PSMA-targeted radioligand therapy improves survival in patients with mCRPC

Case 1: A patient with heavily pretreated mCRPC
History, initial treatments and response
A 63-year-old male with hypertension, hyperlipidaemia and diabetes was diag­nosed with metastatic prostate cancer with lumbar spine metastases in 2018. He initially presented with lower urinary tract symptoms and markedly elevated prostate-specific antigen (PSA) of up to 85.3 ng/mL. He was started on luteinizing hormone–releasing hormone (LHRH) an­tagonist as androgen deprivation therapy (ADT) with good response of PSA drop to 13.4 mg/mL.

After 1 year of disease control on ADT, he experienced disease progression in the thoracic spine and intra-abdominal lymph nodes, for which palliative radiotherapy to lumbar spine was given. In view of development of metastatic castration-resistant prostate cancer (mCRPC), mul­tiple lines of systemic treatments, includ­ing docetaxel, prostate radiotherapy, en­zalutamide, and cabazitaxel followed by abiraterone were sequentially given from 2019 to 2024.

In March 2024, his PSA level rose to 21 ng/mL. He reported neck and back pain but was ambulatory with assistance, having an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1. Germline BRCA test and homologous recombination deficiency (HRD) testing with liquid next-generation sequencing (NGS) were performed and were nega­tive. A prostate-specific membrane anti­gen (PSMA) PET-CT scan revealed multi­ple avid lesions in abdominal lymph nodes and T2 vertebra, for which he received fo­cal radiotherapy to the T2 region, with no PSMA non-avid lesions noted.

Subsequent treatment and response
Based on these findings and his previous treatments, intravenous PSMA-targeted radioligand therapy with ¹⁷⁷Lu-PSMA-617 was started.

Before starting radioligand thera­py, the patient’s baseline PSA level was 30.8 ng/mL. After each cycle of lutetium- ¹⁷⁷–PSMA-617 (¹⁷⁷Lu-PSMA-617), the patient received single-photon emission computed tomography (SPECT)-CT scans and PSA monitoring. Following the first cycle in May 2024, additional metas­tases were seen in the neck, abdominal lymph nodes, lungs and liver apart from the initial metastatic locations. (Figure 1A) However, his PSA level decreased to 6.0 ng/mL. The patient tolerated therapy well, experiencing only grade 1 fatigue and nausea. He reported gradual symptom­atic improvement in neck and back pain during subsequent cycles.

The patient’s PSA level reached a nadir of 1.3 ng/mL after five cycles of ¹⁷⁷Lu-PSMA-617. Follow-up SPECT-CT scan showed reduced metastatic burden with resolution of most of the avid lesions after the sixth cycle in December 2024. (Figure 1B)

By April 2025, his PSA level had risen to 3.9 ng/mL, with repeated PSMA PET-CT indicating residual T2 vertebral uptake but generally stable disease. He remains asymptomatic and is under active surveil­lance at the time of writing.

Case 2: A patient with chemotherapy-naïve mCRPC
History, initial treatments and response
An 83-year-old male was diagnosed in 2013 with clinical stage T3b prostate cancer (Gleason score 5 + 3). He received radical radiotherapy and 3 years of ADT, resulting in undetectable PSA levels. The patient remained well until April 2020, when he developed biochemical recur­rence and restarted ADT.

In March 2021, a bone scan revealed multiple bone metastases, and an in­crease in PSA level was detected. The patient was diagnosed with mCRPC and received radiotherapy to the cervi­cal spine. He also started treatment with enzalutamide plus zoledronic acid, initially resulting in biochemical response.

However, PSMA PET-CT scans in March 2022 and March 2023 identified slowly progressive disease with new met­astatic lesions in the cervical and thoracic spine. In April 2024, repeat PSMA PET-CT revealed additional new bone metas­tases (ie, C6, C7, T11), with PSA levels rising to 6.2 ng/mL. Germline BRCA test and HRD testing with liquid NGS were performed and were negative.

