Abstract
Prostate-specific membrane antigen (PSMA) theranostics has been a momentous triumph for nuclear medicine. The recent approvals of PSMA-targeted imaging agents (68Ga-PSMA-11, 18F-DCFPyL) and radiopharmaceutical therapy (177Lu-PSMA-617) have paved the way for theranostics as a viable care strategy for men with metastatic castration-resistant prostate cancer. The imaging clinical trials OSPREY, CONDOR, and those conducted at the University of California (Los Angeles and San Francisco), as well as the randomized phase 3 therapy trial VISION, have been the fruitful beginnings for PSMA theranostics. There are currently several ongoing clinical trials to expand the reach of PSMA theranostics to the earlier phases of prostate cancer and to optimize its utility in combination therapeutic regimens. We provide a brief narrative review of the many PSMA-directed radiopharmaceutical therapy clinical trials with the β-emitter 177Lu-PSMA-617 and the α-emitter 225Ac-PSMA-617 in prostate cancer.
Radiopharmaceutical therapy (RPT) with radiolabeled agents targeted to the prostate-specific membrane antigen (PSMA) has provided an effective treatment strategy with manageable adverse events in men with metastatic castration-resistant prostate cancer (mCRPC). PSMA RPT is the therapeutic arm of the theranostics algorithm in which sufficient PSMA expression is first documented with imaging in accordance with the concept of precision oncology. The U.S. Food and Drug Administration approval of 68Ga-PSMA-11 on December 1, 2020, was based on 2 comparable new-drug applications submitted by the University of California, Los Angeles, and the University of California, San Francisco. The first commercial 18F-labeled PSMA radiotracer, 2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL, also known as 18F-piflufolastat or Pylarify [Lantheus]) was approved on May 27, 2021. Two kits (Illuccix [Telix Pharmaceuticals] and Locametz [Novartis]) for the preparation of 68Ga-gozetotide (68Ga-PSMA-11) were also approved—on December 20, 2021, and March 23, 2022, respectively. The approved indications are, first, for the imaging evaluation of men with suspected metastasis who are candidates for initial definitive therapy and, second, for suspected recurrence based on elevated serum prostate-specific antigen (PSA) levels. The Locametz kit is also approved for the selection of patients with mCRPC for whom the recently approved 177Lu-vipivotide tetraxetan (Pluvicto [Novartis]) PSMA RPT is indicated. Moreover, the recent National Comprehensive Cancer Network guidelines for prostate cancer, version 4-2022, indicated that both 68Ga-PSMA-11 and 18F-piflufolastat PSMA PET imaging can be used to determine whether patients are eligible to receive 177Lu-PSMA-617 RPT (1). Similar opinions have been expressed in a joint consensus statement by the European Association of Urology and the European Association of Nuclear Medicine (2). Over the past several years, the growing interest in PSMA RPT has ensured an increasing number of clinical trials in this clinical space using the β-emitting radiolabels 177Lu-PSMA-617 and 177Lu-PSMA-I&T (I&T stands for imaging and therapy) and, more recently, the α-emitting 225Ac-PSMA-617 (3–6). The aim of this narrative review is to summarize some of the major PSMA-directed RPT clinical trials.
LUPSMA
LuPSMA was a prospective single-center, single-arm, phase 2 clinical trial conducted in Australia that enrolled 30 men with mCRPC and progressive disease, of whom 28 had received chemotherapy (80% docetaxel, 47% cabazitaxel) and 25 had received second-generation antiandrogens (enzalutamide, abiraterone acetate, or both) (7). The men were screened with 68Ga-PSMA-11 PET/CT to confirm high PSMA expression (a lesion SUVmax of at least 1.5 times the hepatic SUVmean), and no 18F-FDG–positive disease without sufficient PSMA expression. With these dual imaging criteria, 16% of the patients were excluded. The patients were also required to have sufficient renal (glomerular filtration rate > 40 mL/min), hepatic (albumin > 25 g/L), and bone marrow (hemoglobin > 90 g/L, neutrophils > 1.5 × 109/L, platelets > 75 × 109/L) function. The primary endpoint of the trial was PSA response rate according to the Prostate Cancer Clinical Trials Working Group (PCWG) 2 criteria, defined as a 50% or more PSA decline from baseline (PSA50) with confirmation 3–4 wk apart. Treatment toxicity was assessed according to the Common Terminology Criteria for Adverse Events, version 4.03. A mean 177Lu-PSMA-617 dose of 7.5 GBq was administered per cycle (range, 4.4–8.7 GBq) for up to 4 cycles at 6-week intervals. The men received 1 (100%), 2 (93%), 3 (80%), or 4 (47%) therapy cycles. PSA50 was achieved in 57% of patients. The most common adverse event was grade 1 xerostomia, in 87% of patients, and grade 3–4 thrombocytopenia, in 13% of patients. There were no treatment-related deaths. The encouraging results of the LuPSMA trial paved the way for subsequent randomized controlled trials.
