Download PDF
Open Access
CC BY 4.0 · Indian J Med Paediatr Oncol
DOI: 10.1055/s-0046-1816552
Case Report

The 177Lu-PSMA-617 PRLT “Superresponders” Among Metastatic Castration-Resistant Prostate Carcinoma (mCRPC) with Extensive Disease: Case Series with Review of Literature on PSMA-Based Theranostics in the Therapeutic Armamentarium of mCRPC

Authors

  • Sarina Shah

    1   Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, Maharashtra, India
    2   Homi Bhabha National Institute, Mumbai, Maharashtra, India

  • Keerti Sitani 

    1   Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, Maharashtra, India
    2   Homi Bhabha National Institute, Mumbai, Maharashtra, India

  • Sandip Basu 

    1   Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, Maharashtra, India
    2   Homi Bhabha National Institute, Mumbai, Maharashtra, India
Further Information
Also available at
 
 PDF Download Permissions and Reprints

Abstract

The incidence of prostate cancer is increasing worldwide, leading to a growing prevalence of metastatic castration-resistant prostate cancer (mCRPC), which is characterized by treatment resistance and poor prognosis, often posing a challenging clinical setting. Treatment approach to mCRPC necessitates multimodal strategies, including cytotoxic chemotherapy, novel hormonal agents, and targeted therapies. Prostate cancer cells show upregulation of prostate-specific membrane antigen (PSMA), making it an excellent molecular target for radioligand therapy (PRLT). The β-emitting radioisotope lutetium-177 (177Lu), linked to PSMA-targeting ligands, has recently gained prominence as a promising and well-tolerated therapeutic option, demonstrating minimal adverse effects. Recent studies have demonstrated its efficacy in improving survival, delaying disease progression, and enhancing quality of life in patients with mCRPC. We illustrate here two cases of mCRPC with extensive disease burden, both demonstrating remarkable responses to 177Lu-PSMA-617 PRLT following progression on hormonal therapy and chemotherapy, highlighting its therapeutic potential in advanced-stage disease. A brief review has been made on the recently completed and ongoing clinical trials in this domain.


Keywords

mCRPC - prostate cancer - 177lutetium-PSMA-617 PRLT - positron emission tomography/computed tomography - PSMA - cytotoxic chemotherapy - novel hormonal agents - PSA

Introduction

Globally, prostate cancer has emerged as the second most prevalent malignancy among men, with incidence steadily rising in recent years.[1] While androgen deprivation therapy (ADT) initially yields a favorable response, prolonged treatment frequently results in the emergence of a castration-resistant stage, during which tumor cells continue to grow despite low androgen levels. Owing to its heterogeneous nature metastatic castration-resistant prostate cancer (mCRPC) presents a significant clinical challenge with a tendency to develop resistance to treatment. Effective management necessitates a multidisciplinary approach that includes systemic therapies such as chemotherapy, next-generation hormonal agents, targeted therapies, and radionuclide treatments. Supportive care also plays a crucial role in alleviating symptoms like bone pain, pathological fractures, and metabolic disturbances, thereby helping to preserve quality of life. Despite these advances, mCRPC remains associated with high mortality, poor prognosis, and a median overall survival (OS) of 1.86 years approximately.[2] Recent growing interest in precision medicine has spurred the development of novel therapies, including prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) utilizing the β-emitting radionuclide lutetium-177 (177Lu). It has demonstrated promising efficacy in mCRPC, significantly improving OS, progression-free survival (PFS), and time to serum prostate-specific antigen (Sr. PSA) progression, while also enhancing quality of life through pain reduction.[3] Herein, we present two cases of mCRPC, who showed excellent response to PRLT following progression on novel hormonal agents and taxane-based chemotherapy.


Case Details

Case 1: A 72-year-old man, with diabetes mellitus, while undergoing evaluation for lower urinary tract symptoms was diagnosed with conventional adenocarcinoma of the prostate (Gleason score 4 + 3 = 7). At the time of diagnosis, as per the National Comprehensive Cancer Network (NCCN) risk stratification, he had unfavorable intermediate-risk disease. He underwent radical prostatectomy with pelvic lymph node dissection, following which his Sr. PSA level was undetectable.

Four years later, he experienced disease recurrence, evidenced by new skeletal lesions, and was initiated on ADT with a gonadotropin-releasing hormone (GnRH) agonist. Despite initial response, his disease progressed 2 years later, prompting the addition of a novel hormonal agent, abiraterone acetate. Subsequently, he developed castration-resistant prostate cancer (CRPC) and received eight cycles of docetaxel chemotherapy. As his Sr. PSA level was persistently rising, he was referred to our center for consideration of PRLT.

