The role of PSMA radioligands in the diagnosis and treatment of prostate carcinoma

Abstract

Prostate cancer (PC) is the most common tumor in men in the West and the fifth leading cause of cancer-related death. The use of PSMA radioligands has represented an important advance both in its diagnosis, through PET molecular imaging, and in its treatment in advanced stages of the disease. This article reviews the contribution of PET studies with PSMA radioligands in initial staging, in tumor detection in biochemical recurrence (elevation of PSA) after treatment with curative intent, and in the more advanced stages of the disease (castration resistant PC or CRPC). The contribution of PSMA radioligand therapy (PSMA-RLT) in CRPC patients who progress to standard therapy is also analyzed.

Resumen

El cáncer de próstata (CP) es el tumor más frecuente en varones en Occidente y la quinta causa de muerte relacionada con el cáncer. El uso de radioligandos antígeno prostático específico de membrana (PSMA) ha supuesto un importante avance tanto en su diagnóstico, a través de la imagen molecular de tomografía por emisión de positrones (PET), como en su tratamiento en fases avanzadas de la enfermedad. En este artículo, se hace una revisión de la aportación de los estudios PET con radioligandos PSMA en la estadificación inicial, en la detección tumoral en la recidiva bioquímica (elevación del antígeno prostático específico [PSA]) tras un tratamiento con intención curativa, y en los estadios más avanzados de la enfermedad (CP resistente a la castración o CPRC). Se analiza, además, la aportación de la terapia con radioligandos PSMA (PSMA-TRL) en pacientes con CPRC que progresan a la terapia estándar.

Introduction

Prostate cancer (PC) is the most frequent tumor in men in the West and is the fifth cause of cancer-related death¹. Age, African race, and a family history of PC (related to the presence of mutations in DNA repair genes, such as BRCA1 and BRCA2), are well established risk factors². General populational screening based on an increase in serum levels of the prostate-specific antigen (PSA) is not recommended since, despite having demonstrated a reduction in mortality by PC, these values lead to overdiagnosis and over treatment of patients. However, what is recommended is early detection adapted to risk by the determination of basal PSA in men > 50 years of age (or > 40-45 years if they present any of the previously mentioned risk factors)³.

Ninety-five percent of PCs are adenocarcinomas which most frequently develop (65%) in the peripheral posterolateral zone of the gland. To measure the grade of histological aggressiveness the Gleason system modified by the International Society of Urology Pathology (ISUP) is recommended⁴, which uses grading from 1 to 5 (corresponding to Gleason scores of ≤ 6, 3 + 4, 4 + 3, 8 and > 8, respectively).

For tumoral staging, the 2017 tumor, node, metastasis (TNM) classification of the American Joint Cancer Committee is used (Table 1)⁵. A PC is considered to be localized or organ-confined when it does not exceed the anatomical limits of the prostate (stage T1 or T2). If the tumor extends through the capsule that surrounds the prostate and invades adjacent tissue (neurovascular bundles, seminal vesicles, or neighboring organs such as the rectum) this is defined as locally advanced PC (stage T3 -T4 N0M0). Distant tumoral dissemination indicates metastatic disease (M1).

Table 1.

TNM staging of the American Joint Committee on Cancer for prostate cancer.

Primary tumor (T)	Lymph nodes (N)	Distant metastasis (M)
TX: primary tumor cannot be evaluated.	Nx: regional lymph nodes cannot be evaluated.	M0: no distant metastasis.
T0: No evidence of tumor.	N0: no metastasis in the regional lymph nodes (up to the common iliac chain).	M1: presence of distant metastasis (visceral, bone or distant lymph nodes; that is, from the common iliac chain or in inguinal lymph nodes)
T1: Subclinical tumor not evident by DRE studies.	N1: metastasis in regional lymph nodes.
T2: tumor limited to the prostate.
T3: the tumor extends through the prostatic capsule.
T4: the tumor invades adjacent tissues.

For the diagnosis of PC, in addition to the PSA (high levels indicate a greater probability of PC), digital rectal examination, transrectal/transperineal ultrasound-guided prostate biopsy and multiparametric magnetic resonance (mpMR) are used. The latter not only helps to localize the primary tumor but also evaluates locoregional disease extension. The European Society of Medical Oncology recommends performing mpMR in patients with PSA elevation to determine the need or not to carry out prostate biopsy⁶, and also helps to more effectively guide biopsy taking.

In the management of PC, the first step is to determine whether treatment is necessary, taking into account the life expectancy and the general health status of the patient. In localized PC, patients are also staged in groups of risk which help to define the probability of recurrence after intention to cure treatment. To do this the tumoral stage (T), PSA values and the tumor Gleason score are considered. According to Table 2 follows by the European Association of Urology: low risk (PSA < 10 ng/mL, ISUP grade 1, clinical stage T1-T2a), intermediate risk (PSA 10-20 ng/mL or ISUP grade 2/3 or clinical stage T2b) and high risk (PSA > 20 ng/mL, ISUP grade 4/5 and clinical stage T2c)⁷. This classification not only provides prognostic information (the probability of each group being disease free at 5 years after treatment is 85%, 50-70% and 33%, respectively)⁸, but also helps in therapeutic decision making. For example, low risk tumors have slow growth rates, and thus, in older patients with comorbidities that limit their life expectancy to ≤ 10 years active surveillance is recommended⁶.

Table 2.

Risk groups of recurrence following intention to cure treatment according to the European Association of Urology⁸.