THERAP
TheraP was the first randomized study of 177Lu-PSMA-617 RPT. It was an Australian multicenter, unmasked, randomized, phase 2 trial in the clinical setting of progressive mCRPC (prior docetaxel therapy with a rising serum PSA level according to the PCWG 3 criteria) that compared the safety and efficacy of Lu-PSMA-617 therapy in 98 men with the safety and efficacy of cabazitaxel chemotherapy in 85 men (NCT03392428) (8). The eligibility criteria for PET imaging were PSMA-positive disease with an SUVmax of at least 20 at a site of disease, an SUVmax of greater than 10 at all other measurable sites of metastatic disease, and no sites of metastatic disease with discordant 18F-FDG–positive and PSMA-negative findings. On the basis of these imaging criteria, 10% and 18% of men were ineligible because of low metastasis PSMA uptake and discordant 18F-FDG–positive disease, respectively. The primary endpoint was PSA50. The secondary endpoints were progression-free survival (interval from randomization to first evidence of PSA progression per the PCWG 3 criteria) and radiographic progression (RECIST 1.1 for CT and PCWG 3 criteria for bone lesions). 177Lu-PSMA-617 RPT was more effective than cabazitaxel in terms of PSA50, which was observed in 66% of men in the 177Lu-PSMA-617 group versus 44% in the cabazitaxel group. There was also less grade 3–4 toxicity in the 177Lu-PSMA-617 group than in the cabazitaxel group (33% vs. 53%, respectively). Grade 1 or 2 xerostomia was observed in 61% of the patients in the 177Lu-PSMA-617 RPT group only. No deaths were attributable to 177Lu-PSMA-617 RPT. The trial concluded that 177Lu-PSMA-617 may be a viable alternative to cabazitaxel in view of the enhanced efficacy and decreased toxicity of 177Lu-PSMA-617 compared with cabazitaxel.
VISION
The multinational, randomized, phase 3 VISION trial was a pivotal milestone for nuclear medicine. The study design was similar to that of the ALSYMPCA randomized, phase 3 trial that led to the approval of 223Ra-dichloride (Xofigo [Bayer]) for men with bone-dominant mCRPC. Men with mCRPC were randomized 2:1 to receive either 177Lu-PSMA-11 (7.4 GBq [200 mCi] every 6 wk for 4 cycles, with an additional 2 cycles for total of 6 cycles at the discretion of treating physicians in responding patients, plus the best supportive care or the best standard of care [SOC]) or SOC only (NCT03511664) (9). The primary outcome measure was overall survival (OS). The secondary outcome measures were radiographic progression-free survival (rPFS) and time to first skeleton-related events. Eligible patients were those who had progressed on at least one taxane-based chemotherapy (41% were previously treated with 2 taxane regimens) and one or more androgen pathway inhibitors (abiraterone acetate, enzalutamide, darolutamide, or apalutamide). The best SOC did not permit additional chemotherapy (e.g., cabazitaxel), immunotherapy (e.g., pembrolizumab), or use of investigational drugs (e.g., olaparib). This decision was reasoned in view of lack of safety data on combination therapies and potential imbalance that may occur with variable additional treatments between the 2 study arms. However, additional androgen deprivation therapy, bone-health–directed therapy, or palliative radiation therapy were allowed at the discretion of the treating physician. The screening included imaging with contrast-enhanced diagnostic CT of the chest, abdomen, and pelvis; total-body bone scintigraphy; and 68Ga-PSMA-11 PET/CT to confirm sufficient PSMA expression of at least 1 metastatic lesion (defined as uptake greater than that of liver parenchyma in lesions of any size in any organ system; no SUV cutoff threshold) and no PSMA-negative lesions (defined as uptake no higher than that of liver parenchyma in any lymph node with a short axis of at least 2.5 cm, in any solid-organ lesion with a short axis of at least 1.0 cm, or in any bone lesion with a soft-tissue component of at least 1.0 cm in the short axis). Patients with a superscan pattern on bone scintigraphy were excluded. With these imaging selection criteria, 12.6% of patients were excluded after PSMA PET/CT imaging. 