Baseline imaging with gallium-68 labeled PSMA positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) along with 18-fluorodeoxyglucose (18F-FDG) PET/CT revealed multiple sclerotic skeletal lesions, predominantly in the axial skeleton with a few in the appendicular skeleton ([Fig. 1]). All lesions demonstrated intense PSMA expression, while a subset of axial skeletal lesions also showed low-grade 18F-FDG uptake. His Sr. PSA level was 6.8 ng/mL.

Zoom
Fig. 1 Case 1: Maximum-intensity projection image (MIP) and fused PET/CT images of 68Ga-PSMA-11 PET/CT and 18F-FDG PET/CT at baseline (A, B) and after one cycle (C, D) of 177Lu-PSMA-617 therapy show multiple PSMA-expressing sclerotic skeletal lesions in the axial and appendicular skeleton, with low-grade 18F-FDG concentration seen in the axial skeleton lesions. Following the third cycle of 177Lu-PSMA-617 radioligand therapy (PRLT), there is excellent response, with complete resolution of tracer uptake in the sclerotic lesions as seen in the respective MIP (E, F), and fused PET/CT images. The images (G, J, M) are fused sagittal images of 68Ga-PSMA-11 PET/CT and images (H, K, N) are fused sagittal images of 18F-FDG-PET/CT. Images (I, L, O) are corresponding CT slices in bone window.

He received three cycles of PRLT at 6- to 8-week intervals at our center, while continuing ADT with GnRH agonist. Two months after the third cycle, response evaluation revealed significant clinical improvement, including near-complete alleviation of pain. Sr. PSA level was undetectable and dual tracer PET/CT scans showed no evidence of active disease.

Case 2: A 60-year-old man with persistent back pain was diagnosed with high-risk conventional adenocarcinoma of the prostate (Gleason score 5 + 5 = 10) with extensive lymph node and skeletal metastases at baseline. Initial management included bilateral subcapsular orchidectomy and transurethral resection of the prostate, external beam radiotherapy to the pelvis and thoracic spine. Concurrently, he was started on abiraterone acetate, which resulted in disease stabilization for 3 years with undetectable Sr. PSA levels.

Three years later, he developed mCRPC and received nine cycles of docetaxel chemotherapy. Due to disease progression, he was referred to our center for consideration of 177Lu-PSMA therapy. Sr. PSA level was 1.17 ng/mL. Baseline 68Ga-PSMA-11 PET/CT revealed few PSMA expressing pelvic and abdominal lymph nodes, multiple sclerotic osseous lesions in both axial and proximal appendicular skeleton ([Fig. 2]), while concurrent 18F-FDG-PET/CT was negative. He received one cycle of PRLT following which there was favorable clinical and biochemical response. His Sr. PSA level was 0.42 ng/mL and 68Ga-PSMA PET/CT revealed no PSMA-avid active disease. This excellent response was maintained in his follow-up visit at 2 months.

Zoom
Fig. 2 Case 2: MIP image and fused PET/CT image of 68Ga-PSMA PET/CT at baseline (A, D) showing multiple PSMA-expressing skeletal lesions in the axial and appendicular skeleton. There is excellent response seen after one cycle of 177Lu-PSMA therapy (image B, E) and at 2-month follow-up (image C, F). His 8F-FDG PET/CT was negative at baseline. Images (A–C) are MIP images of 68Ga-PSMA-11 PET/CT. Images (D–F) are fused sagittal 68Ga-PSMA-11 PET/CT images.

Discussion

Over the past decade, prostate cancer has shown a consistent upward trend, with incidence increasing by approximately 3% annually.[4] During initial diagnosis, around 13% cases have lymph node involvement, while 8% present with distant metastases. The prognosis is highly dependent on the stage of the disease: the 5-year relative survival rate is nearly 100% for localized disease but drops sharply to 36.6% in cases with metastatic spread.[5]

ADT remains the cornerstone of treatment for prostate cancer across all stages and risk categories. However, prolonged ADT often leads to the development of resistance, with most hormone-sensitive prostate cancers progressing to CRPC within 5 years. This progression is primarily attributed to the tumor's adaptive mechanisms that enable continued growth and survival in an androgen-deprived environment. Development of treatment resistance is driven by several key mechanisms, including androgen receptor (AR) overexpression through gene amplification, epigenetic alterations, modulation by microRNAs,[6] [7] upregulation of CYP17A1 and the glucocorticoid receptor, and PI3K-AKT-mTOR signaling pathway activation.[8] These molecular changes collectively allow tumor cells to evade androgen suppression and continue proliferating, necessitating the exploration of alternative therapeutic strategies. In contrast to hormone sensitive cells, mCRPC tumour cells show increased PSMA expression in response to ADT.[9]