Low risk	Intermediate risk	High risk
PSA<10ng/mL	PSA 10-20 ng/mL	PSA > 20 ng/mL	any PSA
and GS < 7 (ISUP grade 1)	or GS 7 (ISUP grade 2/3)	or GS > 7 (ISUP grade 4/5)	any GS or ISUP grade
and cT1-2a	or cT2b	or cT2c	cT3-4 or cN1
LOCALIZED PROSTATE CANCER			LOCALLY ADVANCED

GS = Gleason score; ISUP = International Society for Urological Pathology.

At present, most cases of PC are diagnosed in initial stages, with only 10-15% corresponding to advanced cases. In the initial stages PC is curable by surgery in an elevated proportion of cases (radical prostatectomy [RP]) or external beam radiotherapy (EBRT)/brachytherapy with or without the addition of hormone therapy based on androgen deprivation therapy (ADT). However, metastatic PC at diagnosis (hormone sensitive) is not receptive to curative options, with ADT being used in these cases since a reduction in testosterone levels delays tumoral growth. This suppression can be achieved by surgical orchiectomy or with the use of drugs such as luteinizing hormone releasing hormone antagonists, which reduce the synthesis of androgens (Goserelin (Zoladex®), Triptorelin (Decapeptyl®) or Leuprorelin (Procrin®, Eligard®) or drugs which act on androgen receptors (bicalutamide (Casodex®) and flutamide (Eulexin®), although the latter should be used in combination with the former drugs or with surgical orchiectomy. After treatment with intention to cure, up to 50% of the patients may present disease recurrence with an elevation of PSA values or biochemical recurrence (BR). The therapeutic approach is defined by the localization of the disease. Thus, if localized and/or with little extension, the use of targeted therapies may be considered, while in cases in which the disease is not localized or is very extended, ADT is normally used. However, this therapy is not without undesirable effects such as cardiovascular events, metabolic syndrome, sarcopenia, sexual dysfunction, and osteoporosis⁹. In addition, between 10% and 20% of the cases treated with ADT develop disease progression together with resistance to hormone treatment over time (castration-resistant PC [CRPC])¹⁰. Therefore, attempts are made to delay the initiation of ADT and treatments targeted to tumoral lesions such as rescue surgery and EBRT or stereotactic radiotherapy are administered. In advanced cases of the disease (CRPC and metastatic hormone-sensitive disease) new generation hormone agents (abiraterone, enzalutamide, apalutamide), chemotherapy (cabazitaxel) and radiopharmaceuticals (Ra-223 dichloride) have been developed, which allowed increasing the survival from 12-18 months in 2005, when only chemotherapy with docetaxel was available, to 32-36 months at present. In addition, it has been demonstrated that patients presenting genetic alterations (BRCA1, BRCA2, ATM) show good response to chemotherapy with platin (carboplatin) and to the new therapeutic agents called poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib, among others)⁸.

Prostate-specific membrane antigen

The prostate-specific membrane antigen (PSMA) is a type II cellular membrane glycoprotein localized in the transmembrane with a dominant extracellular content. Its expression is significantly increased in prostatic tumoral cells and in some other tumor types, with its uptake in positron emission tomography (PET) molecular imaging being a measure of tumoral expression¹¹. Despite being expressed in other non-tumoral tissues, such as the salivary glands, small intestine and proximal renal tubules, the expression is lower than in tumoral cells. This certain specificity makes it an excellent target for theragnosis (use in diagnosis and treatment).

The PSMA radiopharmaceuticals used for diagnosis and treatment in PC are described below.

PSMA radiopharmaceuticals for the diagnosis of PC

The development of radiopharmaceuticals for the visualization of PSMA is aimed at the synthesis of agents with specifically bind to the active site of the extracellular domain, producing their internalization by a mechanism of endocytosis, thereby increasing their accumulation in the interior of the tumoral cell¹².

PSMA inhibitors or ligands are based on small peptide molecules modified with urea and labeled with different radioactive single photon emission computed tomography (SPECT) (^99mTc) and PET isotopes (⁶⁸Ga, ¹⁸F).

[^99mTc]Tc-PSMA-I&T is obtained with the use of a kit system using S-acetylmercaptoacetyltriserine (MAS3) with an elevated purity and radiochemical performance as a chelator. It presents slow blood clearance due to its elevated binding to plasma proteins and great affinity for tissues that overexpress PSMA¹³.

The most frequently used PSMA ligands labeled with ⁶⁸Ga are [⁶⁸Ga]Ga-PSMA -11 and [⁶⁸Ga]Ga-PSMA-617, which present an elevated affinity for the PSMA and specific internalization in cancerous prostate cells^14,15. The difference between the two is the chelator used, with DOTA being used in the synthesis of [⁶⁸Ga]Ga-PSMA-617, allowing the establishment of stable links with therapeutic radioisotopes, while HBED-CC is used in [⁶⁸Ga]Ga-PSMA-11. They present favorable pharmacokinetics with elevated and persistent uptake and rapid elimination, showing great utility in the diagnosis of relapses even with very low PSA levels¹⁶. These radiopharmaceuticals can be obtained by automated synthesis or with kit-type marking. The main inconvenience is the need to have a germanium-68/galium-68 (⁶⁸Ge/⁶⁸Ga) generator or a cyclotron for their production. In addition, their short semi-decay period (67.8 min) limits their distribution to other centers.