18F-FDG PET/CT was not performed. The imaging eligibility criteria that excluded 18F-FDG PET/CT were an operational decision to reduce complexity, meet the basic needs for regulatory approval, avoid potential issues with reimbursement of 2 PET/CT scans, meet the requirement for devising a scheme for combined scan interpretation, and provide reasonable accommodations for patient and physician acceptance. The trial showed a 4.0-mo OS benefit, a 5.3-mo rPFS benefit, and a 4.3-mo benefit regarding the time to the first skeleton-related event with the experimental arm of 177Lu-PSMA-617 plus best SOC over the best-SOC-only arm. The incidence of grade 3 or higher adverse events was higher in the experimental arm than in the control arm (52.7% vs. 38%, respectively), but quality of life was not adversely affected. No grade 3 or higher xerostomia was observed in the experimental arm. The OS benefit with 177Lu-PSMA-617 plus SOC was at par with those previously reported with other nonradioactive drug regimens in the mCRPC clinical space. The favorable results of the VISION trial led to the Food and Drug Administration approval of Pluvicto on March 23, 2022. Despite the approval, the debate on the most optimal imaging selection criteria continues, as does the issue of the potential need for individualized dosimetry for improved outcome (10–16). Nevertheless, reports indicate a poor outcome in patients with low PSMA expression or discordant 18F-FDG–avid disease who are considered ineligible for 177Lu-PSMA-617 treatment (17–19).
ENZAP
The goal of the ongoing open-label, randomized, stratified, 2-arm, multicenter, phase 2 EnzaP clinical trial is to investigate the safety and activity of adding 177Lu-PSMA-617 RPT to enzalutamide (an androgen receptor antagonist) in patients with mCRPC not previously treated with chemotherapy (NCT04419402) (20). The trial is recruiting 160 participants over 12 mo and following them until 150 events occur (approximately another 18 mo). The randomization is 1:1 to either enzalutamide alone or enzalutamide plus 177Lu-PSMA-617 RPT. The enzalutamide dose will be 160 mg per day orally (until there is no benefit or there is unacceptable toxicity). The 177Lu-PSMA-617 will be given as an intravenous dose of 7.5 GBq (±10%) each for 4 doses on days 15, 57, 113, and 169. 68Ga-PSMA-11 PET/CT is performed at mid cycle on day 92. Stratification factors will be study site, volume of disease (>20 vs. <20 disease sites on 68Ga-PSMA-11 PET/CT), prior treatment with early docetaxel for castration-sensitive disease, and prior treatment with early abiraterone acetate (an androgen biosynthesis inhibitor) for castration-sensitive disease. Imaging exclusion criteria entail measurable metastatic lesions (>10 mm) that display an SUVmax of less than 10 on 68Ga-PSMA-11 PET/CT. The primary outcome measure is PSA PFS. PSA progression is defined as a rise in PSA by at least 25% and at least 2 ng/mL above the nadir, which needs to be confirmed by a repeat PSA measurement 3 wk later. There are also several secondary outcome measures, including rPFS, PSA response rate, and others.
PSMAFORE
The purpose of the ongoing open-label, multicenter, 1:1 randomized, phase 3 PSMAFore clinical trial (NCT04689828) is to compare 177Lu-PSMA-617 (7.4 GBq intravenously every 6 wk for 6 cycles) versus a change in androgen receptor–directed therapy in taxane-naïve patients with progressive mCRPC (21). The best supportive care is allowed in both study arms. The primary outcome measure is rPFS according to the PCWG 3–modified RECIST 1.1. OS is a key secondary endpoint. PSMA expression is confirmed with 68Ga-PSMA-11 PET/CT. The estimated enrollment is 450 participants.
