Tanya B. Dorff, MD:
Patients with prostate cancer may present with nonmetastatic prostate cancer that progresses to metastatic disease or with de novo metastatic prostate cancer—either hormone-sensitive metastatic prostate cancer or androgen deprivation therapy (ADT)–resistant mCRPC. The hormone-resistant form of prostate cancer is characterized by rising levels of PSA despite castrate levels of testosterone with ongoing ADT or following orchiectomy.⁵

This module will focus on mCRPC only, which is more likely to develop cancer-related symptomatic disease and comorbidities with an associated higher likelihood of disease mortality.⁶

Tanya B. Dorff, MD:
Patients with mCRPC often stop responding to ADT therapy (eg, docetaxel with or without abiraterone or darolutamide, enzalutamide, apalutamide). Next-generation sequencing (NGS) is then used to help identify appropriate next best treatment options. NGS testing results may identify BRCA mutations (germline or somatic) or homologous recombination repair (HRR) pathway alterations (Palb2), which in turn inform selection of PARP inhibitors (olaparib, niraparib, rucaparib, or talazoparib).⁷ Alternatively, identification of microsatellite instability–high (MSI-H), mismatch-repair deficient (dMMR), or high tumor mutational burden can also inform the tumor agnostic use of immune-checkpoint inhibitor pembrolizumab.⁸

However, actionable mutations are only found in a small fraction of patients,^9,10 and mCRPC lacking actionable biomarkers may receive guideline recommended ARPI or chemotherapeutic agents such as docetaxel or cabazitaxel.^5,7 Patients with asymptomatic or minimally symptomatic mCRPC may also have the option to receive sipuleucel-T, an autologous cellular immunotherapy vaccine that uses the patient’s immune system to fight the cancer.^11,12 Moreover, in patients without actionable biomarkers who progress on ARPI with or without previous docetaxel, now we have access to radioligand therapy options and these will be the main focus of this module.^3,13

Phillip H. Kuo, MD, PhD, FACR:
In 2025, patients have the choice of pursuing radioligand therapy earlier in the treatment course, which has created a need for more education on this topic. Radioligand therapy options are an attractive tool in the treatment of mCRPC, particularly if bone metastases are present and for sites that present with detectable/significant levels of PSMA-positivity in tumor cells.

Tanya B. Dorff, MD:
A persistent unmet need in patients with mCRPC is the fact of disease recurrence. This is often a consideration when ensuring that we offer patients all available therapeutic options with the potential for prolonging survival. As we are counseling patients about the therapeutic choices available to them, we often take into consideration the level of androgen therapy refractoriness and/or previous use of docetaxel, but also the pace of disease progression and the sites of metastases. I would also note that there are differences in disease prognosis based on the location of the metastatic site for mCRPC. For instance, patients who have lymph node–only metastasis have a longer OS (31.6 months) compared with patients who have liver metastasis (13.5 months).¹⁴

Tanya B. Dorff, MD:
At the present time, there are 2 FDA-approved radiopharmaceutical therapy options available in the United States for patients with mCRPC.

The first approved radiopharmaceutical therapy for mCRPC was radium-223 dichloride (or radium-223), an alpha particle emitter that was approved in 2013 for patients with mCRPC with bone metastases and no known visceral metastases present.¹³

The second radiopharmaceutical therapy option is ¹⁷⁷Lu-PSMA-617. Approved in 2022, ¹⁷⁷Lu-PSMA-617 became the first PSMA–targeted radiopharmaceutical therapy for patients who had received previous ARPI and taxane-based chemotherapy.³ More recently, ¹⁷⁷Lu-PSMA-617 received an expanded indication to include patients who have previously undergone treatment with ARPI therapy and are suitable candidates for delaying taxane-based chemotherapy.

Tanya B. Dorff, MD:
Radium-223 is dosed at 55 kBq (1.49 microcurie)/kg body weight every 4 weeks for a total of 6 injections.¹³ In general, radium-223 can distribute across the gastrointestinal tract, liver, lungs, kidneys, heart wall, bone marrow, and salivary glands. Consequently, radium-223 can be absorbed by unintended organs such as bone marrow and digestive system, which may result in adverse events (AEs) occurring in these tissues.

Because of radium-223 distribution patterns, patients must be monitored for anemia, cytopenias (lymphocytopenia, leukopenia, thrombocytopenia), nausea, diarrhea, vomiting, neutropenia, and peripheral edema.

Additional safety considerations include following institutional policies regarding the handling and exposure to radioactive agents including use of personal protective equipment (PPE) and safety screens when appropriate.

