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cancers
Review
PSMA Theranostics: Current Landscape and Future Outlook
Hanbo Zhang 1, Stella Koumna 2, Frédéric Pouliot 3, Jean-Mathieu Beauregard 4and Michael Kolinsky 5, *
Citation: Zhang, H.; Koumna, S.;
Pouliot, F.; Beauregard, J.-M.;
Kolinsky, M. PSMA Theranostics:
Current Landscape and Future
Outlook. Cancers 2021,13, 4023.
https://doi.org/10.3390/
cancers13164023
Academic Editor: Felix M. Mottaghy
Received: 4 July 2021
Accepted: 6 August 2021
Published: 10 August 2021
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Copyright: © 2021 by the authors.
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Attribution (CC BY) license (https://
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4.0/).
1
Department of Medical Oncology and Hematology, University of Manitoba, Winnipeg, MB R3E 0V9, Canada;
hzhang2@cancercare.mb.ca
2Department of Diagnostic Imaging, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada;
Stella.Koumna@albertahealthservices.ca
3
Department of Surgery, UniversitéLaval, Québec City, QC G1R 3S1, Canada; frederic.pouliot@fmed.ulaval.ca
4Department of Radiology and Nuclear Medicine, UniversitéLaval, Québec City, QC G1R 3S1, Canada;
jean-mathieu.beauregard@crchudequebec.ulaval.ca
5Department of Medical Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada
*Correspondence: michael.kolinsky@albertahealthservices.ca
Simple Summary:
The prognosis for metastatic prostate cancer patients remains poor. Prostate-
specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a promising target for
both imaging and therapy. In this review paper, we provide an overview of the evidence for PSMA-
targeted imaging in prostate cancer, focusing on different imaging modalities and their theranostic
applications. We will also review PSMA-targeted radioligand therapy, focusing on lutetium-177
radioligand therapy and alpha-emitting radioligand therapy with actinium-225. Combination reg-
imens with lutetium-177 and other systemic therapy agents will be reviewed. Antibody-based
radioimmunotherapy will also be discussed along with other noteworthy radionuclide agents.
Abstract:
Introduction: Prostate-specific membrane antigen (PSMA) is a promising novel molecular
target for imaging diagnostics and therapeutics (theranostics). There has been a growing body of
evidence supporting PSMA theranostics approaches in optimizing the management of prostate
cancer and potentially altering its natural history. Methods: We utilized PubMed and Google Scholar
for published studies, and clinicaltrials.gov for planned, ongoing, and completed clinical trials in
PSMA theranostics as of June 2021. We presented evolving evidence for various PSMA-targeted
radiopharmaceutical agents in the treatment paradigm for prostate cancer, as well as combination
treatment strategies with other targeted therapy and immunotherapy. We highlighted the emerging
evidence of PSMA and fluorodeoxyglucose (FDG) PET/CT as a predictive biomarker for PSMA
radioligand therapy. We identified seven ongoing clinical trials in oligometastatic-directed therapy
using PSMA PET imaging. We also presented a schematic overview of 17 key PSMA theranostic
clinical trials throughout the various stages of prostate cancer. Conclusions: In this review, we
presented the contemporary and future landscape of theranostic applications in prostate cancer
with a focus on PSMA ligands. As PSMA theranostics will soon become the standard of care for
the management of prostate cancer, we underscore the importance of integrating nuclear medicine
physicians into the multidisciplinary team.
Keywords:
prostate-specific membrane antigen; theranostics; positron emission tomography; radioli-
gand therapy; prostate cancer
1. Introduction
Prostate cancer represents a significant public health problem in the world. It is the
second most common cancer and fifth leading cause of cancer death among men in 2020 [
1
].
While most patients initially present with localized disease and can be offered curative
intent therapies, including surgery and external-beam radiation therapy, a significant pro-
portion of patients initially present with or will later develop metastatic disease. Androgen
deprivation therapy (ADT) is the mainstay of therapy for metastatic and recurrent prostate
Cancers 2021,13, 4023. https://doi.org/10.3390/cancers13164023 https://www.mdpi.com/journal/cancers
Cancers 2021,13, 4023 2 of 17
cancer, but nearly all patients will eventually develop castration-resistance. Despite signifi-
cant advances in systemic therapy options, the prognosis for metastatic castration-resistant
prostate cancer (mCRPC) is poor, with overall survival under two years [2].
Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein
receptor that is overexpressed (up to 1000 times more than normal prostate cells) in most
prostate cancers (>90%). PSMA is normally expressed in the renal tubules and duodenum,
in which it plays an essential role in the processing and uptake of dietary folates, and in
the brain, where it plays a major role in modulating the output of glutamate signaling.
The biological function of PSMA in prostate cancer remains elusive, although evidence
suggests its role in activation of PI3K-Akt signaling in prostate cancer through release of
glutamate as messenger molecule [
3
]. The level of expression may increase with tumor
dedifferentiation and castration resistance, although neuroendocrine prostate cancer may
have a decreased level of PSMA [
4
]. Even though this antigen is not entirely specific to
prostate cancer cells, it can serve as a target for imaging and therapy due to its tumoral
overexpression with relatively low toxicity to healthy tissues showing uptake [5].
2. PSMA PET Imaging in Prostate Cancer
2.1. Imaging Modalities
Many PSMA-targeting small molecule and antibody agents have been developed and
tested for imaging by single-photon emission computerized tomography (SPECT) and
positron emission tomography (PET). Compared to anti-PSMA antibodies, small-molecule
PSMA inhibitors are preferable as PET imaging agents due to faster tumor uptake and more
rapid excretion, which enhance contrast and reduce radiation exposure [
6
,
7
]. Currently,
the most developed radioligands for imaging include gallium-68-labeled PSMA-11 (68Ga-
PSMA-11), gallium-68-labeled PSMA-I&T (
68
Ga-PSMA-I&T), and fluorine-18 (
18
F) labeled
PSMA ligands, including
18
F-DCFPyL and
18
F-PSMA-1007. There is no consensus as
to the optimal PSMA radioligand. Currently,
68
Ga-PSMA-11 and
18
F-DCFPyL are the
only FDA-approved radioligands for PSMA-targeted PET imaging in men with prostate
cancer [8,9].
The fluorinated agents have the advantage of a longer half-life which allows for central
production and distribution over longer distances as well as lower positron energy that
can lead to improved imaging quality. 18F-PSMA-1007 has been found to have diagnostic
accuracy comparable to
68
Ga-PSMA-11 for detection of biochemically recurrent prostate
cancer, with the advantage of minimal excretion in the urinary tract, which allows for better
detection of prostate bed recurrences [
10
,
11
]. However, cautions need to be taken when
interpreting
18
F-PSMA-1007 PET scans, as there have been reports of focal unspecific bone
uptake, defined as focal mild-to-moderate uptake (SUVmax < 10.0) not obviously related
to a benign or malignant cause [12].
2.2. Clinical Applications of PSMA-Targeted Imaging
PSMA-targeted imaging has been extensively explored in primary staging and restag-
ing of prostate cancer. Conventional imaging with CT, MRI and bone scan have limited
sensitivity and specificity for detecting occult metastatic disease, particularly in the setting
of low PSA values [
13
]. Prospective studies have demonstrated advantage of PSMA-
targeted imaging in both primary staging, as well as in the biochemical recurrence setting
in providing useful clinical information that may ultimately change management [
14
–
17
].
Various international guidelines have recommended PSMA-PET imaging to be performed
for the clarification of equivocal findings, particularly if the results will influence subse-
quent treatment decisions [18,19].
Recent evidence has suggested that treatment of the primary tumor or metastasis-
directed therapy (MDT) in carefully selected patients with low-volume metastatic prostate
cancer may confer a survival advantage [
20
]. Improved detection of metastatic prostate
cancer using PSMA-targeted imaging may improve the success rate of MDT. ORIOLE is
a randomized phase 2 study investigating whether stereotactic body radiation therapy
Cancers 2021,13, 4023 3 of 17
(SBRT) for recurrent oligometastatic metastatic hormone-sensitive prostate cancer can
improve survival outcomes compared to observation. Patients with oligometastatic disease
(3 or fewer lesions) identified by conventional imaging were randomized to either SBRT
to all metastatic lesions or observation. Salvage RT to the prostate bed or pelvis was
permitted. Those randomized to MDT underwent
18
F-DCFPyL PET/CT prior to MDT.
