177Lu–Prostate-specific Membrane Antigen Radioligand Therapy in Patients with Metastatic Castration-resistant Prostate Cancer
Abstract
A 76-year-old man with metastatic castration-resistant prostate carcinoma progressing with antiandrogen and taxane therapy was treated with lutetium 177 prostate-specific membrane antigen (PSMA)-617 and showed marked biochemical and imaging response, with improvement in clinical status and osseous pain. A summary of nuclear medicine theranostics with emphasis on PSMA targeting agents is presented.
© RSNA, 2022
Summary
The theranostic concept, applied to targeting prostate-specific membrane antigen, offered an advantage for patients with treatment-refractory prostate cancer by a precise and personalized “see what you treat” treatment option.
Teaching Points
■ Theranostic nuclear medicine involves imaging-based verification of target expression at disease sites and its subsequent targeting using a therapeutic radiopharmaceutical.
■ Prostate-specific membrane antigen (PSMA) is a glycoprotein that is overexpressed in the prostate cancer cell membrane and can be used for imaging and therapy.
■ Lutetium 177 (177Lu)-PSMA-617 is a U.S. Food and Drug Administration–approved radiopharmaceutical for the treatment of men with PSMA-avid metastatic castration-resistant prostate cancer with disease progression despite androgen-pathway inhibition and taxane therapy.
■ 177Lu-PSMA-617 radioligand therapy is proven to be a clinically efficacious treatment option with acceptable safety profile in patients with metastatic castration-resistant prostate cancer.

Dr Ashwin Singh Parihar is a postdoctoral research associate at the Mallinckrodt Institute of Radiology, Washington University School of Medicine (St Louis, Mo). He completed his residency and fellowship in nuclear medicine from PGIMER (Chandigarh, India) and is interested in nuclear medicine theranostics. He serves as an associate editor on the Radiology In Training editorial board and is an editorial board member of Clinical Nuclear Medicine. His research work has produced over 50 publications, presentations at several scientific meetings, research grants, and awards. He was recently awarded the SNMMI Radiopharmaceutical Therapy Fellowship.

Dr Amir Iravani is an assistant professor at the Mallinckrodt Institute of Radiology, Washington University School of Medicine (St Louis, Mo), leading the clinical Theranostic Nuclear Medicine program. He finished residency training in internal medicine and nuclear medicine and a fellowship in molecular imaging and radiopharmaceutical therapy at Peter MacCallum Cancer Center, Melbourne, Australia. Dr Iravani has been actively involved in the multiple practice-changing theranostic clinical trials and contributed to multiple seminal publications. He is the recipient of multiple awards and is currently a member of several national theranostic committees at the National Cancer Institute and SNMMI.
Case Presentation (Dr Ashwin Singh Parihar)
A 76-year-old man with metastatic castration-resistant prostate carcinoma presented for the assessment of the suitability of treatment with lutetium 177 (177Lu)–prostate-specific membrane antigen (PSMA)-617–based radioligand therapy (RLT). He was diagnosed with prostate adenocarcinoma (Gleason score, 10) 5 years before. The patient was treated with androgen deprivation therapy with gonadotropin-releasing hormone receptor agonist with a stable prostate-specific antigen (PSA) of 5 ng/mL for 3 years before he developed rising PSA levels and osseous metastases were detected at bone scan. At this time, an antiandrogen treatment with bicalutamide was added followed by six cycles of docetaxel. Restaging imaging after the completion of chemotherapy showed new osseous and hepatic metastases. Biopsy of the hepatic lesions was consistent with metastatic adenocarcinoma of the prostate. The patient was treated with an androgen receptor pathway inhibitor (enzalutamide) with an initial response but subsequent progression of the liver metastases 7 months later. The patient was referred to a phase II clinical trial investigating the efficacy and safety of 177Lu-PSMA-617. The PSA was 13.1 ng/mL with a doubling time of 1.2 months.
The initial workup including pretreatment gallium 68 (68Ga)-PSMA-11 PET/CT imaging showed multiple intensely tracer-avid osseous and hepatic metastases with the lesions exhibiting uptake intensity above background liver not involved by tumor (Fig 1). Based on the clinical trial protocol, the patient underwent contemporaneous fluorine 18 (18F)-fluorodeoxyglucose (FDG) PET/CT (1). Whereas lesions demonstrated intense 18F-FDG uptake, there was no measurable FDG-avid, non–PSMA-avid lesion to preclude the patient from the clinical trial (Fig 1). The patient’s Eastern Cooperative Oncology Group performance score was 2 and the laboratory workup was within acceptable range for the clinical trial including blood counts (hemoglobin level: 96 g/L [normal level, 130–170 g/L]; total leukocyte count, 2.4 × 109/L [normal level, 4.0–11.0 × 109/L]; platelet count, 251 × 109/L [normal, 150–400 × 109/L]), renal function (estimated glomerular filtration rate, 66 mL/min/1.73 m2; serum creatinine, 96 µmol/L), and hepatic function (albumin, 29 g/L [normal level, 34–45 g/L] with normal-range liver enzymes). Therefore, the patient was deemed suitable for treatment with 177Lu-PSMA-617.