Although not listed in the prescribing information, I consider a hemoglobin level less than 9.0 g/dL to be a relative contraindication for using radium-223. In addition, exhibiting a “superscan” that may be associated with marrow toxicity.

Phillip H. Kuo, MD, PhD, FACR:
In my experience, radium-223 is a generally well-tolerated drug. Also when considering a patient for radium-223, a hemoglobin less than 9.0 g/dL might certainly give me pause, but it is not an absolute contraindication for whether or not the patient qualifies for this therapy. Other things that I might consider to be relative contraindications might be cytopenias such as thrombocytopenia, and to a lesser extent neutropenia.

Tanya B. Dorff, MD:

Radium-223 is a calcium mimic that works by binding into new abnormal bone formations associated with mCRPC bone metastases.¹⁷ Once bound to hydroxyapatite and incorporated into bone-associated prostate cancer metastases, radium-223 releases 4 alpha particles for every atom which in turn promote double-stranded breaks in DNA. The short-range linear effects of the alpha particles emitted by radium-223 result in a shorter-range cell killing and favorable sparing of normal bone structures vs metastatic prostate cancer cells.

Phillip H. Kuo, MD, PhD, FACR:

Radium is chemically similar to calcium and thus incorporates into the inorganic boney matrix, a very different mechanism from the typical cellular-targeted therapies. Therefore, the familiar nuclear medicine bone scan provides an important imaging biomarker to assure good uptake of radium at the site of bone metastases, since the imaging radiopharmaceutical has a similar mechanism of uptake as radium-223. 

In my experience, radium-223 is rarely discontinued due to side effects. Instead, the drug is more often discontinued due to disease progression. It also should be noted that serum PSA is not a good marker to track for response and PSMA-PET, CT, or MRI must be used to evaluate for soft tissue disease progression if PSA is rising during radium-223 treatment.

Tanya B. Dorff, MD:
According to the prescribing information, ¹⁷⁷Lu-PSMA-617 is prepared from a single-dose vial (1000 MBq/mL [27 mCi/mL]) used for intravenous administration.³ The recommended treatment dose is 7.4 GBq (200 mCi/mL) given intravenously every 6 weeks for 6 doses. Of note, radiation exposure from ¹⁷⁷Lu-PSMA-617 may increase in patients with a certain degree of renal impairment (CrCl 30 mL/min-50 mL/min).

We can often minimize exposure to normal tissues particularly the kidneys and urinary bladder by asking the patient to increase fluid intake and to void as often as possible. Other considerations for minimizing exposure to other individual bystander and family members include social distancing (≥3 feet) for at least 2-3 days (approximately 7 days for children and pregnant women). The prescribing information suggests sleeping in separate rooms from children for 7 days or pregnant women for 15 days.³

Patients with poor renal function (CrCl <50 mL/min) were not included in the in the clinical trials supporting the use of ¹⁷⁷Lu-PSMA-617 (NCT03511664). However, I consider select patients with CrCl <50 mL/min who may be candidates for ¹⁷⁷Lu-PSMA-617 if no unresolvable kidney obstructions, not on hemodialysis, and if they do not have a very low glomerular filtration rate of <30 mL/min.

Before receiving this ¹⁷⁷Lu-PSMA-617, we should educate patients about the signs and symptoms of anemia (eg, fatigue, weakness, pale skin, shortness of breath, easier bruising or bleeding), and about management of dry mouth to avoid consequences such as dental cavities, anorexia/weight loss.

Similar to radium-223, safety considerations for handling ¹⁷⁷Lu-PSMA-617 include following institutional policies regarding radioactive agent use in nuclear medicine and use of PPE and safety screens.

Phillip H. Kuo, MD, PhD, FACR:
¹⁷⁷Lu-PSMA-617 is predominantly cleared by the kidneys and patients with decreased renal function may potentially have the drug stay in their body longer, resulting in a greater exposure of radiation to normal tissues, particularly the bone marrow, than in patients without renal impairment. I also do not consider a mildly impaired renal function to be an absolute contraindication to receiving this therapy. We must always weigh the risks and benefits of all therapies and we often proceed in patients with mild comorbidities because the benefits of radioligand therapy outweigh the risks.

Tanya B. Dorff, MD:
¹⁷⁷Lu-PSMA-617 works by targeting the PSMA transmembrane protein on the surface of prostate cancer cells and upon binding to the PSMA receptor it causes internalization of the complex via endocytosis.^{1 8} The internalized radioligand (Lutetium 177), which is linked to PSMA, delivers beta particle radiation to the target cell which leads to double-stranded DNA damage and cell death.