The treating radiation oncologists were blinded to the result of PSMA scans and treatment
plans were based on conventional imaging. The PSMA scans were compared to the SBRT
treatment plans, and patients were categorized as having total or subtotal consolidation
of PSMA-avid lesions. In the SBRT arm, disease progression at six months was 10% vs.
61% in the observation arm (p= 0.005). For those who received total consolidation, rate
of new metastases at six months was 16% vs. 63% in those with subtotal consolidation
(p= 0.006). Remarkably, median distant metastasis-free survival was 29 months in those
with total consolidation vs. six months in those with any untreated lesions [
21
]. This study
illustrates the important role of PSMA-imaging in guiding and optimizing therapeutic
efficacy of MDT.
With the advent PSMA-targeted imaging, there are many ongoing clinical trials in
oligometastatic-directed therapy (Table 1) in both the castration-sensitive and castration-
resistant settings, involving various treatments strategies. Although it is encouraging to see
early indications of benefit with the use of PSMA-targeted imaging in guiding treatment of
oligometastatic prostate cancer, further evidence regarding efficacy, safety, and quality of
life needs to be obtained prior to establishing this approach as the standard of care.
Table 1. Ongoing clinical trials in oligometastatic-directed therapy using PSMA PET imaging.
Clinical Trial
Identifier. Study Description Phase
NCT04302454 MDT +/−ADT in oligo-recurrent hormone-sensitive prostate cancer (ADOPT) 3
NCT04222634 MDT in oligometastatic mCRPC (MEDCARE) 2
NCT03902951 SBRT with ADT, abiraterone and apalutamide for oligometastatic hormone-sensitive
prostate cancer 2
NCT03795207 SBRT +/−durvalumab in oligometastatic recurrent hormone-sensitive prostate cancer
(POSTCARD) 2
NCT03569241 MDT +/−whole pelvic radiation for oligorecurrent nodal prostate cancer (STORM) 2
NCT03298087
Newly diagnosed oligometastatic hormone-sensitive prostate cancer treated with radical
prostatectomy, metastasis-direct SBRT, ADT, abiraterone and apalutamide 2
NCT02974075 Salvage lymph node dissection of nodal recurrence after radical prostatectomy with
curative intent 1/2
2.3. Biomarker for Evaluating Treatment Response
PSMA-targeted imaging has been explored as a biomarker for assessment of treatment
response. However, this can be challenging as PSMA avidity can be affected by a multitude
of factors such as castration-sensitive versus castration-resistant disease, timing and type of
therapy received, and location of the lesions. PSMA expression appears to be upregulated
with ADT and androgen-axis inhibitors such as enzalutamide in the first three months
of treatment initiation [
22
,
23
]. PSMA response heterogeneity has also been reported
for patients on ADT, with a higher PSMA response in nodal lesions compared to non-
nodal lesions [
24
]. In one study, chemotherapy with docetaxel seems to have reasonable
correlation between changes in PSMA avidity and RECIST measurements, although the
correlations between PSA, RECIST and PSMA avidity were not completely concordant in
those who were partial responders as per RECIST [25].
According to consensus statements on PSMA PET/CT response assessment crite-
ria, from a panel of international experts recruited by European Association of Nuclear
Medicine (EANM) and EAU (European Association of Urology), PSMA PET/CT should
not be performed to assess response within three months after initiation of systemic therapy
in hormone sensitive prostate cancer. The panel also recommended that PSMA PET/CT
Cancers 2021,13, 4023 4 of 17
response assessment should be implemented and evaluated only in the context of clinical
trials [
26
]. PSMA imaging as a response/progression biomarker is somewhat promising,
although significant research in this field is required.
3. PSMA-Targeted Radioligand Therapy
3.1. Overview
Prostate cancer is sensitive to radiotherapy (RT), in which various forms of RT, such as
external beam RT (EBRT) and brachytherapy, have become standard treatment options for
localized prostate cancer, and SBRT is currently explored in patients with oligometastatic
prostate cancer. Systemic radiation with alpha particle-emitting calcium mimetic Radium-
223 (
223
Ra) has been established for metastatic prostate cancer localized to the bone [
27
].