Figure 1: Pretreatment maximum intensity projections of (A) gallium 68 (68Ga)-prostate-specific membrane antigen (PSMA)-11 PET/CT and (B) fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT show intensely 68Ga-PSMA-11 avid bone and liver metastases with most of the lesions also showing 18F-FDG avidity. (C) Technetium 99m–methylene diphosphonate planar bone scan shows tracer uptake in some of the bone metastases. SUV = standardized uptake value.
The patient underwent treatment with 7.4 GBq (200 mCi) of 177Lu-PSMA-617 according to the trial protocol (1). The posttherapy scintigraphy performed by using the γ emissions of 177Lu showed intense retention of tracer at all disease sites. A large decline in the PSA was noted and became undetectable 4 weeks after the second cycle of treatment (Fig 2). A reduction of the volume of disease was also noted after the second cycle of posttherapy scintigraphy. One month after the second cycle of treatment, the patient underwent restaging 68Ga-PSMA-11 PET/CT, which showed a marked partial response to treatment with minimal residual PSMA-avid disease. Significant improvement in the patient’s clinical status with an Eastern Cooperative Oncology Group score of 1 and a reduction in pain scores was also noted. After multidisciplinary team discussion and by considering the imaging response, a lack of residual PSMA-avid disease, and undetectable PSA, subsequent cycles of treatment were deferred.

Figure 2: Clinical course, treatments, imaging, and serum prostate-specific antigen (PSA) chart of the patient. Baseline gallium 68 (68Ga)–prostate-specific membrane antigen (PSMA)-11 PET showed widespread intensely tracer avid disease in the bones and liver. Baseline fluorine 18 (18F)-fluorodeoxyglucose (FDG) PET showed intensely tracer avid disease in a distribution matching the 68Ga-PSMA-11 PET with no 18F-FDG-avid/non-68Ga-PSMA-avid sites of disease. Lutetium 177 (177Lu)-PSMA-617 SPECT after the first cycle of treatment showed high tracer retention in all known sites of disease. 177Lu-PSMA-617 SPECT after the second cycle showed marked reduction of the tracer-avid disease. Follow-up 68Ga-PSMA-11 PET at 3 months showed marked response to treatment with minimal tracer-avid residual disease in the bone and the liver and, in conjunction with undetectable PSA, subsequent cycles of treatment were deferred. The response was sustained at 5 months. Follow-up at 10 months showed progression of disease on 68Ga-PSMA-11 PET images with high tracer avidity, which indicated ongoing suitability for subsequent cycles of treatments. Two additional cycles of 177Lu-PSMA-617 led to further response but it was less durable than the initial response before the disease rapidly progressed within 5 months of the last cycle of treatment. Restaging scans at this point show progressive disease in the liver and bones with evidence of more extensive 18F-FDG-avid than 68Ga-PSMA-avid disease. This was most evident in the right pelvis (brackets). Subsequently, the patient was administered cabazitaxel.
After 8 months of observation, disease progression was noted, with PSA reaching 13 ng/mL. PSMA PET/CT helped to confirm tracer-avid osseous and hepatic disease. An additional two cycles of 177Lu-PSMA-617, 6 weeks apart, led to a favorable response at follow-up imaging and a biochemical response with decline in PSA (Fig 2). A PSA nadir of 0.3 ng/mL occurred, although the response was less durable with a rapid PSA increase to 29.1 ng/mL within 5 months after the last cycle of treatment. At that time, although 68Ga-PSMA-11 PET/CT showed tracer avid disease in the liver, contemporaneous 18F-FDG PET/CT showed spatially discordant disease that was most evident in the right pelvic bone with more extensive 18F-FDG–avid disease than 68Ga-PSMA-11 PET/CT. Subsequently, the patient was administered cabazitaxel for 6.5 months before dying of the disease 30 months after starting treatment with 177Lu-PSMA-617.