Therefore, in the last years multiple ligands labeled with fluorodeoxyglucose F 18 (¹⁸F) have been developed. Table 3 shows the most relevant¹⁷. Ligands labeled with ¹⁸F have a series of advantages compared to those labeled with ⁶⁸Ga and determine their generalized use in clinical practice. First, they may be distributed from a distance from the site of production to small patient volume PET centers in which the presence of a ⁶⁸Ge/⁶⁸Ga generator is not justified. Second, radiopharmaceutical labeled with ¹⁸F have greater positron production (¹⁸F 96.86% vs. 68Ga 89.14%) and these positrons have less energy (¹⁸F 633 keV vs. 68Ga 1,899 keV), resulting in images with less noise and greater resolution of contrast. However, a network meta-analysis reported that the rate of detection of recurrence is quite similar among the three most commonly used PSMA radiopharmaceuticals ([⁶⁸Ga]Ga-PSMA-11, [¹⁸F]F-PSMA-1007, [¹⁸F]F-DCFPyl) and this rate is much higher than that of choline derivatives. Thus, there is insufficient evidence in favor of one PSMA ligand over another. Moreover, there is wide overlapping between PSMA radiopharmaceuticals labeled with ⁶⁸Ga and ¹⁸F in regard to the tumoral detection rate¹⁸.

Table 3.

Prostate-specific membrane antigen radiopharmaceutical ligands labeled with [¹⁸F].

Radiopharmaceutical	Chemical synthesis	Advantage	Disadvantage
[^18F]F-DCFPyL	Simple, elevated yield	Low hepatic uptake	High urinary elimination
[^18F]F-PSMA-1007	A single passage	Low urinary elimination	Elevated hepatic uptake
[^18F]F-CTT1057	Complex	Elevated lesion/background ratio (phosphoramidite group)	Greater dosimetric rate
		Low small intestine uptake
[^18F]F-FSU-880	Complex	Rapid plasma clearance	–
		Elevated affinity
[^18F]F-JK-PSMA-7	Complex	Elevated lesion/background ratio	Less sensitivity
[^18F]F-AlF-PSMA-11	A single passage	Low urinary elimination	Increase of bone uptake due to defluoridation
[^18F]rhPSMA-7.3	Isotopic silicon-fluoride acceptor (SiFA) exchange	Vesicle retention less than that of ^68Ga-PSMA-11 achieved with the use of a diuretic	–

PSMA radiopharmaceuticals for the treatment of PC

Therapeutic radiopharmaceuticals based on PSMA are internalized in the tumoral cells releasing high doses of radiation with a low rate of secondary effects¹⁹.

The first radioligands used in PSMA therapy were monoclonal antibodies. The first clinical trial was with [¹⁷⁷Lutetium]-J591, which is a deimmunized monoclonal antibody that specifically binds and has an elevated affinity to the extracellular domain of PSMA. In addition, the PSMA-J591 complex is internalized within the tumoral cell releasing the therapeutic isotope. The slow diffusion of the antibody in solid lesions and its elevated hematologic toxicity due to its long circulation time are limitations for its use²⁰.

There are mainly two beta-emitting radiopharmaceuticals for use in radionuclide therapy with PSMA radioligands (PSMA-RLT) - [¹⁷⁷Lu]-PSMA-617 and [¹⁷⁷Lu]-PSMA-I&T. Although the first is more widely used in most prospective studies, both present similar characteristics of pharmacokinetics and biodistribution, with comparable results of efficacy. [¹⁷⁷Lu]-PSMA-617 (T1/2 = 6.65 d) presents great affinity for PSMA thanks to the presence of the urea group and good internalization in the tumoral cells due to the use of the DOTA and DOTAGA chelators, releasing beta particles that destroy the tumoral cells while causing little damage to the surrounding cells since they act at very short distances (0.5 to 2 mm)²¹. At present, their radiochemical synthesis is totally automated. The main inconveniences of [¹⁷⁷Lu]-PSMA-617 are their gamma emission and elevated accumulation in the salivary glands which can deteriorate the quality of life of the patient.

In the last years the use of an alpha particle emitter [²²⁵Ac]-PSMA-617 (T1/2 = 9,9 d) has been evaluated, which due to its high energy and low penetration power (47 to 85 mm)²² causes a greater quantity of DNA ruptures and results in less toxicity, respectively. This radionuclide has shown to be very useful in not only monotherapy but also in combined therapy with [¹⁷⁷Lu]-PSMA-617²³. Its main limitation is its low availability worldwide since [²²⁵Ac] is known as the “rarest drug in Earth”.

Finally, of particular interest is [¹⁶¹Tb]-PSMA-617 (T1/2 = 6.89 d), which has chemical and physical properties similar to those of [¹⁷⁷Lu]-PSMA-617, while also presenting the emission of Auger electrons with great yield (12 per decay) and a radiation dose from 2- to 4-fold greater than [¹⁷⁷Lu]-PSMA-617 in tumoral lesions²⁴.

PET-PSMA in the initial staging of prostate cancer

The current European clinical guidelines recommend computerized tomography (CT) and bone scintigraphy (BS) for the evaluation of lymph node involvement and the detection of bone metastases. However, these recommendations are limited to patients with PC of intermediate and high risk. Both imaging modalities have a low sensitivity for the detection of lesions, being 40% for the localization of lymph node metastasis with CT²⁵ and 80% for the detection of bone involvement by BS²⁶. This sensitivity is even lower with PSA values less than 10 ng/mL.

In the evaluation of local involvement, PET/CT with [⁶⁸Ga]Ga-PSMA has shown to be able to accurately localize disease because of its high grade of uptake with respect to healthy tissue, with a diagnostic accuracy of 86% for the detection of infiltration of seminal vesicles and 71% for capsular invasion²⁷. In addition, Eiber et al. demonstrated greater detection of tumoral foci of up to 8.5% with the use of the integration of PET/MR images compared with PET imaging (92%) and MR (66%) alone²⁸. Nonetheless, it should be taken into account that benign conditions may coexist in the prostate (foci of prostatitis, benign prostate hyperplasia, among others), which may cause false positives and up to 10% of primary prostatic carcinomas do not express PSMA receptors²⁹.