Concurrent with the development of PSMA-targeted imaging, the application of PSMA-
targeted radioligand therapy is an ongoing area of great potential, and several PSMA-
targeted radiopharmaceuticals have been developed for the treatment of advanced prostate
cancer which enable the delivery of radiation to both bone and soft tissue tumor sites.
Figure 1illustrates a schematic overview of active PSMA-targeted radioligand therapy
trials. Table 2contains a descriptive summary of these trials.
Cancers 2021, 13, x 4 of 17
non-nodal lesions [24]. In one study, chemotherapy with docetaxel seems to have reason-
able correlation between changes in PSMA avidity and RECIST measurements, although
the correlations between PSA, RECIST and PSMA avidity were not completely concordant
in those who were partial responders as per RECIST [25].
According to consensus statements on PSMA PET/CT response assessment criteria,
from a panel of international experts recruited by European Association of Nuclear Med-
icine (EANM) and EAU (European Association of Urology), PSMA PET/CT should not be
performed to assess response within three months after initiation of systemic therapy in
hormone sensitive prostate cancer. The panel also recommended that PSMA PET/CT re-
sponse assessment should be implemented and evaluated only in the context of clinical
trials [26]. PSMA imaging as a response/progression biomarker is somewhat promising,
although significant research in this field is required.
3. PSMA-Targeted Radioligand Therapy
3.1. Overview
Prostate cancer is sensitive to radiotherapy (RT), in which various forms of RT, such
as external beam RT (EBRT) and brachytherapy, have become standard treatment options
for localized prostate cancer, and SBRT is currently explored in patients with oligometa-
static prostate cancer. Systemic radiation with alpha particle-emitting calcium mimetic
Radium-223 (223Ra) has been established for metastatic prostate cancer localized to the
bone [27]. Concurrent with the development of PSMA-targeted imaging, the application
of PSMA-targeted radioligand therapy is an ongoing area of great potential, and several
PSMA-targeted radiopharmaceuticals have been developed for the treatment of advanced
prostate cancer which enable the delivery of radiation to both bone and soft tissue tumor
sites. Figure 1 illustrates a schematic overview of active PSMA-targeted radioligand ther-
apy trials. Table 2 contains a descriptive summary of these trials.
Figure 1. Schematic overview of selected PSMA theranostics clinical trials as of June 2021.
Figure 1. Schematic overview of selected PSMA theranostics clinical trials as of June 2021.
Table 2. Selected key PSMA theranostics clinical trials as of June 2021.
Clinical Trial
Identifier Brief Study Description Phase
NCT04430192 177Lu-PSMA-617 prior to prostatectomy (LuTectomy) 1/2
NCT04343885 Sequential 177Lu-PSMA-617 + docetaxel vs. docetaxel in mHSPC (UpFrontPSMA) 2
NCT04720157 177Lu-PSMA-617 + SOC vs. SOC alone in mHSPC (PSMAddition), 3
NCT04443062 177Lu-PSMA-617 in oligometastatic mHSPC (Bullseye) 2
NCT04419402 Enzalutamide + 177Lu-PSMA-617 vs. Enzalutamide alone in mCRPC (ENZA-P)) 2
ACTRN12615000912583
177Lu-PSMA-617 in progressive mCRPC (LuPSMA) 2
NCT0392428 177Lu-PSMA-617 vs. cabazitaxel in progressive mCRPC (TheraP) 2
NCT03511664 177Lu-PSMA-617 + SOC vs. SOC in progressive mCRPC (VISION) 3
NCT03874884 177Lu-PSMA-617 + olaparib in progressive mCRPC (LuPARP) 1
Cancers 2021,13, 4023 5 of 17
Table 2. Cont.