PSMADDITION
PSMAddition (NCT04720157) is an ongoing international, prospective, open-label, 1:1 randomized, phase 3 trial comparing the safety and efficacy of 177Lu-PSMA-617 (7.4 GBq intravenously every 6 wk for up to 6 cycles) plus SOC versus SOC alone in men with metastatic castration-sensitive prostate cancer (22). SOC is defined as androgen receptor pathway inhibitors and androgen deprivation therapy. Docetaxel is not allowed. Eligible patients are treatment-naïve or minimally treated hormonal therapy candidates with PSMA-positive disease on 68Ga-PSMA-11 PET/CT. Patients with rapidly progressing tumors who require chemotherapy are excluded. The approximate cohort will be 1,126 patients. rPFS is the primary endpoint.
UPFRONTPSMA
UPFrontPSMA is an ongoing open-label, multicenter Australian, 1:1 randomized, phase 2 clinical trial comparing the efficacy of 177Lu-PSMA-617 (7.5 GBq intravenously every 6 wk for 2 cycles) followed 6 wk later by docetaxel chemotherapy (75 mg/m2 every 3 wk for 6 cycles) versus docetaxel chemotherapy in patients with newly diagnosed high-volume (4 or more bone metastases with 1 or more bone lesion outside the axial skeleton, or visceral metastases) metastatic castration-sensitive prostate cancer (NCT04343885) (23). All patients also receive continuous androgen-deprivation therapy, and up to 4 wk of androgen-deprivation therapy are permitted before commencement of screening. PSMA expression is confirmed with 68Ga-PSMA-11 PET/CT with no major discordance on 18F-FDG PET/CT (defined as 18F-FDG–positive disease with minimal PSMA expression in more than 5 sites or more than 50% of total disease volume). The primary endpoint is undetectable PSA (<0.2 ng/mL) at 12 mo. There are also several secondary and exploratory endpoints. The planned cohort is 140 participants.
SPLASH
SPLASH is an ongoing multicenter, open-label, phase 3 clinical trial evaluating the efficacy of 177Lu-PNT2002 (177Lu-PSMA I&T) in men with progressive mCRPC after androgen receptor pathway inhibitor therapy (NCT04647526) (24). In the dosimetry phase, 25 patients will receive up to 4 cycles of 177Lu-PNT2002, 6.8 GBq intravenously, every 8 wk. In the randomization phase, about 390 patients will be randomized 2:1 to receive either 177Lu-PNT2002 (n = 260) or androgen receptor pathway inhibitor therapy (enzalutamide or abiraterone acetate, with prednisone or dexamethasone; n = 130). The primary endpoint is rPFS as assessed by RECIST 1.1. and PCWG 3 criteria. Crossover of patients progressing on the androgen receptor pathway inhibitor therapy arm to the 177Lu-PNT2002 therapy arm is allowed. Sufficient PSMA expression is confirmed with PSMA PET/CT. Exclusion criteria include patients with prior cytotoxic chemotherapy for mCRPC, hepatic metastases 1 cm or larger, central nervous system metastases, and a superscan on bone scintigraphy.
ECLIPSE
ECLIPSE is an ongoing prospective, multicenter, open-label, randomized, phase 3 study to compare the safety and efficacy of 177Lu-PSMA I&T versus hormone therapy in mCRPC patients (NCT05204927) (25). Approximately 400 patients will be randomized at a 2:1 ratio to receive either 177Lu-PSMA I&T or SOC hormone therapy (abiraterone acetate with prednisone, or enzalutamide). PSMA expression is confirmed with either 68Ga-PSMA 11 PET/CT or 18F-DCFPyL PET/CT as determined by central readers. Exclusion criteria include prior treatment with radioligand therapy, 223Ra-dichloride therapy within the past 12 wk, prior chemotherapy, or any other concurrent therapy. The primary outcome measure is rPFS as assessed by RECIST 1.1 and PCWG 3 criteria. There are also several secondary outcomes, including OS and PSA50 response rate, among others.