Case Discussion (Dr Amir Iravani)
The Theranostic Principle
The word theranostics is a blend of therapeutics and diagnostics. Essentially, it refers to the use of a common molecule for localization and targeted treatment (2). In nuclear medicine, theranostics is performed by using either different radionuclides of the same element (eg, iodine 123 diagnostic, iodine 131 [131I] theranostic) or using molecules with a common target with one radionuclide for diagnosis and another for therapy (eg, 68Ga-1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetra-acetic acid-Tyr3-octreotate, known as DOTATATE, diagnostic; and 177Lu-DOTATATE therapy). A key feature of nuclear medicine theranostics is the imaging-guided verification of adequate target expression, which is the basic prerequisite for performing therapy. Radioiodine therapy of thyroid disease with 131I–sodium iodide is the first application of theranostics in nuclear medicine and remains the classic example of the high therapeutic index offered by the precise and personalized treatment with theranostic pairs (3). In the case of radioiodine, the γ-emitting iodine 123 with a half-life of 13.2 hours is used to image the thyroid tissue, and the β- and γ-emitting 131I with a half-life of around 8 days is used for treating several benign and malignant thyroid diseases.
The application of theranostics has increased with the development of tracers that can target specific components of the tumor and its microenvironment (2,4–6). Key applications with demonstrated clinical effect include theranostics in neuroendocrine tumors by targeting the somatostatin receptors (68Ga-DOTATATE imaging and 177Lu-DOTATATE therapy); neuroblastoma, targeting the norepinephrine transporter (iodine 123 mIBG imaging and 131I metaiodobenzylguanidine therapy); lymphoma, targeting CD20 (131I tositumomab low dose for imaging, high dose for therapy); and prostate cancer, targeting PSMA (68Ga-PSMA-11 imaging and 177Lu-PSMA 617 therapy) (7–12). These theranostic agents were approved by the U.S. Food and Drug Administration (FDA) and include 177Lu-PSMA-617, which was recently approved (March 23, 2022) following favorable results from the phase III VISION trial (11).
The theranostic concept offers several practical advantages. First, the use of the diagnostic radiopharmaceutical permits the target to be viewed in vivo. At this stage, inadequate or absent target expression at the disease sites will render the therapy unsuitable for that patient. This information helps avoid a futile treatment with its associated adverse effects in a patient who is unlikely to achieve any major clinical benefit, underscoring the foundation of precise and personalized medicine (13). Second, the diagnostic imaging can potentially inform about the need for additional supportive therapy during the administration of the therapeutic radiopharmaceutical. As an example, corticosteroids and/or local external beam radiation therapy might be required when treating patients with closed-cavitary metastases, such as those in the brain or orbit, or those that compress the spinal cord. Third, peritherapy imaging can help in calculating the absorbed doses to the tumor sites and the healthy tissues or organs. This can be achieved either by using longer half-life diagnostic radiopharmaceuticals or by exploiting the γ radiation emitted from the therapeutic pair. The dose estimates help in optimizing the administered activity of the therapeutic radiopharmaceutical by delivering a sufficiently high dose for tumoricidal activity while remaining within the safety limits of the healthy organs (14,15). Last, the diagnostic radiopharmaceutical can be used to monitor response to the targeted therapy and guide additional cycles of treatment. As an example, exceptional responders might show no change at conventional imaging (especially in the case of sclerotic osseous lesions), but would show a marked reduction in radiotracer avidity at the companion imaging (16).
PSMA–The target and targeting agents.—PSMA is a type II transmembrane glycoprotein that is present in the cytoplasm of the healthy prostate cells with a minimal expression on the cell surface but is over-expressed in the membrane of the prostate cancer cells (Fig 3). Physiologic uptake of PSMA-targeting radiopharmaceuticals is also seen in several tissues, including the liver, spleen, kidneys, salivary glands, and proximal small bowel (17). However, despite its name, PSMA is not specific to prostate cancer. PSMA expression is seen in the neovasculature and cell surface of multiple malignancies that are not in the prostate, although the intensity of PSMA avidity is commonly lower than that in prostate cancer (18–22). This is not a unique phenomenon in functional imaging. The radiopharmaceuticals used for imaging have specific pathways for localization (eg, 18F-FDG–glucose metabolism), many of which overlap between different malignancies. Therefore, it is not uncommon to view distinct malignancies with the same radiopharmaceutical agent (18,23–26).

Figure 3: Schematic representation of the structure of prostate-specific membrane antigen (PSMA) and its targeting by diagnostic and therapeutic radiopharmaceuticals. (Created using biorender.com.)