Clinical Trial
Identifier Brief Study Description Phase
NCT03658447 177Lu-PSMA-617 + pembrolizumab in progressive mCRPC (PRINCE) 1/2
NCT04647526 177Lu-PSMA-I&T vs. ARAT in progressive mCRPC (SPLASH) 3
NCT04597411 225Ac-PSMA-617 in progressive mCRPC (AcTION) 1
NCT00538668 177Lu-J591 Antibody in progressive mCRPC 1
NCT04506567 225Ac-J591 Antibody in progressive mCRPC 1/2
NCT03724747 227Th-PSMA-TTC in progressive mCRPC 1
NCT03939689 131I-MIP-1095 + enzalutamide in progressive mCRPC (ARROW) 1
NCT03490838 177Lu-PSMA-R2 in progressive mCRPC 1/2
3.2. PSMA and Fluorodeoxyglucose (FDG) PET/CT as Predictive Biomarker for PSMA
Radioligand Therapy
The intensity of uptake (avidity) in PSMA PET/CT represents the PSMA expression in
prostate cancer cells. The level of avidity generally increases with tumor dedifferentiation
and castration resistance. However, dedifferentiated neuroendocrine prostate cancer maybe
an exception in which PSMA-avidity can be low owing to suppression of PSMA gene
(FOLH1) [
4
]. Pretreatment imaging is necessary prior to PSMA radioligand therapy to
document the presence of PSMA-avid lesions. Currently, there is no established exact level
of PSMA-avidity considered adequate for treatment eligibility. However, most centers
consider 1.5 as the minimum ratio of the mean standardized uptake value (SUVmean) of
the lesion to liver [
28
]. Based on a recent meta-analysis, PSMA-avidity is predictive of
response to PSMA radioligand therapy with improved OS [
29
]. Higher PSMA-avidity is
associated with higher radioligand uptake which allows cancer lesions to be exposed to a
higher radiation dose [
30
]. Furthermore, the change in SUVmax of the metastatic lesions
may have an association with PSA response [31].
18
F-fluorodeoxyglucose (FDG) is a PET tracer that is preferentially taken up by cancer
cells due to increased glucose metabolism known as “Warburg effect” [
32
]. FDG-PET is
commonly used to stage, detect recurrences, and monitor response to therapies for various
types of cancers such as lymphoma, melanoma, colorectal, esophageal, breast and lung [
33
].
In prostate cancer, the utility of FDG-PET is less established due to studies showing
conflicting results for sensitivity [
34
,
35
]. This is likely due to the fact that prostate cancers
demonstrate a wide variety of differentiation with varying degrees of aggressiveness. FDG
uptake has been reported to be higher in prostate cancer with higher grades (Gleason score
> 7) and more aggressive behaviors, especially in dedifferentiated and castration-resistant
prostate cancer [
35
–
37
]. FDG-PET appears to be a prognostic biomarker in mCRPC patients.
In a cohort study, 133 patients with mCRPC underwent imaging with
18
F-FDG and
18
F-
fluorodihydrotestosterone (FDHT), which is an androgen receptor probe. Patients with
more than 12 FDG-avid lesions had a significantly worse OS than their counterparts. The
study also demonstrated an increased risk of death in patients with discordant lesions
(positive FDG-avid lesion but negative androgen receptor expression with
18
F-FDHT) [
38
].
Tumor sites with low PSMA-avidity and high FDG-avidity represent sites of aggressive
disease which cannot be effectively targeted by radioligand therapy. Discordance between
PSMA-PET and FDG-PET has been observed in very advanced mCRPC, with dismal OS of
2.5 months based on the LuPSMA trial [
28
]. Thus, FDG-PET maybe a useful imaging tool
in conjunction with PSMA-PET to better select patients for PSMA radioligand therapy. This
may help explain the higher response rates observed in the Australian trials of LuPSMA
and TheraP in which stringent imaging selection criteria was applied which required
patients to have highly PSMA avid disease without any FDG-positive/PSMA-negative
lesions (discordant) [
28
,
39
]. Similarly, this patient selection strategy has been accepted
and applied in peptide receptor radionuclide therapy (PRRT) with
177
Lu-DOTATATE in
patients with neuroendocrine tumors, in which FDG-PET is recommended to be used in
Cancers 2021,13, 4023 6 of 17
conjunction with somatostatin-receptor (SSR) imaging to exclude patients with discordant
lesions (FDG-positive/SSR-negative) from receiving PRRT treatment [40].
3.3. Lutetium-177 PSMA Radioligand Therapy
3.3.1. Introduction
Lutetium-177 (
177
Lu) is a beta-emitting radioisotope that has a mean energy of
133.6 keV with maximum penetration depth of <2 mm and 6.7-days half-life [
41
,
42
]. Due
to its favorable physical properties and the feasibility of post-treatment scintigraphy as-
sessment,
177
Lu labelled PSMA has been studied extensively to date and it has become a
promising new therapeutic approach for treatment of mCRPC. The most studied of the
177
Lu labelled PSMA radioligands include
177
Lu-PSMA-I&T (imaging and therapy) and
177
Lu-PSMA-617, with the latter being preferred owing to reduced kidney uptake [
43
].