Basis of PSMA PET/CT Use as a Companion Diagnostic in mCRPC

Phillip H. Kuo, MD, PhD, FACR:
Patients must be qualified for ¹⁷⁷Lu-PSMA-617  radioligand treatment using a diagnostic radiotracer and PET/CT scanning to assess the level of PSMA-expression on metastatic prostate cancer lesions throughout the body. This method can also be used to monitor the status of radioligand target lesions during and after treatment.^3,19

To properly select patients for ¹⁷⁷Lu-PSMA-617, we currently use visual assessment of PSMA PET/CT. We may use a score of 0, 1, 2, or 3 for uptake-avid lesions. PSMA-positive is visually greater than liver, while PSMA-negative is visually the same or less than liver. PSMA-positive and PSMA-negative in this setting is not about whether the lesion is a prostate cancer. We are assessing the PSMA uptake of prostate tumors/metastases for the purpose of eligibility for  ¹⁷⁷Lu-PSMA-617. If the lesion has an uptake value that is equal to or lower than the blood pool, it receives a score of 0. If the lesion has an uptake value equal to or lower than liver but higher than blood pool it receives a score of 1. If the lesion has an uptake value higher than liver and equal to or lower than parotid gland or higher than parotid gland it receives a score of 2 or 3, respectively.¹ Lesions scoring 2 or higher are regarded as PSMA-positive and patient is deemed eligible for radioligand therapy based on this visual PET/CT assessment. Just as or even more important and more challenging than identifying at least one site of PSMA-positive disease is identifying PSMA-negative tumors.

Tanya B. Dorff, MD:
The PSMA PET/CT procedure has a high degree of sensitivity and is much better at assessing tumor burden than PSA testing alone. With PSMA PET/CT assays we can:

• Determine whether a patient is a suitable candidate for treatment with radioligand therapy
• Identify sites of metastasis in patients who have already had surgery or radiation
• Monitor response to PSMA-targeted radioligand therapy, chemotherapy-inclusive treatment regimens, and first and second-line ARPIs
• Potentially use PSMA-PET/ CT as a prognostic marker when assessing biochemical recurrence

Of importance, 20% to 50% of patients with prostate cancer will experience biochemical recurrence following definitive therapy.^20,21 In this setting, it is well established to perform metastasis-directed radiation and oligometastatic disease–directed radiation and we are using PET scans to accomplish this as well.

Although most of us can perform these types of scans quite readily in standard practice, there can be challenges regarding access and insurance authorization. In California where I practice, we have favorable coverage for prostate cancer through Medicare. In general, we can obtain PSMA PET/CT and insurance approval when being used to select a patient for ¹⁷⁷Lu-PSMA-617.

Phillip H. Kuo, MD, PhD, FACR:
As a reminder, the FDA selection rules for ¹⁷⁷Lu-PSMA-617 were based on the phase III VISION trial² that evaluated use of ¹⁷⁷Lu-PSMA-617 vs protocol-defined standard of care (SoC) (ie, excluding chemotherapy, systemic radioisotope, immunotherapy, and investigational drugs) in patients with PSMA-positive mCRPC and ≥1 prior ARPI and prior ≥1 taxane. The selection criteria included first assessing to ensure  at least one PSMA-positive lesions (defined as having an uptake greater than liver by visual assessment). Then assess for the presence of even one PSMA-negative lesion (defined as having uptake same or less than liver by visual assessment) that meets the size criteria (ie, lymph node ≥2.5 cm in short axis anywhere in the body; solid organ ≥1 cm in short axis; and bone metastases with soft tissue component ≥1 cm in short axis).²² In brief, if no PSMA-positive lesions were identified then patients would be excluded from consideration of PSMA-targeted radioligand therapy—this was a fairly unusual patient. The more common reason for exclusion was having one or more PSMA-negative lesions (≥1) lesions meeting the size threshold (ie, lymph node: ≥2.5 cm; solid organ ≥1 cm; bone metastases ≥1 cm). Importantly, a PSMA-negative node that is less than 2.5 cm in short axis would not exclude the patient from eligibility for  ¹⁷⁷Lu-PSMA-617.

Tanya B. Dorff, MD:
The randomised, double-blind, phase III ALSYMPCA trial evaluated radium-223 vs placebo 2:1 in patients with symptomatic mCRPC, with at least 2 symptomatic bone metastases, no known visceral metastases, and receiving best SoC, including those with previous docetaxel use and no previous docetaxel use (n = 921).²³ ALSYMPCA showed that radium-223 improved OS compared with placebo in both the previous docetaxel (HR: 0.70; P = .01) and no previous docetaxel (HR: 0.69; P = .01) groups and was well tolerated in patients with mCRPC with symptomatic bone metastases, leading to its FDA approval in 2013.