Several diagnostic and therapeutic radiopharmaceuticals have been used to target PSMA. Whereas most have a similar (but not identical) biodistribution, there are advantages and disadvantages associated with each, including logistical concerns. Table 1 lists some of the common PSMA-targeting radiopharmaceuticals, including experimental molecules and those in clinical use. Since its first-in-human application in 2013, 68Ga-PSMA-11 has remained the most widely tested PSMA targeting diagnostic radiopharmaceutical around the world (27,28). 18F-2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, known as DCFPyL, is a fluorinated PSMA-targeting radiopharmaceutical that has a similar biodistribution to 68Ga-PSMA-11 and is equivalent (29). Both are FDA-approved diagnostic radiopharmaceuticals, and the selection of one over the other is likely going to be driven by logistic issues and preferences of individual sites.
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PSMA-based radioligand therapy in prostate cancer.—177Lu-PSMA-617 (Pluvicto; Novartis) was approved by the FDA for the treatment of adults with metastatic castration-resistant prostate cancer who have PSMA-expressing disease and underwent prior androgen receptor pathway inhibition and taxane-based therapy. Additionally, a companion diagnostic 68Ga-PSMA-11 (Locametz; Novartis) was also approved for verifying in vivo PSMA expression. As is the case with any radionuclide therapy, appropriate patient selection is vital to a successful outcome in terms of both efficacy and safety. Selection of 177Lu-PSMA RLT should be made in a multidisciplinary meeting where experts from the relevant specialties can discuss the intricacies of the treatment plan, incorporating an overall assessment of the patient, including performance status, life expectancy, current symptoms, and quality of life.
Demonstration of adequate PSMA expression at imaging at the disease sites is a prerequisite for consideration of PSMA-RLT. Prior prospective trials (16) used differing functional imaging–based criteria for patient selection, some of which are shown in Table 2. Briefly, the VISION trial included patients with at least one PSMA-positive metastatic lesion, defined as 68Ga-PSMA-11 uptake more than that of the liver parenchyma. Additionally, patients with a PSMA-negative lesion were excluded, defined as PSMA uptake equal to or lower than that of the liver parenchyma in a metastatic lymph node with short-axis diameter of 2.5 cm or more, in a solid-organ metastasis of short-axis 1 cm or more, or in any metastatic bone lesion with soft-tissue component measuring 1 cm or more in the short-axis (11).
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The adequacy of PSMA expression has been variably defined in studies; an optimal threshold for determining outcomes after RLT remains to be refined. However, the higher PSMA expression appears to be predictive of a higher likelihood of response (30). An additional and important consideration is that performing in vivo imaging of PSMA expression alone might not completely help assess the interlesion heterogeneity. As an example, PSMA PET imaging can potentially miss low-volume, PSMA-negative disease that is relatively more aggressive and avid at 18F-FDG PET/CT. Whereas comparison with morphologic imaging would allow for identification of the sites of disease that are not exhibiting sufficient PSMA expression, 18F-FDG PET would potentially be useful in detecting sites with osseous metastases with high FDG-avidity and low PSMA avidity, which would otherwise have remained occult at morphologic imaging. The addition of 18F-FDG PET/CT can help with the heterogeneity assessment because 18F-FDG–avid and PSMA-nonavid lesions are likely to be associated with unfavorable outcomes (31,32). Baseline laboratory tests verifying adequate hematologic and renal reserve are required for therapy eligibility (Fig 4).

Figure 4: Course of lutetium 177 (177Lu)-prostate-specific membrane antigen (PSMA) radioligand therapy, including patient selection, treatment procedure, and follow-up. The acceptable values of the laboratory tests at baseline are as follows: transaminases, less than five times the upper limit of normal; total bilirubin, less than 1.5 times the upper limit of normal; serum creatinine, less than two times the upper limit of normal; estimated glomerular filtration rate greater than 30 mL/min; white blood count greater than 2500/mm3; platelet count greater than 75000/mm3; hemoglobin greater than 9 g/dL. FDG = fluorodeoxyglucose. (Created using biorender.com.)
177Lu-PSMA RLT is typically performed in an outpatient setting in most countries such as the United States, Australia, and India because of low radiation exposure. However, local and national radiation safety guidelines may require it to be performed as an in-patient procedure with 1–3 days of admission in some jurisdictions, including several sites in Europe. Adequate oral or intravenous hydration must be ensured prior to administering 177Lu-PSMA to permit rapid urinary excretion of the unbound radiotracer and reduce the radiation dose delivered to the kidneys. Patients with urinary incontinence or lower urinary symptoms because of an enlarged prostate might require per-urethral catheterization prior to therapy. The recommended activity of 177Lu-PSMA per the FDA label is 7.4 GBq (200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity (33). The next cycle may be temporarily withheld in patients with certain severe adverse effects until improvement or return to baseline levels. Alternatively, the injected activity of 177Lu-PSMA-617 may be reduced by 20% to 5.9 GBq (160 mCi) in the next cycle. After confirming the patency of the intravenous catheter, 177Lu-PSMA is administered as a slow intravenous injection for 1–10 minutes.