Since 2015, an increasing number of studies have reported encouraging safety and efficacy
of
177
Lu-PSMA radioligand therapy [
42
]. According to a systemic review of 12 studies and
669 mCRPC patients who were treated with
177
Lu-PSMA radioligand therapy in the 3rd
line setting, 44% of treated patients had PSA decline
≥
50% or more, with median overall
survival of 14 months [43].
3.3.2. 177Lu-PSMA-617
In the first prospective single-arm phase 2 study (LuPSMA),
177
Lu-PSMA-617 has
demonstrated PSA decline >50% in 57%, improvements in pain, and median PFS and OS
of 7.6 months and 13.5 months, respectively in heavily pretreated mCRPC patients. The
treatment was well tolerated with grade 1 xerostomia being the most common adverse
event (87%) and grade 3–4 thrombocytopenia in 27% of patients [28].
Cabazitaxel is a chemotherapy agent for patients with mCRPC who have progressed af-
ter previous treatment with docetaxel. Based on the CARD study, cabazitaxel is the current
standard of care for treatment for patients who have progressed on one of androgen-
receptor-axis-targeted therapies (ARATs) (abiraterone or enzalutamide) and docetaxel [
44
].
TheraP is a randomized phase 2 clinical trial conducted by the Australian and New
Zealand Urogenital and Prostate Cancer Trial Group (ANZUP) evaluating
177
Lu-PSMA-617
(
6.0–8.5 GBq
intravenously every six weeks for up to six cycles) vs. cabazitaxel (20 mg/m
2
intravenously every three weeks for up to 10 cycles) for mCRPC patients who have pro-
gressed on docetaxel. The majority (91%) of patients on the trial had prior ARAT. In this
study, the
177
Lu-PSMA-617 arm had an improved PSA response rate (PSA reduction
≥
50%)
of 66% vs. 37% for cabazitaxel, as well as improved one-year PFS rate of 19% vs. 3% (HR
0.63, 95% CI 0.46–0.86; p= 0.003) with a median follow-up of 18.4 months. Objective
response rate (ORR) was significantly greater in
177
Lu-PSMA-617 arm (49% vs. 24%, RR
2.1, 95%CI 1.1–4.1; p= 0.019). Pain response was also numerically higher with
177
Lu-PSMA-
617 (60% vs. 43% compared to chemotherapy. The safety profile was also favorable for
177
Lu-PSMA-617, with Grade 3 or 4 AEs of 35% (neutropenia 4%, thrombocytopenia 11%,
and fatigue 5%) versus 54% for cabazitaxel [
39
]. This study suggests that
177
Lu-PSMA-617
is a promising alternative to cabazitaxel in men who have progressed following docetaxel
for mCRPC.
The VISION study (NCT03511664) is an international phase 3 randomized trial of
177
Lu-PSMA-617 (7.4 GBq every six weeks
×
six cycles) plus best standard/standard-of-
care (SOC) versus best SOC care alone in heavily-pretreated mCRPC patients who have
received at least one ARAT and were previously treated with 1–2 taxane chemotherapy
regimens. The study enrolled 831 patients with 551 patients allocated to
177
Lu-PSMA-
617 + SOC. Over a median follow-up of 20.9 months, treatment with
177
Lu-PSMA-617
significantly improved OS by a median of 4.0 months (median OS, 15.3 vs. 11.3 months; HR,
0.62 (95% CI: 0.52, 0.74); p< 0.001, one-sided), compared to SOC alone. The radiological
PFS (rPFS) was also improved by treatment with
177
Lu-PSMA-617 + SOC compared to
SOC alone (median rPFS, 8.7 vs. 3.4 months; HR, 0.40 (99.2% CI: 0.29, 0.57); p< 0.001,
one-sided). Overall
177
Lu-PSMA-617 therapy was well tolerated. This is the largest and
Cancers 2021,13, 4023 7 of 17
latest prospective study to date investigating
177
Lu-PSMA-617 in treatment of mCRPC.