I also found interesting the data showing there was a significantly prolonged median time to first symptomatic skeletal event with radium-223 vs placebo (15.6 vs 9.8 months; HR: 0.66; 95% CI: 0.52-0.83; P = .0004) and reduced time in the hospital.

Tanya B. Dorff, MD:
More recently, the international, randomized, open-label, phase III PEACE-3 trial compared the efficacy and safety of adding radium-223 to enzalutamide vs treatment with enzalutamide alone in patients with confirmed prostate cancer and 4 or more bone metastases with or without lymph node involvement and who were either asymptomatic or mildly symptomatic and no central nervous system or visceral metastases. Patients previously treated with or concomitantly using CYP17 inhibitors were excluded, which I think is important to note.^24,25 The primary endpoint of the study was rPFS.

Tanya B. Dorff, MD:
For patients receiving radium-223 plus enzalutamide in PEACE-3, early on we saw an increase in the cumulative incidence of fractures compared with enzalutamide alone (24.3% vs 13.4%). This highlighted a need of using bone protective agents (BPA; zoledronic acid or denosumab) and fortunately following implementation of BPAs in this trial we saw a dramatic reduction in bone fractures for both treatment arms. Most grade 3 treatment-emergent AEs were comparable between treatment arms.

Tanya B. Dorff, MD:
Regarding the primary endpoint of rPFS and key secondary endpoint of OS, both were improved with the addition of radium-223 to enzalutamide. The median rPFS in the radium-223 plus enzalutamide arm was 19.4 months (95% CI: 17.1-25.3) compared with 16.4 months (95%CI: 13.8-19.2) with enzalutamide alone (HR: 0.69; 95% CI: 0.54-0.87; P  = .0009).²⁵ Similarly, median OS was prolonged in the combination arm at 42.3 months (95% CI: 36.8-49.1) compared with 35 months (95% CI: 28.8-38.9) with enzalutamide alone.

Tanya B. Dorff, MD:
With radioligand exposure expected in the bone marrow, we  worry about whether treatment with the alpha emitter radium-223 in the setting of bone metastases might lead patients to suffer from a diminished bone marrow reserve. Data from a real-world, observational, long-term safety analysis (REASSURE study) looked at this very question.²⁶

The REASSURE study previously reported that AEs of interest, including serious AEs and drug-related AEs within ≤30 days after radium-223 completion, grade 3/4 hematologic AEs ≤6 months after last radium-223 dose, and drug-related serious AEs after radium-223 therapy completion occurred in approximately 48% of patients overall. Serious AEs leading to death were seen in 9 (1%) patients treated with radium-223. Posttreatment grade 3/4 hematologic AEs occurring ≤6 months after radium-223 treatment completion were observed in approximately 16% of patients (grade 3: 14%; grade 4: 2%). I think it would also have been useful to determine hematologic toxicity in detail beyond 6 months. Nevertheless, investigators did look at drug-related serious AEs for up to 7 years and they report that the rate of any serious AE was 2% overall and less that 1% resulted in patient deaths.

Tanya B. Dorff, MD:
Based on the REASSURE trial data, the proportion of patients who required red blood cell transfusions, erythropoiesis-stimulating drugs, and colony stimulating factors with or without previous chemotherapy or with or without subsequent chemotherapy was notably increased with the use of radium-223.

Tanya B. Dorff, MD:
Data were presented at the 2025 American Society of Clinical Oncology annual meeting for the randomized phase I/II COMRADE trial evaluating radium-223 in combination with olaparib vs radium-223 alone in patients with progressive mCRPC, with 2 or more bone metastases, and without visceral metastases (n = 133).²⁷ The primary endpoint of the phase II portion of this trial was rPFS. Key secondary endpoints included rPFS by disease extent of bone metastases, previous use of docetaxel, and HRR mutation status.

Tanya B. Dorff, MD:
Results from the COMRADE trial showed that the study met its primary endpoint of improving rPFS in the intention-to-treat population.²⁷ Patients who received radium-223 plus olaparib vs radium-223 alone had prolonged median rPFS (8.9 vs 4.7 months; HR: 0.47; P =.0013). In addition, benefits of the combination vs radium-223 alone were observed in patients with no prior docetaxel (median rPFS: 13.7 vs 5.7 months; HR: 0.24), with prior docetaxel (median rPFS: 6.6 vs 3.3 months; HR: 0.73), and equal or fewer than 20 bone metastases (median rPFS: 13.4 vs 4.2 months; HR: 0.21), but not for those with more than 20 bone metastases (median rPFS: 4.7 vs 4.8 months; HR: 1.17). With regard to rPFS outcomes by mutation status, a benefit was observed in patients with HRR-negative status (median rPFS: 11.5 vs 4.5 months (HR: 0.49; 90% CI: 0.34-0.71) but not for those with HRR-positive status (median rPFS: 5.5 vs 4.7 months; HR: 0.47).