It has been demonstrated that some factors can influence the grade of radiopharmaceutical uptake, including the ISUP grades and the PSA level. In a series of 90 patients with PC, tumors with an ISUP grade between 1 and 3 showed lesser intensity of uptake compared to those with ISUP > 4. Likewise, significantly greater uptake was observed in patients with PSA ≥ 10 ng/mL than those with PSA values < 10 ng/mL (maximum standard uptake value [SUVmax]: 17.6 vs. 7.7; p < 0.001)³⁰.

PET/CT with [⁶⁸Ga]Ga-PSMA-11 has shown to have an adequate sensitivity and specificity for detecting lymph node involvement in patients with PC (Fig. 1). A recent meta-analysis studied a subgroup of patients who, after having been evaluated by PET/CT with [⁶⁸Ga]Ga-PSMA-11 for initial staging, underwent RP plus extensive pelvic lymph node dissection. In the patient-based analysis, they obtained a sensitivity and specificity for the localization of lymph node infiltration of 77% and 97%, respectively³¹

Fig. 1.

50-year-old patient with prostate adenocarcinoma Gleason 3 + 4 (ISUP grade 2) with an initial PSA of 12 ng/mL and a normal CT and BS. Initial staging with [⁶⁸Ga]Ga-PSMA-11 PET/CT was performed prior to radiotherapy treatment. PET/CT images with [^68.Ga]Ga-PSMA-11 (A: MIP, B: PET, B: CT, C: Axial fusion PET/CT and E: Sagittal fusion PET/CT) showed two foci with elevated PSMA receptor expression in the right prostate lobe and two presacral adenopathies compatible with tumoral infiltration.

In a systematic review including 13 studies and a large number of patients (n = 1597), PET/CT with [⁶⁸Ga]Ga-PSMA-11 presented a higher sensitivity than MR with a similar specificity in the evaluation of lymph node involvement in patients with PC patients with intermediate-high risk. The grouped sensitivity and specificity of [⁶⁸Ga]Ga-PSMA-11 PET/CT was 0.65 (95% confidence interval [CI]: 0.49–0.79) and 0.94 (95% CI: 0.88–0.97), being 0.41 (95% CI: 0.26–0.57) and 0.92 (95% CI: 0.86–0.95), respectively for MR³².

Nevertheless, although PET-PSMA has shown greater diagnostic accuracy for the detection of lymph node metastasis than MR, it should be taken into account that lymph node metastases below the PET limit of resolution (∼3-4 mm) may not be detected in CT with contrast or PET/CT with choline³³.

In addition, the current evidence demonstrates that both PET/CT with choline and PET-PSMA and MR present a greater sensitivity for the detection of lymph node and bone metastases compared to the classical diagnostic approach with abdominal-pelvic CT and BS²⁶. In this regard, a prospective multicenter study (proPSMA) described the superiority of [⁶⁸Ga]Ga-PSMA-11 PET/CT versus conventional imaging studies (CT and BS) in the initial staging of patients with high-risk PC. The diagnostic accuracy of [⁶⁸Ga]Ga-PSMA-11 PET/CT was 27% higher than CT and BS (92% vs. 65%; p < 0.0001) and also demonstrated greater sensitivity and specificity (85% and 98 %) compared to conventional imaging studies (38% and 91%). In 28% of the patients there was also a change in therapeutic management after the information provided by the [⁶⁸Ga]Ga-PSMA-11 PET/CT compared with 15% with conventional imaging, as well as a lower number of erroneous results with [⁶⁸Ga]Ga-PSMA-11 PET/CT (7% vs. 23%)³⁴.

Based on these results, the recent National Comprehensive Cancer Network (NCCN) 2022 guidelines included [⁶⁸Ga]Ga-PSMA, [¹⁸F]DCFPyL (also known as piflufolastat) and PET/MR as effective alternatives to traditional diagnostic modalities (CT, BS and MR) in initial staging. In addition, the panelists mentioned that in their opinion conventional imaging studies should not be a prerequisite for the performance of PET-PSMA in initial staging since the latter “presents the same (if not greater) efficacy in the initial evaluation of these patients”³⁵. In Europe the recommendations of the European Cancer Organization are similar³⁶.

• •

  Key point: PET-PSMA presents better diagnostic accuracy with greater sensitivity and specificity versus conventional imaging studies (CT and BS) in the initial staging of high-risk PC patients.

PET-PSMA in the recurrence of prostate cancer

Up to 50% of PC patients treated with intention to cure by RP or EBRT develop BR during follow-up³⁷. BR is defined as an elevation of serum PSA levels above the nadir value after primary treatment (PSA > 0.2 ng/mL after RP or nadir PSA nadir +2 ng/mL after EBRT)³⁸. The PSA value is the most reliable and cost-effective biomarker of BR in the follow-up of patients with PC; however, it does not localize recurrence. Recurrence may be found in the prostatic bed, at the level of the locoregional lymph nodes, the extrapelvic lymph nodes or distant dissemination producing bone or visceral metastases. The therapeutic approach varies according to the localization of recurrence, making determination of the exact localization of the recurrence imperative.

Normally, conventional imaging techniques are used for the detection of recurrence (CT, MR and BS), but these have shown a low diagnostic yield when PSA levels are low (<2 ng/mL)³⁹. However, we know that the therapeutic efficacy of the treatment of recurrence is greater the earlier it is administered; that is, when the PSA levels are very low. These limitations have led to the development of new techniques with greater diagnostic accuracy such as PET/CT with choline-based radiopharmaceuticals labeled with [¹¹C] or with [¹⁸F], or the metabolism of amino acids ([¹⁸F]Fluciclovine) or PSMA ligands labeled with positron-emitter isotopes such as [⁶⁸Ga] and [¹⁸F].

