When to use 177Lu-PSMA-617 in metastatic prostate cancer: before or after taxanes?

Understanding Metastatic Castration-Resistant Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC) represents an advanced stage of prostate cancer where the disease continues to progress despite androgen deprivation therapy. Patients with mCRPC face a poor prognosis, and treatment options aim to extend survival and improve quality of life. Prostate-specific membrane antigen (PSMA) is a protein highly expressed on the surface of prostate cancer cells, making it an attractive target for diagnostic imaging and therapeutic interventions ^1,2.

Lutetium-177 (¹⁷⁷Lu)-PSMA-617 is a radioligand therapy designed to deliver beta-particle radiation directly to PSMA-expressing cancer cells and their surrounding microenvironment. This targeted approach has shown promise in clinical trials, leading to its evaluation in different stages of mCRPC progression ^1,2.

The VISION Trial: ¹⁷⁷Lu-PSMA-617 in Later-Line Therapy

The VISION trial was an international, open-label, phase 3 study that investigated ¹⁷⁷Lu-PSMA-617 in patients with mCRPC who had previously received at least one androgen-receptor-pathway inhibitor (ARPI) and one or two taxane regimens. Patients were required to have PSMA-positive gallium-68 (⁶⁸Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans ¹.

A total of 831 patients were randomized in a 2:1 ratio to receive either ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care, or standard care alone. Standard care excluded chemotherapy, immunotherapy, radium-223, and investigational drugs. The primary endpoints were imaging-based progression-free survival (PFS) and overall survival (OS) ¹.

Key Findings from VISION

The VISION trial demonstrated significant benefits for patients receiving ¹⁷⁷Lu-PSMA-617. The median follow-up was 20.9 months. ¹⁷⁷Lu-PSMA-617 plus standard care significantly prolonged imaging-based PFS compared to standard care alone (median, 8.7 vs. 3.4 months; hazard ratio [HR] for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001). Furthermore, overall survival was also significantly extended (median, 15.3 vs. 11.3 months; HR for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001) ¹.

All key secondary endpoints, including objective response, disease control, and time to symptomatic skeletal events, significantly favored the ¹⁷⁷Lu-PSMA-617 group. The incidence of grade 3 or higher adverse events was higher with ¹⁷⁷Lu-PSMA-617 (52.7% vs. 38.0%), but this did not adversely affect the patients' quality of life ¹.

The PSMAfore Trial: ¹⁷⁷Lu-PSMA-617 in Earlier-Line Therapy

Building on the VISION trial's success, the PSMAfore trial investigated the efficacy of ¹⁷⁷Lu-PSMA-617 in an earlier treatment setting: taxane-naive patients with mCRPC who had progressed once on a previous ARPI. This phase 3, randomized, controlled trial enrolled 468 eligible patients across Europe and North America ².

Patients were randomly allocated (1:1) to receive open-label intravenous ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for six cycles) or a change of ARPI (to abiraterone or enzalutamide). Crossover from the ARPI change group to ¹⁷⁷Lu-PSMA-617 was permitted after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival (rPFS) ².

Key Findings from PSMAfore

In the PSMAfore trial, ¹⁷⁷Lu-PSMA-617 significantly prolonged rPFS compared to a change in ARPI. In the primary analysis, the median rPFS was 9.30 months (95% CI 6.77-not estimable) in the ¹⁷⁷Lu-PSMA-617 group versus 5.55 months (4.04-5.95) in the ARPI change group (HR 0.41; 95% CI 0.29-0.56; P<0.0001). An updated analysis at a median follow-up of 24.11 months showed a median rPFS of 11.60 months (95% CI 9.30-14.19) for ¹⁷⁷Lu-PSMA-617 versus 5.59 months (4.21-5.95) for ARPI change (HR 0.49; 95% CI 0.39-0.61) ².

The safety profile was favorable for ¹⁷⁷Lu-PSMA-617 in this earlier line. The incidence of grade 3-5 adverse events was lower in the ¹⁷⁷Lu-PSMA-617 group (36% of patients) compared to the ARPI change group (48% of patients). Notably, none of the four grade 5 events in the ¹⁷⁷Lu-PSMA-617 group were treatment-related ².

Clinical Implications and Future Directions

The VISION and PSMAfore trials collectively demonstrate that ¹⁷⁷Lu-PSMA-617 offers significant clinical benefits for patients with PSMA-positive mCRPC, both in pre- and post-taxane settings. The VISION trial established its role in heavily pretreated patients, showing improvements in both imaging-based PFS and OS. The PSMAfore trial extends this evidence, suggesting that ¹⁷⁷Lu-PSMA-617 can be an effective treatment alternative for taxane-naive patients who have progressed on a prior ARPI, offering superior rPFS with a favorable safety profile compared to switching to another ARPI ^1,2.

Why this matters for clinical practice today

These findings provide crucial guidance for clinicians managing mCRPC. The data from PSMAfore suggest that ¹⁷⁷Lu-PSMA-617 could be considered earlier in the treatment paradigm, potentially before taxane-based chemotherapy, for appropriate PSMA-positive patients who have progressed on one ARPI. This offers an additional, effective therapeutic option that can delay progression and potentially improve patient outcomes. The decision on sequencing should be individualized, taking into account patient comorbidities, prior treatments, PSMA expression, and shared decision-making. The favorable safety profile observed in the taxane-naive setting further supports its potential for earlier integration into treatment plans.

Limitations and Next Steps

While both trials provide robust evidence, certain limitations should be considered. The VISION trial was open-label, which could introduce some bias, although primary endpoints were objectively assessed. The PSMAfore trial allowed for crossover from the ARPI change group to ¹⁷⁷Lu-PSMA-617, which may confound the long-term overall survival analysis for the ARPI change arm. Further research is needed to fully understand the long-term overall survival benefit in the taxane-naive setting and to identify specific patient subgroups who might benefit most from earlier ¹⁷⁷Lu-PSMA-617 administration ^1,2. Ongoing studies will continue to refine the optimal integration of radioligand therapies into the evolving treatment landscape for mCRPC.