Tanya B. Dorff, MD:
Ongoing trials for radium-223 include:

• A phase II study evaluating sequencing of radium-223 followed by docetaxel or docetaxel followed by radium-223 in 70 patients with symptomatic bone-only mCRPC (RAPSON; NCT03230734)
• A phase III study of radium-223 plus docetaxel vs docetaxel alone in 738 patients with documented progressive mCRPC with 2 or more bone lesions (DORA; NCT03574571)
• A phase I/II study of radium-223 combined with ¹⁷⁷Lu-PSMA-I&T in 36 patients with mCRPC following progression on 1 or more second-generation ARPI (AlphaBet; NCT05383079)
• A phase I study of radium-223 plus nivolumab in 39 patients with mCRPC without evidence of visceral metastases and symptomatic bone metastases (Rad2Nivo; NCT04109729)
• A phase II study of radium-223 plus bipolar androgen therapy in 47 patients with adenocarcinoma mCRPC and bone metastases with asymptomatic or minimally symptomatic disease (BAT-RAD; NCT04704505)
• A phase II study of radium-223 with or without radiation-enhancing agent (M3814; nedisertib) vs radium-223 plus nedisertib and avelumab in 90 patients with hormone-unresponsive advanced prostate cancer (NCT04071236)

Tanya B. Dorff, MD:
The phase III VISION trial evaluated ¹⁷⁷Lu-PSMA-617 radioligand therapy plus protocol‑defined SoC (defined as either a second ARPI, radiation therapy, dexamethasone, or supportive care, and excluded chemotherapy, immunotherapy, systemic radioisotopes, and investigational drugs) compared with the same SoC in patients with mCRPC.² VISION enrolled patients with previous ARPI and who also had received 1 or more previous taxane chemotherapy regimen. Patients had to have an Eastern Cooperative Oncology Group performance status of 2 or less as well as adequate organ and bone marrow function. Patients were selected for ¹⁷⁷Lu-PSMA-617 radioligand therapy based on visual assessment of PSMA‑PET with diagnostic CT or MRI.^3,22 They were randomized 2:1 to receive either ¹⁷⁷Lu-PSMA-617 plus SoC vs SoC alone. The coprimary endpoints of the study were rPFS and OS. Key secondary endpoints included objective response, disease control rate, and time to symptomatic skeletal event.

Tanya B. Dorff, MD:
 Based on the results from VISION, we saw that addition of ¹⁷⁷Lu-PSMA-617 to SoC prolonged OS vs giving SoC alone (median OS: 15.3 vs 11.3 months; HR: 0.62; 95% CI: 0.52-0.74; P <.001). This was equivalent to a 38% reduction in the risk of death from mCRPC. The benefit of ¹⁷⁷Lu-PSMA-617 was noticed early on with the Kaplan-Meier curves beginning to separate at 2-3 months after the start of therapy and remaining parallel until after more than 2 years of follow-up.

The coprimary endpoint of rPFS was also improved with a median rPFS of 8.7 months for ¹⁷⁷Lu-PSMA-617 plus SoC compared with 3.4 months with SoC alone  (HR: 0.40; 99.2% CI: 0.29-0.57; P <.001). The rPFS benefit of adding ¹⁷⁷Lu-PSMA-617 to SoC was noted early after starting treatment (approximately 3 months) and it was maintained until approximately 1.5 years.

We know that mCRPC remains incurable for even the population of men with the better prognosis. Nonetheless, the VISION trial showed a benefit with a 60% reduction in the risk of progression or death seen with the addition of ¹⁷⁷Lu-PSMA-617 to SoC leading to its FDA approval in March of 2022 for patients with PSMA-positive mCRPC who had previously been treated with ARPI and taxane-based chemotherapy.³

Tanya B. Dorff, MD:
Until recently ¹⁷⁷Lu-PSMA-617 was available only after docetaxel chemotherapy. There were a few select cases where we considered using it before taxane chemotherapy. For instance, if a patient was ineligible for or was a poor candidate for taxane chemotherapy (ie, good PSMA expression and not too rapid/symptomatic progression, not neuroendocrine histology).

Interest in moving radioligand therapies earlier in the treatment of mCRPC led to the initiation of the phase III PSMAfore trial evaluating earlier use of ¹⁷⁷Lu-PSMA-617 vs switching ARPI (to abiraterone or enzalutamide) in patients who had a PSMA-positive lesion (per VISION criteria), had no exclusionary PSMA-negative lesions, had mCRPC progressing on previous ARPI, had not yet received taxanes, and who were not candidates for a PARP inhibitor (n = 468).²⁸ The primary endpoint of PSMAfore was rPFS per Blinded Independent Review Committee (BICR) by RECIST v1.1. Secondary endpoints included OS, rPFS2, and PFS as assessed by the investigator.