PET/CT with [⁶⁸Ga]Ga-PSMA-11 presents a greater rate of detection of recurrence than PET/CT with [¹⁸F]F-Choline, independently of the PSA level, although this higher detection rate is more evident in patients with low PSA levels (< 0.5 ng/mL)⁴⁰. At present, a prospective, multicenter, phase II clinical trial (Phyton) is ongoing and is aimed at comparing the recurrence detection rate of PET/CT with [¹⁸F]F-DCFPyL versus PET/CT with [¹⁸F]F-Choline in patients with PC presenting the first biochemical relapse after initial intention to cure treatment. The results of this trial are expected in 2022 (EudraCT number 2020-000121-37)⁴¹. Another prospective clinical study comparing PET/CT with [¹⁸F]F-fluciclovine versus PET/CT with [⁶⁸Ga]Ga-PSMA-11 in patients with early recurrence of PC showed a significantly lower detection rate with [¹⁸F]F-fluciclovine (26%) compared to [⁶⁸Ga]Ga-PSMA-11 (56%). With this detection rate, PSMA should be the radiopharmaceutical of choice for the detection of recurrence in patients with PC and biochemical relapse after treatment with intention to cure and low PSA levels⁴²·

In the last years many studies with PSMA have been published, most with [⁶⁸Ga]Ga-PSMA-11, and have increased the knowledge of the utility of this diagnostic modality. Moreover, these studies have demonstrated that PET-PSMA has an impact on the clinical management of patients with PC, modifying the therapeutic decision in up to 54% of the patients⁴³. A systematic review by Perera and col. published in 2020 reported that the percentage of positive PET-PSMA increased with the PSA values. Thus, for PSA values < 0.2 ng/mL the rate of positivity was 33%, increasing to 45%, 59%, 75% and 95% for PSA values between 0.2-0.49, 0.5-0.99, 1-1.99 and >2 ng/mL; respectively. Likewise, no statistically significant differences were found between Gleason scores ≤ 7 and ≥ 8, and the rate of positive results was greater in patients receiving EBRT than in those undergoing RP (52% vs. 22%, respectively)³¹. However, one of the criticisms of these studies was the heterogeneity of the cohorts studied; including, for example, patients with different initial treatments, patients receiving ADT, etc. Patients primarily treated with EBRT should not be mixed with patients treated with RP since in the case of BR the PSA values between the two groups cannot be compared. Neither should patients receiving chemotherapy be included since this indicates advanced stages of the disease, and therefore, a greater probability of recurrence than in patients with earlier stages of the disease.

To overcome these limitations, Asfar-Oromieh and col. carried out a retrospective multicenter study including an elevated number of patients (n = 2012) with the objective of obtaining more robust results in relation to the functioning of PET/CT with [⁶⁸Ga]Ga-PSMA in patients with PC relapse after RP. They found that the probability of having a positive study increased with higher PSA values, ranging from 43% for PSA values ≤ 0.2 ng/mL to up to 93% for PSA > 10 ng/mL. The percentage of 100% was not achieved because there is a percentage of PC that does not express PSMA in prostatic neoplastic cells. They also found a significant association between a positive PET and higher Gleason scores; that is, with more aggressive tumors. However, they found no association between a positive study and the PSA doubling time, or with the speed of increase of PSA levels⁴⁴. The differences with other authors⁴⁵ in regard to the association with the doubling time and speed of PSA increase may be due to some strict criteria used in the inclusion of patients and the large sample size.

The EC CONDOR study was designed based on the previous results of the EC OSPREY study (NCT02981368)⁴⁶, which evaluated the role of PET/CT with [¹⁸F]F-DCFPyL in the initial staging of patients with PC of high risk and in the detection of metastatic lesion/suspicious relapse visualized in conventional imaging techniques. This was a prospective, multicenter, phase II trial (NCT03739684) aimed at studying the capacity of detection of tumoral disease by PET/CT with [¹⁸F]F-DCFPyL in patients with BR[48]. PET/CT with [¹⁸F]F-DCFPyL correctly localized the disease in 86% of the patients, all of whom had non conclusive results in conventional imaging studies. The rate of correct localization varied according to the PSA value; in patients with PSA values < 0.5 ng/mL the rate was 73.3% while in patients with PSA values >5 ng/mL it was 96.4%. The rate of detection of relapse increased with higher PSA values, ranging from 36.2% (< 0.5 ng/mL) to 96.7% (> 5 ng/mL). The PET findings modified the clinical management in 64% of the patients⁴⁷. These results support the use of PET/CT with [¹⁸F]F-DCFPyL for the localization of disease in patients with BR since it is significantly superior to that achieved with conventional imaging techniques (Fig. 2). Based on the OSPREY and CONDOR studies, in May 2021, the Food and Drug Administration of the United States approved the use of the PET-PSMA [¹⁸F]F-DCFPyL radiopharmaceutical for the identification of recurrence or metastasis in patients with PC. This has undoubtedly represented an advance since the recent 2022 NCCN guidelines recommend the use of PET-PSMA ([⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]F-DCFPyL) and PET/MR for the detection of recurrence. As specified in the guidelines, this is due to PET-PSMA presenting a “better sensitivity and specificity for detecting micrometastatic disease in comparison with conventional imaging (CR and MR)”³⁵. In Europe, the European Cancer Organization also recommends their use³⁶.

• •

  Key point: PET-PSMA should be the radiopharmaceutical of choice for the detection of recurrence in patients with PC following treatment with intention to cure and BR with low PSA levels (PSA < 0.5 ng/mL).

Fig. 2.

