioligand therapy in either SUV group, suggesting that SU­V_mean was prognostic but not predictive of rPFS. [Chi KN, et al, ESMO 2025, ab­stract LBA89]

“Taken together, current evidence does not clearly rule out any patients with mCRPC from ¹⁷⁷Lu-PSMA-617’s benefits,” he remarked. “Rather, these findings support an inclusive, ‘opt‑in’ approach to ¹⁷⁷Lu‑PSMA‑617 in chemotherapy‑naïve mCRPC, instead of excluding patients based on visceral disease or lower SUV_mean.”

Monitoring response to ¹⁷⁷Lu-PSMA-617: Beyond radiographic progression
The current approved dosing reg­imen of ¹⁷⁷Lu-PSMA-617 is 7.4 GBq given intravenously Q6W (±1 week) for up to six cycles or until disease progres­sion or unacceptable toxicity. [Pluvicto Hong Kong Prescribing Information]

“Dosing lower than this may not be ideal,” explained Chi. “This is indirectly suggested by comparing the difference in magnitude of treatment response observed in PSMAfore, which used the recommended dosing regimen for ¹⁷⁷Lu-PSMA-617, and the open-label phase III SPLASH trial, which used an­other radioligand, ¹⁷⁷Lu-PNT2002 [¹⁷⁷Lu-PSMA-I&T], at a lower dosing regimen [ie, 6.8 GBq Q8W for up to four cycles], likely reflecting concerns over the rela­tively higher renal radiation exposure re­ported.” [Lancet 2024;404:1227-1239; Sartor O, et al, ESMO 2024, abstract LBA65; Front Oncol 2025;14:1483953]

SPLASH met its primary rPFS end­point (ie, 9.5 months vs 6.0 months for ARPI switch; HR, 0.71; 95 percent CI, 0.55–0.92; p=0.0088). However, the magnitude of benefit was lower than that in PSMAfore (HR, 0.49). SPLASH also had a numerically unfavourable OS HR (1.11; 95 percent CI, 0.73–1.69; p=0.6154), and lower PSA50 and ORR.

“Although SPLASH was a positive study, the reduced rPFS benefit vs PS­MAfore suggests that reduced treatment intensity may compromise efficacy,” ex­plained Chi.

“SPECT‑CT changes are difficult to interpret and should not, on their own, drive treatment decisions, especially when PSA is improving,” he cautioned. “For ¹⁷⁷Lu‑PSMA‑617, I recommend fol­lowing a ‘two‑out‑of‑three’ rule before stopping radioligand therapy, requiring concordant progression in ≥2 domains [ie, radiographic evidence, presence of clinical symptoms, PSA elevation], ex­cept in cases of new aggressive liver metastases.”

Conclusions
¹⁷⁷Lu-PSMA-617 has demonstrat­ed consistent efficacy across later and earlier mCRPC settings, with robust re­sponse rates and favourable tolerability. Evidence from VISION, PSMAfore and PLUDO supports its use before ARPI switching or docetaxel in most patients, using an inclusive “opt‑in” selection strategy and multidimensional response assessment to maximize long‑term benefit.