Tanya B. Dorff, MD:
PSMAfore met its primary endpoint of improving rPFS by BICR. When compared with an ARPI therapy switch, treatment with ¹⁷⁷Lu-PSMA-617 radioligand therapy significantly prolonged median rPFS (11.6 vs 5.6 months; HR: 0.49; 95% CI: 0.39-0.61) including in patients who had not received previous taxane therapy. By contrast, the secondary endpoint of OS in the intention-to-treat population was not improved with median OS being similar for both treatment arms (median OS: 23.66 vs 23.85; HR: 0.98; 95% CI: 0.75-1.26; P = .44).

Based on data from PSMAfore, on March 28, 2025, the FDA expanded the indication for ¹⁷⁷Lu-PSMA-617 radioligand therapy to include adults with PSMA-positive mCRPC who have been treated with ARPI therapy and are considered appropriate to delay taxane-based chemotherapy.³

Tanya B. Dorff, MD:
Ongoing trials for ¹⁷⁷Lu-PSMA-617 include:

• A phase III study evaluating ¹⁷⁷Lu-PSMA-617 plus SoC (either ADT and ARPI) vs SoC followed by docetaxel in 1144 patients with previously untreated or minimally treated PSMA-positive mCRPC (PSMAddition; NCT04720157)
• A phase III study of ¹⁷⁷Lu-PSMA-617 vs observation in 450 patients with oligometastatic PSMA-positive prostate cancer (PSMA-DC; NCT05939414)
• A phase II study of ¹⁷⁷Lu-PSMA-617 plus pembrolizumab in 48 patients with confirmed mCRPC adenocarcinoma that progressed on second-generation ARPI (ie, abiraterone, apalutamide, darolutamide, or enzalutamide) (NCI-2023-01660; NCT05766371)
• 2 phase I studies evaluating ¹⁷⁷Lu-PSMA-617 using a personalized or fixed dosing schedule in 60 patients with mCRPC adenocarcinoma with ≥1 previous ARPI (PRODIGY-2; NCT06943495) or ¹⁷⁷Lu-PSMA-617 plus SBRT in 27 patients with mCRPC adenocarcinoma previously treated with surgery or definitive radiation, previous salvage therapy to prostate bed or pelvis allowed (21-158; NCT05079698).

Tanya B. Dorff, MD:
The most recent National Comprehensive Cancer Network (NCCN) guideline recommendations list ¹⁷⁷Lu-PSMA-617radioligand therapy including for patients with previous hormone therapy (eg, ARPI) and no prior docetaxel if mCRPC and PSMA-positive, as well as for those who previously received ARPI and docetaxel if PSMA-positive metastatic disease is present.⁷ By contrast, radium-223 plus enzalutamide is recommended for patients with bone metastases in the setting of previous ARPI and/or irrespective of prior ARPI or previous docetaxel for symptomatic, bone-predominant metastases. 

Tanya B. Dorff, MD:
¹⁷⁷Lu-PNT2002 (also known as zadavotide guraxetan) is another PSMA-targeted small molecule radioligand therapy linked to a DOTAGA radiometal chelator, a bifunctional chelating agent that binds radiometals to form stable complexes via a functionalized glutamic acid moiety which allows it to attach to other molecules including  antibodies or peptides via its carboxylic acid groups. It is also designed to specifically deliver radiation to prostate cancer cells.²⁹ 

Tanya B. Dorff, MD:
The international, open-label, randomized phase III SPLASH trial evaluated ¹⁷⁷Lu-PNT2002 at a dose of 6.8 GBq (±10%) every 8 weeks for up to 4 cycles compared to treatment with abiraterone or enzalutamide in 468 patients with taxane-naive mCRPC progressing on previous ARPI therapy and confirmed to have PSMA-positive metastases via PET/CT with no exclusionary PET-negative lesions.²⁹ Patients also were ineligible for a PARP inhibitor. The primary endpoint of the study was rPFS per BICR per RECIST v1.1. Key secondary endpoints included OS, rPFS2, and PFS by investigator.

What I found most interesting about the SPLASH study is that it explored radioligand therapy every 8 weeks, whereas ¹⁷⁷Lu-PSMA-617 radioligand is given every 6 weeks. It also adds to the body of evidence that these radioligand treatments are safe and effective in patients who have not previously received docetaxel.