Recent advances in the mCRPC treatment have highlighted 177Lu-PSMA-617 PRLT as a promising targeted option in PSMA expressing metastatic disease. In 2022, the Food and Drug Administration granted approval to 177Lu-PSMA-617 after the promising results of the pivotal phase III VISION trial that demonstrated improved OS with PRLT added to standard-of-care (SOC) as compared with SOC alone in mCRPC patients who showed progression on chemotherapy and AR pathway inhibitors (ARPIs). In light of these results, the NCCN now recommends 177Lu-PSMA therapy for mCRPC patients whose disease has advanced after taxane-based chemotherapy and novel hormonal agents.[10]

Suman et al retrospectively evaluated the therapeutic efficacy and safety of PRLT in 40 mCRPC patients.[11] Median OS and PFS after the first PRLT cycle were 12 and 7 months, respectively. Adverse events were generally mild, with xerostomia (grade I) in 5% and hematologic toxicity (grade I–II) in 19%. The study concluded that PRLT is a safe and effective option, even in heavily pretreated patients. Similar findings from Heck et al[12] and Yadav et al[13] further support the therapeutic value of PRLT in advanced mCRPC.

The TheraP trial,[14] a randomized, phase II, multicenter, open-label study published in 2021, compared 177Lu-PSMA-617 with cabazitaxel in 200 mCRPC patients who were previously treated with docetaxel. Patients received either 6 weekly 177Lu-PSMA-617 (6.0–8.5 GBq, up to six cycles) or cabazitaxel (20 mg/m2 every 3 weeks, maximum of 10 cycles). The primary endpoint—Sr. PSA response (≥ 50% decline from baseline)—was significantly higher in the 177Lu-PSMA group. Favourable secondary outcomes—such as radiographic PFS (rPFS), OS, and safety—further reinforced its efficacy, establishing 177Lu-PSMA-617 as a compelling alternative to cabazitaxel in this clinical setting.

The PSMAfore trial[15] addressed a critical gap by evaluating 177Lu-PSMA-617 targeted therapy in 469 taxane-naive mCRPC patients. This multicentre, phase III study enrolled patients with PSMA-avid disease who showed disease progression on a single ARPI. Randomized patients received either 177Lu-PSMA-617 or an alternative ARPI (enzalutamide or abiraterone). There was a 59% reduction in radiographic progression risk, a significant improvement in rPFS (11.6 vs. 5.6 months), better quality of life, and a 2.5-fold higher likelihood of Sr. PSA response—supporting its potential as a first-line option in taxane-naive mCRPC.

UpFront PSMA and PSMAddition are two trials investigating the role of PRLT in early hormone-sensitive stage. Upfront PSMA trial[16] that compared 177Lu-PSMA-617 plus docetaxel to docetaxel alone, showed median PFS of 31 months versus 20 months, with undetectable Sr. PSA level in 41% versus 16% patients. However, one-third cases in the combination arm required dose reduction of docetaxel. In ongoing global phase III trial PSMAddition study,[17] 1,126 patients are randomized to either 177Lu-PSMA-617 SOC (ARPIs plus ADT) or SOC alone. While rPFS is the primary endpoint, other secondary endpoints include OS, ≥ 90% Sr. PSA decline, composite PFS, time to progression to mCRPC, safety, and quality of life.

The ongoing international PSMA-DC trial,[18] launched in March 2024, is a phase III study assessing the role of 177Lu-PSMA-617 in PSMA-avid oligometastatic prostate cancer (OMPC) post-stereotactic body radiation therapy (SBRT). Approximately 450 patients have been randomized 2:1 to receive 177Lu-PSMA-617 or observation with a metastasis-free survival being the primary endpoint. Secondary outcomes include Sr. PSA progression, time to hormonal therapy, OS, rPFS, safety, and quality of life. This study is expected to conclude by July 2030.

Beyond major phase III trials, several studies are investigating 177Lu-PSMA-617 in OMPC. The results of randomized phase II BULLSEYE trial[19] comparing 177Lu-PSMA-617 with SOC in low-volume hormone-sensitive patients demonstrated a significantly higher PFS and longer time to biochemical progression in the PRLT arm. The POPSTAR II trial[20] (NCT05560659) is recruiting 92 OMPC patients to evaluate biochemical PFS over 24 months for stereotactic ablative radiotherapy (SABR) versus SABR plus two cycles of 177Lu-PSMA therapy.