Subsequent treatment and response
The patient remained in good gen­eral condition (ECOG PS, 1) and opted for radioligand therapy with intravenous ¹⁷⁷Lu-PSMA-617, along with ADT, en­zalutamide and zoledronic acid. The pa­tient was deemed a candidate to delay taxane-based chemotherapy due to ad­vanced age so as to avoid chemotherapy-related toxicity and risk of myelosuppres­sion.

During radioligand therapy, his dis­ease was monitored with serial SPECT-CT scans and PSA assays after each cy­cle. Following the first cycle, new lesions were detected in the left parietal skull in addition to existing spinal metastases. (Figure 2A) However, the patient’s PSA dropped from a pretreatment level of 7.4 to 0.62 ng/mL after two cycles, be­coming undetectable (<0.02 ng/mL) after completing six cycles in November 2024. Successive scans showed a marked re­duction in radiotracer uptake at all previ­ously active sites, without emergence of new lesions. (Figure 2B)

The patient tolerated the radioli­gand therapy well and experienced only mild, self-limiting grade 1 fatigue and dry eyes. There were no episodes of bone marrow suppression or gastro­intestinal adverse events (AEs). As of the last follow-up in May 2025, the pa­tient’s PSA level remained undetectable since November 2024 and he had no new symptoms or radiological progres­sion. He remains on enzalutamide and is under active surveillance.

Discussion
PSMA has emerged as a promising target in mCRPC as it is highly expressed on most prostate cancer cells, especially in metastatic lesions, which are associat­ed with poor prognosis. Innovative radi­oligand therapy with ¹⁷⁷Lu-PSMA-617 is a promising strategy for selectively deliv­ering cytotoxic radiation to cancer cells while sparing normal tissue.^1,2

¹⁷⁷Lu-PSMA-617’s efficacy and tolerability in ARPI-and taxane-refractory mCRPC
¹⁷⁷Lu-PSMA-617 with ADT, with or without an androgen receptor pathway inhibitor (ARPI), is currently approved for treatment of adult patients with progres­sive PSMA-positive mCRPC who have received an ARPI and taxane-based chemotherapy.¹ Approval was based on the international, open-label phase III VISION trial that included 831 patients with mCRPC and PSMA-positive meta­static lesions who were previously treated with ≥1 ARPI and 1–2 taxane regimens.²

Patients received ¹⁷⁷Lu-PSMA-617 (7.4 GBq Q6W, 4–6 cycles) plus standard-of-care (SoC) or SoC alone. Me­dian progression-free survival (PFS) was 8.7 vs 3.4 months in favour of radioligand therapy (hazard ratio [HR] 0.40; 99.2 per­cent confidence interval [CI], 0.29–0.57; p<0.001). Overall survival (OS) and key secondary endpoints, including response rates, disease control, skeletal events, and PSA decline of ≥50 percent (PSA50), also favoured ¹⁷⁷Lu-PSMA-617.²

Approximately 76 percent of pa­tients in VISION received radioligand treatment as fourth- or later-line therapy. This demonstrates that ¹⁷⁷Lu-PSMA-617 provides significant clinical benefit even in heavily pretreated patients. The results also showed consistent improvements in radiographic PFS and OS even in pa­tients with visceral metastases such as liver involvement (ie, 12.2 percent in the ¹⁷⁷Lu-PSMA-617 arm).² These results parallel the treatment response of our patient in case 1. Despite being heavily pretreated with two ARPIs (ie, abiraterone and enzalutamide) and two taxanes (ie, docetaxel and cabazitaxel), as well as the presence of visceral metastases, our patient still experienced durable radiolog­ic and biochemical responses and good tolerability to ¹⁷⁷Lu-PSMA-617 plus SoC.