Comparison of maximum intensity projections (MIP) of [18F]F-Choline and [18F]F-DCFPyl in a patient with prostate cancer treated with radical prostatectomy presenting progressive elevation of PSA levels (2.13 ng/mL) and suspicion of biochemical recurrence. The study with [18F]F-Choline (A) did not detect the localization of recurrence. However, the study with [18F]F-DCFPyl (B) localized the site of recurrence as two hypermetabolic foci in the left internal iliac chain corresponding to lymph node infiltration. The deposits visualized on the right correspond to physiological ureteral retention of the radiopharmaceutical.

PET-PSMA in castration-resistant prostate cancer

Disease progression in a patient receiving ADT is called CRPC. This phase is defined a castrated serum testosterone < 50 ng/dl or 1.7 nmol/L together with biochemical progression (3 consecutive PSA elevations) and/or radiological progression³⁸. Cases demonstrating disease in the imaging studies are classified as metastatic CRPC (mCRPC) or, to the contrary, non-metastatic PC (nmCRPC). The natural evolution of nmCRPC is towards mCRPC, and the mean duration of this transition from the initiation of ADT is 19 months⁴⁸.

CRPC is a complex disease and during progression multiple pathways are activated, including an increase in PSMA expression and an activation of oncogenic pathways as a survival strategy of the tumor cells⁴⁹. Although debatable, ADT started in patients with CRPC does not condition a reduction in PSMA expression⁵⁰. Therefore, in this stage of the disease, a PET-PSMA study may be a useful tool for three key aspects: more accurate staging of the disease, for guiding the patient to the most adequate therapy and for evaluation of therapeutic response.

For correct disease staging several studies have described greater accuracy with PET-PSMA compared to the imaging techniques recommended by the different scientific societies in this stage of the disease (BS and CT)⁵¹. The greater accuracy of this technique is most evident in the detection of tumoral disease in patients in whom conventional imaging studies were negative, and were, thus, classified as nmCRPC⁵⁰. In a retrospective study including 200 patients with nmCRPC, PET-PSMA detected disease in 196 patients, 55% of whom presented distant metastasis (M1)⁵³. In line with these results, in a review of the literature from the last 10 years, Weber et al. determined that PET-PSMA identifies the true reach of CRPC, especially nmCRPC⁵² (Fig. 3). Nonetheless, the clinical benefits of this migration of nmCRPC to mCRPC is still not clear and further studies are needed to clarify if this represents an advantage in terms of survival. Notwithstanding, the 2022 NCCN guidelines have incorporated the use of PET-PSMA as a valid alternative to BS and CT for the evaluation of bone and tissue disease in patients with CRPC³⁵.

Fig. 3.

PET/CT study with [⁶⁸Ga]Ga-PSMA-11 in a patient with a history of Gleason 6 (3 + 3) prostate cancer treated with brachytherapy 10 years previously and current biochemical progression despite hormone treatment. Although the conventional imaging studies (CT and BS) were negative, PET-PSMA detected tumoral disease in the left acetabulum (blue arrow in 1b), left ischium (blue arrow in 2b) and left iliac crest (blue arrow in 3b) not visible in the radiological CT image of PET/CT (1a, 2a and 3a). The lesions were treated with stereotactic radiotherapy with PSA response at 8 months.

It is easy to understand that greater accuracy in defining the extension of the disease more accurately guides the most adequate therapy to implement. The results of PET-PSMA in the staging of CRPC have demonstrated that they can change the therapeutic management in up to 70% of the patients evaluated⁵⁴. In this sense, as occurs in hormone sensitive disease, the detection of oligometastatic progression (progression of a limited number of lesions under ADT) by PET-PSMA allows the administration of metastasis-directed therapies (MDT), such as stereotactic body radiation therapy (SBRT). The use of SBRT^55,56 has shown to be effective and well tolerated, prolonging the efficacy of ADT, and thereby delaying the need for next line systemic treatment. Nonetheless, at present, no prospective study has confirmed that the use of MDT directed by PET-PSMA improves the survival of patients with CRPC.

In addition, the use of PET-PSMA for evaluating the suitability of a patient as a candidate for radioligand therapy (RLT) has been studied. A study by Ahmadzadehfar et al. demonstrated that a greater proportion of patients staged with PET-PSMA and BS before therapy responded to radium-223 dichloride (Ra-223) treatment compared to those without a previous PET-PSMA study⁵⁷. This can likely be explained in that PET-PSMA improves the selection of patients by excluding patients with extraosseous disease who have a lower probability of response. In line with these results, Brauer et al. detected visceral disease by PET-PSMA in 15% of patients with mCRPC whose disease had been considered exclusively osseous⁵⁸. On the other hand, as shown in the next section, PET-PSMA is used in most centers in which PSMA-RLT is available, being the most important selection criteria for this therapy.

It can be considered that PET-PSMA is an effective tool for accurately evaluating therapeutic response in mCRPC, allowing the definition of changes that the treatment produces in tumor cells expressing PSMA. However, little is known of the effect of treatment on the mechanisms regulating PSMA expression, which is an aspect that needs to be clarified in future studies. However, as mentioned above, promising results in this respect have been reported in several studies such as the previously mentioned study by Ahmadzadefar et al. who demonstrated that following Ra-223 treatment PET-PSMA allowed even better evaluation of response than that provided by PSA⁵⁷. Evaluation of treatment efficacy is usually evaluated by the response of PSA. However, as Han reported in their meta-analysis⁵⁹, response evaluated by PET-PSMA and by PSA is discordant in almost one fourth of the patients with mCRPC treated with systemic therapies (chemotherapy with taxanes, PSMA-RLT, Ra-223 or combined therapy). Therefore, more studies are needed to establish the clinical significance of this discordance since PET-PSMA could represent a better tool than PSA for evaluating response to treatment.