Tanya B. Dorff, MD:
As presented at the European Society of Medical Oncology meeting in 2024, treatment with ¹⁷⁷Lu-PNT2002 led to improved median rPFS (9.5 vs 6.0 months; HR: 0.71; 95% CI: 0.55-0.92; P = .0088). OS remained immature at the time of that analysis. With regards to tumor response, we also saw improved best ORR rate (38.1% vs 12%) and median duration of response (9.4 vs 7.3 months).

In a press release, the manufacturer of ¹⁷⁷Lu-PNT2002 indicated it would not continue development of this agent due to subsequent analysis showing that it did not improve OS.

Tanya B. Dorff, MD:
The international randomized phase III ECLIPSE trial is exploring a radioligand therapy known as ¹⁷⁷Lu-PSMA-I&T in a similar population of 439 patients with progressive mCRPC who were previously treated with ARPI in the setting of hormone-sensitive or castration resistant-disease. In this study patients are randomized to either ¹⁷⁷Lu-PSMA-I&T 7.4 GBq (200 mCi/mL) (± 10%) intravenously every 6 weeks for up to 6 cycles compared with ARPI hormone therapy switch to either abiraterone or enzalutamide (NCT05204927). The primary endpoint of this trial is rPFS. Key secondary endpoints include OS, PFS, PSA response, QoL, and safety.

A press release for the ECLIPSE clinical trial indicated the study had met its primary endpoint of improving rPFS in patients with mCRPC compared with hormonal therapy. We are still awaiting presentation of this data at an upcoming congress.

Tanya B. Dorff, MD:
Additional studies are evaluating other radioisotopes as therapy for mCRPC like the alpha-emitter actinium 225 (²²⁵Ac), a man-made radioisotope with an approximately 10-day half-life, under development as the active radioligand in various prostate cancer studies.

These studies include:

• The phase III AcTFirst trial evaluating the combination of ²²⁵Ac-PSMA-617 with or without ARPI compared with SoC (either ARPI or taxane) in 605 patients with taxane-naive mCRPC adenocarcinoma (excluding neuroendocrine histologies) who had received previous hormonal therapy (NCT06855277)
• The phase II/III AlphaBreak study of ²²⁵Ac-PSMA-I&T in 100 patients with PSMA-positive mCRPC who have had previous treatment with¹⁷⁷Lu-PSMA-617 or another ¹⁷⁷Lu-PSMA-targeting radioligand therapy (NCT06402331)
• A phase I/II study exploring the use of pembrolizumab plus ARPI with or without ²²⁵Ac-J591 in mCRPC adenocarcinoma previously treated with ARPI (NCT04946370)
• A phase I study evaluating various dose levels of ²²⁵Ac-PSMA-Trillium in 235 patients with mCRPC adenocarcinoma (excluding small-cell or neuroendocrine features) who previously received novel antihormonal treatments

Tanya B. Dorff, MD:

The selection of appropriate patients for radioligand therapy can be complex and often involves ensuring that the patient is not eligible for available biomarker-driven therapy such as BRCA/HRR-mutation (Palb2) status or MSI-H/dMMR status—which is often a smaller group of patients. After excluding for potential molecular biomarker–driven therapy, a patient who previously received ARPI and who wishes to delay or has already received docetaxel with mCRPC would be a good candidate for ¹⁷⁷Lu-PSMA-617 assuming they meet the PSMA-PET imaging criteria.^3,7 As discussed previously, in patients with no previous taxane (ie, docetaxel) and who have mCRPC and bone predominant or symptomatic bone metastases, positive bone scan, and no known visceral metastatic disease, radium-223 plus enzalutamide might be an option.^7,13

Tanya B. Dorff, MD:
There are 4 key factors I consider when developing a multidisciplinary treatment plan that involves radioligand therapy. These consider the tumor, treatment itself, the patient, and the care team.

• The cancer: Consider the volume of disease, pace of disease progression (PSA doubling time), and whether it is associated with symptoms (ie, pain) that may require prescription opioids.
• Treatment: Determine whether the desired therapy is readily available and whether there are systems in place that would allow the care team to administer the treatment safely and successfully.
• The patient: Look closely at marrow and renal/urinary function because these therapies can be associated with cytopenias (thrombocytopenia, neutropenia, anemias) which in some instances may require some hematologic support; monitor renal function because these radioligand drugs are cleared via the kidneys; and remember that socioeconomic considerations are also an important patient factor.
• Healthcare professionals (HCP): Ensure there is comfort in applying radioligands in the management of mCRPC, confidence in outcomes, and the team is able to remain engaged with the needed multidisciplinary care.