Although the incidence of grade ≥3 AEs was higher in the ¹⁷⁷Lu-PSMA-617 plus SoC vs SoC alone arm (52.7 vs 38.0 percent), our patients’ quality of life (QoL) was not adversely affected and they ex­perienced symptomatic relief while on radioligand therapy.² This is consistent with the health-related QoL and pain outcomes of VISION, which showed that ¹⁷⁷Lu-PSMA-617 treatment was as­sociated with marked delays in time to worsening of patient-reported QoL (ie, improved Functional Assessment of Can­cer Therapy-Prostate [FACT-P] score) and pain intensity (ie, improved Brief Pain Inventory-Short Form [BPI-SF] score) vs SoC, underscoring the therapy’s im­pact on both disease control and daily function.³

Earlier use of ¹⁷⁷Lu- PSMA-617 in mCRPC
Emerging data suggest that ¹⁷⁷Lu- PSMA-617 may be offered earlier to pa­tients with mCRPC, especially those who wish to delay taxane-based chemother­apy, such as our elderly patient in case 2.^4,5 Earlier use of ¹⁷⁷Lu-PSMA-617 in el­igible patients is supported by the results from the open-label, phase III randomized PSMAfore trial, which included 468 pa­tients with taxane-naïve, PSMA-positive mCRPC who had progressed once on a previous ARPI. Patients in the trial re­ceived either ¹⁷⁷Lu-PSMA-617 Q6W for six cycles, or a change of ARPI (ie, abi­raterone or enzalutamide). Crossover from ARPI to ¹⁷⁷Lu-PSMA-617 was allowed after centrally confirmed radio­graphic progression.⁴

At the first data cut-off (7.26 months’ median time from randomization), ¹⁷⁷Lu-PSMA-617 was associated with a significant improvement in radiographic PFS vs change of ARPI (median, 9.30 vs 5.55 months; HR, 0.41; 95 percent CI, 0.29–0.56; p<0.0001). This was sus­tained at the third data cut-off (24.11 months’ median time from randomiza­tion; 11.60 vs 5.59 months; HR, 0.49; 95 percent CI, 0.39–0.61).⁴

Objective and PSA50 response rates were significantly higher in the ¹⁷⁷Lu- PSMA-617 arm, consistent with the VI­SION trial. ¹⁷⁷Lu-PSMA-617 was also as­sociated with fewer grade ≥3 AEs vs the ARPI arm (36 vs 48 percent), and no new safety signals were identified.^2,4

PSMAfore data indicate that ¹⁷⁷Lu-PSMA-617 is a more effective second-line option with a better safety profile than a change of ARPI after pro­gression on first-line ARPI in patients with mCRPC. It offers an effective alter­native to chemotherapy and delays the need for cytotoxic agents.⁴ As experi­enced by our patient in case 2, ¹⁷⁷Lu- PSMA-617 helped achieve disease control and symptom management without the risks associated with tax­ane-based regimens, which is a crucial consideration in elderly populations. Offering ¹⁷⁷Lu-PSMA-617 earlier when patients have lower tumour burden, pre­served marrow reserve, and better PS may also help optimize efficacy and du­rability of response.

Importance of completing the prescribed regimen
VISION and PSMAfore utilized up to six cycles of ¹⁷⁷Lu-PSMA-617 un­less there was disease progression or unacceptable toxicity, with inter­im imaging and laboratory monitoring to assess response and tolerability.^2,4 This underscores the importance of completing the prescribed regimen for ¹⁷⁷Lu-PSMA-617 to maximize disease control, as residual uptake on im­aging may indicate ongoing disease activity.^1,2,4 In both patients, while new lesions were observed after the first cy­cle, both patients had good response by the end of treatment.

In both of our patients, six cycles of ¹⁷⁷Lu-PSMA-617 were completed with good tolerability. Only self-limiting grade 1 fatigue, nausea, and dry eyes were reported, which are expected AEs asso­ciated with ¹⁷⁷Lu-PSMA-617 treatment. Nevertheless, it is important to remain vigilant of signs and symptoms of mye­losuppression and renal impairment.^1,2,4

Summary
Radioligand therapy with ¹⁷⁷Lu- PSMA-617 offers a highly targeted, ef­fective and tolerable treatment option for patients with PSMA-positive mCRPC. Clinical data from VISION and PSMAfore and our patients’ experience support its use in both chemotherapy-naïve and heavily pretreated populations.

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