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  Key points: PET-PSMA is a valid alternative to conventional imaging studies (BS and CT) for the evaluation of bone and tissue disease in patients with CRPC.

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  PET-PSMA can localize relapse in an elevated proportion of patients considered as nmCRPC in conventional imaging studies.

Therapy with PSMA ligands

The concept of theragnosis, which is the combination of the terms therapeutic and diagnostic applied in nuclear medicine, is based on the ability of using the same radiopharmaceutical for two different applications by only changing the isotope used from a gamma-emitter for diagnostic purposes to a beta- or alpha-emitter for therapeutic purposes. This concept, which is already used in nuclear medicine for other diseases such as neuroendocrine tumors (⁶⁸Ga-DOTATATE/177Lu-DOTATATE), has recently begun to be applied in mCRPC using radiopharmaceutical ligands of PSMA inhibitors with excellent results. The two beta-emitter radiopharmaceuticals usually used for PSMA-RLT ([¹⁷⁷Lu]-PSMA-617 and [¹⁷⁷Lu]-PSMA-I&T) were initially developed in Germany and used in a compassion-focused therapy program, which led to the collection of multiple series of patients with results, showing that therapy with [¹⁷⁷Lu]-PSMA-617 was effective and well tolerated in patients with mCRPC.

PSMA-RLT consists of the administration of 7.4 GBq of [¹⁷⁷Lu]-PSMA per cycle for a total of 4-6 cycles with an interval of 6-8 weeks. The response rate with a reduction in PSA of > 50% (PSA₅₀) in the whole of these first studies was 46%⁶⁰. These data were corroborated in the first prospective phase II performed in Australia, albeit with even higher response rates, with reductions in PSA₅₀ in 64% of the cases⁶¹. One of the possible hypotheses to explain these differences in the rate of response could be the use of more selective inclusion criteria in the Australian study based on the evaluation of intra-patient tumoral heterogeneity using dual molecular imaging: PET-FDG and PET-PSMA. The use of FDG in PC is not recommended in initial stages of the disease since well differentiated prostatic cells hardly express the Glut-1 transporter, thereby impeding the incorporation of FDG in their interior and leading to negative PET results. However, when prostatic neoplastic disease evolves to advanced metastatic stages with the presence of aggressive dedifferentiated clones, the uptake of FDG increases. Thus, the use of PET-FDG can be considered as a prognostic biomarker in patients with metastatic PC, providing a use in the selection of patients similar to that with FDG in neuroendocrine tumors. The use of both studies in the same patient (PET-FDG and PET-PSMA) can: 1) verify if the therapeutic target (PSMA) is present in all the metastatic lesions, and 2) detect the presence of “aggressive” metastatic disease with positive hypermetabolic FDG lesions. Cases in which positive FDG are detected but they do not express PSMA are defined as “mismatch” or FDG+/PSMA- discordance. In these cases, the aggressiveness of positive FDG lesions determines the final prognosis of the patient and the efficacy of PSMA-RLT is drastically reduced. That is why mismatch patients treated with [¹⁷⁷Lu]-PSMA-617 present a lower overall survival than patients who do not present discordance (6 months versus 16 months, respectively)⁶². This dual imaging criteria was also used as exclusion criteria in the first recently published randomized phase II study. In addition to excluding patients with discordance, a minimum expression of PSMA was required in all the lesions (with a SUVmax > 10) and at least one lesion with a SUVmax > 20. This study (TheraP) was performed in patients with mCRPC and compared the use [¹⁷⁷Lu]-PSMA-617 with a second line of chemotherapy with cabazitaxel. The results were in favor of [¹⁷⁷Lu]-PSMA-617 in all the aspects⁶³. In terms of efficacy, [¹⁷⁷Lu]-PSMA-617 practically doubled the results obtained with cabazitaxel: PSA₅₀ response (66% vs. 37%) and objective radiological response based on Response Evaluation Criteria in Solid Tumors 1.1 (49% vs. 24%). Patients treated with [¹⁷⁷Lu]-PSMA-617 presented a reduction of the risk of progression of 37%, with progression-free survival at 12 months of 19% versus 3% with cabazitaxel. In terms of toxicity, the study arm treated with [¹⁷⁷Lu]-PSMA-617 presented a lower percentage of severe grade 3-4 adverse effects (33%) compared with the group treated with cabazitaxel (53%). Based on these excellent results and while awaiting the overall survival results yet to be published, PSMA-RLT is currently considered an effective third line systemic treatment in patients with mCRPC previously treated with a line of new generation ADT treatment (enzalutamide or abiraterone) and a line of chemotherapy with docetaxel.

The first and only randomized phase II study published to date is the VISION trial⁶⁴. This study was mainly aimed at obtaining authorization for the commercialization of PSMA-RLT, with progression-free survival and overall survival as the main variables of evaluation. This study included patients with mCRPC who had received at least one line of new ADT and one or two lines of chemotherapy with taxanes. The patients were randomized into two study arms: [¹⁷⁷Lu]-PSMA-617 and standard treatment vs. standard treatment alone. The standard treatment did not accept either chemotherapies or other antineoplastic treatments such as immune therapy or Ra-223. In this case, the use of dual molecular imaging with FDG was not an inclusion criterion, but the study did require pretherapeutic PSMA-PET/CT with the presence of at least one metastatic lesion with PSMA expression higher than the hepatic physiological activity and the absence of lesions measurable by CT that did not express PSMA. With these imaging criteria they excluded 12% of patients, leading to the inclusion of a total of 851 patients. The results were in favor of [¹⁷⁷Lu]-PSMA-617. The study showed a reduction in the risk of death and the risk of progression of 38% and 60%, respectively. The median overall survival and progression-free survival were 15.3 and 18.7 months, respectively in the patients treated with [¹⁷⁷Lu]-PSMA-617 and 11.3 and 3.4 months in the control arm. Therapeutic PSA₅₀ response was observed in 46% of the cases versus 7% in the standard treatment arm alone. Likewise, this study demonstrated that PSMA-RLT can delay the appearance of symptomatic bone events by 5 months. Nonetheless, since chemotherapy, immune therapy or Ra-223 were not included in the standard treatment, it is not possible to compare the results obtained with those of these therapies which may also have effects on bone.