Posttreatment scintigraphy (using the γ emissions of the administered 177Lu), although not mandatory, has several benefits. Whole-body imaging with or without SPECT/CT from 4–6 hours to 7 days can confirm the correct localization of the therapeutic radiopharmaceutical and the adequacy of the target expression. It also helps in obtaining dosimetry estimates that can guide activity titration for the subsequent cycles, although dosimetry-guided dose titration of 177Lu-PSMA is not widely practiced (34). Patients are followed after therapy with serum PSA levels and conventional imaging (CT, MRI, and bone scintigraphy). There are insufficient data to recommend 68Ga-PSMA PET/CT for assessing response to treatment; however, this may change in the near future with more availability and inclusion of this imaging examination in clinical trials. Complete blood counts and liver and renal function tests are performed at regular intervals (every 2–4 weeks) along with clinical assessment for any adverse events and to plan for the next cycle of therapy.
The FDA approval of 177Lu-PSMA-617 PSMA was largely based on the results from the phase III VISION trial that compared 177Lu-PSMA-617 RLT and the best standard of care with the best standard of care alone (11). Patients in the RLT arm of the study had a 38% reduction in risk of death with a median overall survival of 15.3 months compared with 11.3 months in the control group (P < .001). The median imaging-based progression-free survival was higher in the RLT arm (8.7 months) versus in the control group (3.4 months). Additionally, of the 248 patients with a measurable target lesion per Response Evaluation Criteria in Solid Tumors, or RECIST 1.1, 9.2% had a complete response on the RLT arm (vs none in the control group) whereas 41.8% had a partial response (vs 3% in the control group). PSA response rate, defined as at least a 50% decline in PSA levels from baseline, was 46% in the RLT arm versus 7.1% in the control group. Similar results on treatment efficacy were reported from the TheraP trial that compared 177Lu-PSMA-617 RLT versus cabazitaxel therapy in patients with metastatic castration-resistant prostate cancer (12). The PSA response rate was 66% in the RLT arm versus 37% in the control group. The objective response rate in patients with measurable disease (RECIST 1.1) was higher in the RLT arm (49% vs 24% in the control group).
The most commonly reported adverse events with 177Lu-PSMA RLT were fatigue, dry mouth, and nausea, although these are frequently of low grade (11). Hematotoxicity is the major serious adverse event after RLT (Common Terminology Criteria for Adverse Events version 5.0). In the VISION trial, 12.9% of patients had anemia that was at least grade 3 after RLT versus 4.9% in the control arm. This was followed by thrombocytopenia (7.8%) and lymphopenia (7.8%). Similar rates of hematotoxicity have been reported in other studies (12,35). The occurrence of hematotoxicity following RLT is multifactorial. Patients with metastatic castration-resistant prostate cancer have often undergone multiple prior lines of therapy that can lead to diminishing bone-marrow reserves. Extensive marrow involvement by the cancer cells can reduce the hematopoietic stem cell population. Further, the crossfire effect by 177Lu-PSMA can damage the healthy marrow, especially in patients with a high marrow disease burden. Whereas patients with extensive bone marrow involvement were excluded in the VISION trial, other studies have demonstrated efficacy and tolerability of 177Lu-PSMA in this advanced stage of the disease (36). Further research is required to accurately predict the occurrence of significant hematotoxicity in patients undergoing RLT. Acute or subacute nephrotoxicity is an uncommon adverse event after RLT; however, data regarding delayed toxicities are limited (37).
Conclusion
RLT with 177Lu-PSMA is an effective and well-tolerated treatment for patients with metastatic castration-resistant prostate cancer and its clinical use is likely to expand with its recent FDA approval. Ongoing research areas include the development of newer PSMA-targeting radiotracers including targeted α-therapy, use of RLT earlier during the disease course, and improving imaging biomarkers for patient selection and response assessment. Additional topics investigated include strategies for rechallenge RLT in previous responders and development of alternative treatment strategies for patients who do not respond to RLT, including rational combination therapies with chemotherapy and radiation therapy, and nonradioactive agents such as androgen receptor pathway inhibitors, immunotherapeutic drugs, and inhibitors of poly (adenosine diphosphate-ribose) polymerase (38–43).
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Article History
Received: Apr 12 2022Revision requested: May 13 2022
Revision received: June 23 2022
Accepted: June 28 2022
Published online: Sept 20 2022