It is key for the medical oncologist to be involved in shared decision-making and patient education. It is also important for the patient and HCP to check in to assess whether to continue radioligand therapy with ¹⁷⁷Lu-PSMA-617.

At our center, we are fortunate to have a ¹⁷⁷Lu-PSMA-617 tumor board. During such meetings, we perform a multidisciplinary assessment as to whether we need to continue treatment with ¹⁷⁷Lu-PSMA-617. For most patients, I can make that decision on my own, but complex cases where PSA levels go down but the PET/CT scan does not look better, or vice versa, are when the tumor boards are most helpful to review the imaging with the nuclear medicine physician or radiologist.  

Tanya B. Dorff, MD:
Assessing response in the context of liver metastases is very important and working closely with a radiologist to interpret liver findings is key. I say this because it can be challenging to assess liver metastases because they are not well delineated on results from PSMA-PET/CT without the use of intravenous contrast. As mentioned earlier, the liver does have some uptake of the PSMA radiotracer, and we want to be certain that there are no PSMA-low/nonavid lesions “hiding” within the liver.

I often involve my radiology and nuclear medicine colleagues, and we may perform other types of imaging (MRI, and IV contrast imaging), particularly when we get discordant cases where disease-related pain gets better but the scans look worse, or the pain is not getting better and the scan does look better. In those scenarios, it is crucial to have the crosstalk between radiation oncology, nuclear medicine, and the medical oncologist.

Phillip H. Kuo, MD, PhD, FACR:
Single photon emission computer tomography (SPECT) is a technique that uses a radioactive tracer like ¹⁷⁷-Lu labeled PSMA to help detect recurrent prostate cancer. ¹⁷⁷Lu is also a good imaging agent for SPECT. Although less sensitive than PSMA PET/CT, it can also be used to monitor treatment effectiveness and inform personalized therapy in mCRPC cases by providing another useful biomarker to integrate with other biomarkers and clinical assessment.

There might be some variability about how often (after which cycles) to use SPECT/CT given variability in scanner availability. We might consider it in a situation where we suspect that the PSA levels are not accurately reflecting the disease burden. In the setting of a rising PSA, SPECT can localize the site of worsening disease; for example, new disease in the liver generally requires a change of therapy. Use of SPECT in that setting can help assess if the drug adequately reaches and is retained in the tumors. I also think that optimizing the use and interpretation of SPECT/CT is an unmet need and more education and research are needed in this area.

A substudy of the VISION trial mandated by the FDA looked at quantitative ⁶⁸Ga-PSMA-11 PET parameters using artificial intelligence and semiautomated manual segmentation to determine if there was a correlation between quantitative PET parameters such as whole-body tumor mean standardized uptake value (SUV_mean) and patient outcomes.³⁰  The underpinning concept is that tumors with higher uptake on PSMA-PET have higher PSMA target expression and therefore should receive more dose from radioligand therapy and thus are expected to respond better and patients should live longer. We used rPFS as the outcome for tumor response and were able to show that patients with the highest tumor expression of PSMA— for example, lesions with highest uptake of radiotracer— had the longest rPFS. We showed that in the highest uptake quartile of whole body SUV mean ( ≥10.2) in the experimental arm there was a higher rPFS of 14.1 months compared with those in the middle quartiles (≥6.0 to <10.2) 7.8 and 9.8 months and the bottom quartile (<6.0) at 5.8 months. However, I want to make sure that we understand that these quartiles are a function of the distribution of whole body SUV mean in the patient population and do not represent any cutoff that should be used to predict responses. What we do want to emphasize was the finding that the whole-body tumor SUV mean was the best predictor of ¹⁷⁷Lu-PSMA-617 efficacy for overall survival and rPFS and it was a linear correlation.  In other words, a 1-unit whole-body tumor SUV_mean increase was associated with a 12% and 10% decrease in risk of rPFS and death, respectively. Lastly, the pre-therapy PSMA-PET whole body SUVmean is a predictive biomarker for rPFS and OS outcomes since there was a lower hazard ratio in the ¹⁷⁷Lu-PSMA-617 plus standard of care arm compared with the standard of care alone control arm.

Although not done in standard clinical practice, the quantification of PSMA-PET scans through segmentation of tumors throughout the body provides proof of concept that the higher the target expression, the better response is going to be.^30,31,32 This quantitative imaging biomarker approach for predicting and assessing response is limited to a small fraction of centers currently but should grow.

What we most frequently do in clinical practice is use the visual estimate of high (greater than salivary gland uptake) and low expression with the parameters previously described to help inform which patients are more likely to have better outcomes and thus inform decision-making on whether to use ¹⁷⁷Lu-PSMA-617 as the next line of therapy or weighing potential benefits versus risks.