Despite occasionally being heterogeneous, the positive results obtained in different studies demonstrate that optimization of patient selection improves PSMA-RLT results. In this sense different independent predictive factors of response and survival have been described using multivariate analyses. The presence of hepatic metastasis, the basal hemoglobin value, or the intensity of PSMA expression in the pretherapeutic PET are some examples. Although not a determining factor, the use of these factors provides additional information that can be used during decision making⁶⁵. On one hand, the response to treatment is usually evaluated after 12 weeks; that is, after 2 cycles, with patients presenting a reduction of PSA₅₀ at 12 weeks being those presenting greater benefits in terms of overall survival.

With regard to the tolerability of RLT, the studies published to date demonstrate that this therapy is well tolerated with a very low percentage of acute secondary effects during or in the first hours post-administration. The most frequent secondary effects are mild nausea, normally well controlled with the use of antiemetics on demand, fatigue and xerostomy, since PSMA is physiologically expressed in the salivary and lacrimal glands. Despite various attempts at reducing the uptake of PSMA ligands in the salivary glands, there is currently no strategy that has demonstrated to be effective in this regard. Xerostomy is usually mild, and patients recover on finalization of the treatment. However, the effect is greater with the use of alpha isotopes such as actinium-225 (²²⁵Ac), leading to total permanent xerostomy in some cases and deterioration in the quality of life. Despite presenting mainly renal excretion, PSMA-RLT is not considered a nephrotoxic treatment, since only 3% of the cases develop severe renal toxicity. Nonetheless, it is important to evaluate renal function before beginning treatment, recommending the use of a nephrogram to exclude possible ureteral obstruction. Seventy percent of renal excretion occurs during the first 12 hours post administration, which is why the treatment is exclusively performed in hospital centers with rooms prepared to collect urine in specific containers. The main long-term secondary effect is bone marrow toxicity with leucopenia or thrombocytopenia (described in around 15% of the cases) as well as anemia (in 30%), which, on occasions, requires a therapeutic break or a reduction in the activity administered. Thus, it is important to ensure regular follow-up with the measurement of hemoglobin values and neutrophil and platelet counts before each new cycle.

The future of PSMA-RLT treatment is aimed at evaluating the efficacy of its combination with other systemic treatments such as immune therapy or the use of alpha-emitting isotopes such as actinium-225 (²²⁵Ac) ( in early stages of the disease. The results of the first studies with [²²⁵Ac]-PSMA-617 are promising, with excellent responses in patients who progressed prior to [¹⁷⁷Lu]-PSMA-617. Despite the important toxicity of the alpha emitters in the salivary glands, the rate of response in the last meta-analysis published was 59%⁶⁶. With the aim of maximizing the therapeutic effect of [²²⁵Ac]-PSMA-617 and minimizing its toxicity, different strategies are currently being studied such as the use of combined therapies (the so-called cocktails), in which [¹⁷⁷Lu]-PSMA-617 and a decreasing dose of [²²⁵Ac]-PSMA-617 are used sequentially or simultaneously.

Finally, with the excellent results obtained with PSMA-RLT together with the high prevalence of PC in Spain it can be predicted that there will be an exponential increase in the demand for PSMA-RLT in the next years. The adaptation of the Nuclear Medicine Departments to take in this demand as well as the training of nuclear medicine physicians in the therapeutic management of patients with advanced PC are essential. It should also be noted that in all these diagnostic and therapeutic procedures multidisciplinary work is essential as described in the recommendations of the ECCO [36].

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  Key points: Treatment with [177Lu]-PSMA-617 has demonstrated to be an effective third line treatment in patients with mCRPC in a randomized phase III study.

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  In comparison with cabazitaxel, [177Lu]-PSMA-617 has shown to be a more effective and less toxic treatment, and also provides longer progression-free survival and a reduction in bone events.

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  Pretherapeutic images with PSMA-PET/CT are necessary to adequately select the patients who can be candidates to PSMA-RLT, ensuring minimum PSMA expression in metastatic lesions. In this sense, the use of dual imaging allows optimizing the selection of patients excluding those who present aggressive disease with PSMA expression (“mismatch” FDG+/PSMA-).

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  Treatment with alpha isotopes such as [225Ac] -PSMA-617 seems to be promising but has a limiting factor of possible severe xerostomy. Different therapeutic strategies are currently under evaluation.

Conclusion

The use of PSMA radioligands has led to important advances in the diagnosis (by PET molecular imaging) and treatment of PC. On one hand, its use allows significantly more accurate staging than conventional imaging techniques in tumors of high or intermediate risk. In addition, it has demonstrated the ability to localize disease in a significant number of patients with biochemical recurrence following intention to cure treatment when PSA values are still very low (<0, 5 ng/mL). Likewise, its use is a valid alternative to conventional imaging studies in the evaluation of bone and tissue disease in patients with CRPC, and even allows detecting the presence of metastasis in patients classified as nmCRPC by CT or BS. On the other hand, its use as PSMA-RLT has shown to be effective and safe in patients with mCRPC previously treated with a line of new generation antiandrogens and a chemotherapy line with docetaxel.