Several early-phase trials are currently exploring combination strategies with 177Lu-PSMA-617 and agents such as pembrolizumab, ipilimumab, abemaciclib, cabozantinib, enzalutamide, and cabazitaxel to potentially enhance therapeutic efficacy.[21] The PRELUDE Trial is evaluating the use of neoadjuvant 177Lu-PSMA-617 prior to radical prostatectomy.[22]

Additionally, the long-term safety of PRLT is being studied by a phase IV safety study (NCT05803941) wherein approximately 700 patients previously treated with 177Lu-PSMA-617 in industry-sponsored trials are being monitored. This observational study will assess delayed or cumulative toxicities, with completion expected by July 2033.[23]

Across the major PSMA trials (UpFrontPSMA, PSMAddition, PSMA-DC, BULLSEYE, POPSTAR II, and Lutectomy), the main limitations include the following (but not limited to): (1) patient and disease heterogeneity, (2) early-phase design, (3) short follow-up, and (4) incomplete understanding of who truly benefits from PSMA-targeted interventions. Imaging-based selection also risks underestimating the microscopic disease biology since PSMA-PET cannot detect these characteristics. Methodologically, trials vary widely in radioligand choice, number of cycles, dosimetry, endpoints, and follow-up duration, complicating comparison across studies. In earlier-stage or oligometastatic settings (BULLSEYE, POPSTAR II, Lutectomy), the magnitude and durability of benefit remain uncertain, with unclear impact on OS.

Thus, a balanced appraisal of current PSMA-targeted trials reveals several gaps that merit acknowledgment. Many studies—such as the PSMAddition trial—use fixed treatment schemes (e.g., six cycles of 177Lu-PSMA-617) despite limited evidence that this is the biologically optimal dose or schedule across PSMA-expressing heterogeneously responding tumors.[24] Similarly, emerging use of PSMA-RLT in post-SBRT or oligometastatic settings raises unanswered question regarding PSMA receptor stability and target expression after local external radiotherapy, which may influence both dosimetry and efficacy.[25] More broadly, despite encouraging short-term outcomes, long-term data on marrow toxicity, renal adverse effects, and cumulative radiation burden remain sparse.[13] Future challenges include determining the ideal sequencing of PSMA-RLT with existing systemic therapies, establishing biomarkers beyond PSMA-PET uptake to better predict responders,[26] and ensuring equitable access—particularly in low- and middle-income countries where radioligand availability, cost, and regulatory frameworks may limit implementation. Addressing these limitations will be essential for translating early success of this very promising targeted treatment into a durable, population-level benefit.


Conclusion

In summary, 177Lu-PSMA-617 radioligand therapy demonstrates significant promise across all stages of prostate cancer, from oligometastatic to advanced castration-resistant disease. Its consistently encouraging clinical outcomes support its expanding role in the prostate cancer treatment landscape.



Conflict of Interest

None declared.

Patient Consent

Informed patient consent was obtained for this study.



Address for correspondence

Sandip Basu, MD
Radiation Medicine Centre (BARC), Tata Memorial Hospital Annexe
Jerbai Wadia Road, Parel, Mumbai 400012, Maharashtra
India   

Publication History

Article published online:
25 February 2026

© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India


  Permissions and Reprints
Zoom
Fig. 1 Case 1: Maximum-intensity projection image (MIP) and fused PET/CT images of 68Ga-PSMA-11 PET/CT and 18F-FDG PET/CT at baseline (A, B) and after one cycle (C, D) of 177Lu-PSMA-617 therapy show multiple PSMA-expressing sclerotic skeletal lesions in the axial and appendicular skeleton, with low-grade 18F-FDG concentration seen in the axial skeleton lesions. Following the third cycle of 177Lu-PSMA-617 radioligand therapy (PRLT), there is excellent response, with complete resolution of tracer uptake in the sclerotic lesions as seen in the respective MIP (E, F), and fused PET/CT images. The images (G, J, M) are fused sagittal images of 68Ga-PSMA-11 PET/CT and images (H, K, N) are fused sagittal images of 18F-FDG-PET/CT. Images (I, L, O) are corresponding CT slices in bone window.
Zoom
Fig. 2 Case 2: MIP image and fused PET/CT image of 68Ga-PSMA PET/CT at baseline (A, D) showing multiple PSMA-expressing skeletal lesions in the axial and appendicular skeleton. There is excellent response seen after one cycle of 177Lu-PSMA therapy (image B, E) and at 2-month follow-up (image C, F). His 8F-FDG PET/CT was negative at baseline. Images (A–C) are MIP images of 68Ga-PSMA-11 PET/CT. Images (D–F) are fused sagittal 68Ga-PSMA-11 PET/CT images.