LUTECTOMY
LuTectomy is an ongoing Australian open-label, nonrandomized, phase 1/2 trial to assess the dosimetry, efficacy, and safety of 177Lu-PSMA-617 in men with high-risk (defined as PSA > 20 ng/mL, International Society of Urological Pathology grade group 3–5, clinical stage T2c or higher) localized or locoregional (N1) prostate cancer before undergoing radical prostatectomy and pelvic lymph node dissection (NCT04430192) (26). The first 10 patients will receive 5 GBq of 177Lu-PSMA-617 intravenously for the dosimetry study. The subsequent 10 patients will receive 2 cycles of 5 GBq of 177Lu-PSMA-617 intravenously, separated by 6 wk. The primary outcome measure is to determine the absorbed radiation dose in the prostate and metastatic lymph nodes. PSMA PET/CT will be performed to confirm high PSMA expression defined as an SUVmax of more than 20. Patients with prior prostate radiotherapy or androgen-deprivation therapy, and evidence of metastatic disease involving the bone, viscera, and lymph nodes above the common iliac bifurcation, are excluded.
PRINCE
PRINCE is an ongoing Australian phase 1/2 study assessing the safety and efficacy of the combination of 177Lu-PSMA-617 (up to 6-week cycles with an initial intravenous dose of 8.5 GBq reduced by 0.5 GBq for each of the subsequent 5 cycles) and the programmed death 1 protein inhibitor pembrolizumab (200 mg every 3 wk for up to 35 doses) in 37 mCRPC patients (NCT03658447) (27). Major exclusion criteria include any prior exposure to immunotherapy drug regimens, cabazitaxel chemotherapy, and 177Lu-PSMA-617 RPT. The primary outcome measures are PSA50, incidence of adverse events, and tolerability (defined as time from treatment commencement to treatment discontinuation due to toxicity).
LUPARP
LuPARP is an Australian dose-escalation and dose-expansion phase 1 trial evaluating the safety and tolerability of the poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib in combination with 177Lu-PSMA-617 in 52 mCRPC patients (NCT03874884) (28). Patients will be administered 177Lu-PSMA-617 (7.4 GBq intravenously every 6 wk) together with olaparib on days 2–15 of each cycle for total of 4 cycles; a cycle is 42 d. The recommended phase 2 dose of olaparib will be used during the dose expansion part of the trial. Exclusion criteria include patients with a superscan pattern on bone scintigraphy, 18F-FDG–positive disease with low PSMA expression (SUVmax < 10), a history of brain or leptomeningeal metastases, and prior exposure to 177Lu-PSMA-617, cabazitaxel, platinum, PARP inhibitors, mitoxantrone, or cyclophosphamide. The primary outcome measures are determination of the dose-limiting toxicity, maximum tolerated dose, and recommended phase 2 dose. PSA50 and rPFS are among several secondary outcome measures.
TATCIST
TATCIST is an oncoming prospective, open-label, single-arm study to assess the efficacy of PSMA-targeted α-particle therapy with 225Ac-PSMA I&T in approximately 100 patients with mCRPC (NCT05219500) (29). Eligible patients include those with progressive disease on taxane chemotherapy or those who are naïve to or have been treated previously and progressed with 177Lu-PSMA-617 or 177Lu-PSMAI& T. All patients will receive 225Ac-PSMA I&T at an interval of 8 ± 1 wk, with the initial activity of 100 kBq/kg (±10%), followed by deescalation to 87 kBq/kg (±10%), 75 kBq/kg (±10%), or 50 kBq/kg (±10%) in cases of good response at the discretion of the investigator. The primary outcome measure is PSA50.
SUMMARY
We have reviewed several major clinical trials that use PSMA-directed RPT (Table 1). The VISION trial established PSMA-directed therapy as a viable treatment strategy option in men with mCRPC. The other ongoing trials will hopefully expand the applicability of PSMA-targeted RPT to earlier phases of prostate cancer and shed light on the proper sequencing and combination with other treatments to optimize overall therapeutic efficacy and patient outcome at acceptable biologic and financial toxicities.
Clinical Trials of PSMA RPT
DISCLOSURE
This work was supported in part by grant P30‐CA014089 from the U.S. National Institutes of Health. Hossein Jadvar is on the advisory boards of Radiomedix and PharmaLogic, is on the speakers’ bureau for Lantheus, and is a consultant to Bayer and Blue Earth Diagnostics. No other potential conflict of interest relevant to this article was reported.
Footnotes
CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org. Complete the test online no later than March 2026. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 80% of the questions correctly to receive 1.0 CEH (Continuing Education Hour) credit. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test.
Published online Jan. 4, 2023.
REFERENCES
- Received for publication September 15, 2022.
- Revision received December 6, 2022.