The positive results of this study support the adoption of
177
Lu-PSMA-617 as a standard
armamentarium against advanced PSMA-positive mCRPC [45].
3.3.3. 177Lu-PSMA-I&T
PSMA-I&T is a small molecule PSMA inhibitor initially developed in Germany in 2015.
177
Lu-PSMA-I&T has similar PSMA-affinity, dosimetry and pharmacokinetics profile com-
pared to
177
Lu-PSMA-617 [
44
]. In a retrospective study, 56 patients with mCRPC received
a total of 125 cycles, with mean dose of 5.76 GBq per cycle. PSA PFS was 13.7 months with
58.9% of patients achieving >50% PSA decline. The kidneys and parotid gland had the
highest absorbed doses [
46
]. The largest cohort of patients treated with
177
Lu-PSMA- I&T
consisted of 100 mCRPC patients, who underwent 319 cycles with a mean dose of 7.4 GBq.
PSA decline over 50% was seen in 38% of patients with PSA PFS and OS of 4.1 and 12.9
months, respectively. High grade hematological toxicities included 9% of anemia, 6% of
neutropenia, and 4% of thrombocytopenia. High grade non-hematological toxicities were
not observed [47].
SPLASH is a phase 3, open-label, randomized study evaluating the efficacy of
177
Lu-
PSMA-I&T (AKA.
177
Lu-PNT2002) versus abiraterone or enzalutamide in delaying radio-
graphic PFS in the second line setting after progression on 1st line ARAT (abiraterone or
enzalutamide) in mCRPC patients. This study recently started recruitment in March 2021
with estimated enrollment of 415 participants (NCT04647526).
3.3.4. Combination of 177 Lu-PSMA-617 with ARATs
Preclinical observational studies have shown upregulation of PSMA messenger RNA
production and PSMA receptor expression during AR inhibition [
48
]. In patients with
CRPC, ARAT administration leads to increase in PSMA expression [
23
]. Furthermore,
ARATs may lead to radiosensitization [
49
]. Based on these findings, it is postulated that
combining
177
Lu-PSMA radioligand therapy with ARAT may lead to improved tumor
control in CRPC.
ENZA-P (NCT04419402) is a phase 2 randomized multicenter study evaluating enza-
lutamide in combination with
177
Lu-PSMA-617 vs enzalutamide monotherapy as first-line
therapy in patients with mCRPC who have sufficient PSMA expression on PSMA PET/CT.
This study aims to recruit 160 men with mCRPC who are deemed at high-risk for early
failure on enzalutamide monotherapy (two or more high-risk features as per PREVAIL and
PROPHECY trials) [
50
,
51
]. Patients randomized to the treatment arm will receive up to
four cycles of 7.5 GBq
177
Lu-PSMA-617 in combination with 160 mg enzalutamide daily.
Primary endpoint is PSA-PFS. Secondary endpoints include rPFS, OS, PSA-response rate,
quality of life and adverse events. This study is expected to be completed in 2023.
PSMAddition (NCT04720157) is a phase 3 randomized study comparing
177
Lu-PSMA-
617 in combination with standard of care vs. standard of care in patients with metastatic
hormone-sensitive prostate cancer (mHSPC). In this study, the standard of care is defined
as a combination of ARAT and ADT. Approximately 1126 patients will be randomized in
this study. This study is anticipated to start recruiting in May 2021.
Although there is a biological basis to support combining ARAT with
177
Lu-PSMA-
617, it will be important to determine long term safety and the impact of early use of
177
Lu-PSMA-617 on subsequent lines of therapy, such as chemotherapy. Other important
questions that need to be answered will include the consideration of optimal dose, schedule,
and patient selection.
3.3.5. Combination of 177 Lu-PSMA-617 with DNA Damage Repair Inhibitors
Radiation induces single-stranded and double-stranded DNA breaks through forma-
tion of oxidative free radicals. The enzyme poly ADP ribose polymerase (PARP) is crucial in
repairing radiation-induced single-stranded DNA breaks, which allows for radio-resistance
of cancer cells [
52
]. Thus, PARP inhibition could lead to radiosensitization when combined
Cancers 2021,13, 4023 8 of 17
with radioligand therapy. Furthermore, germline and somatic alterations in DNA damage
repair (DDR) genes such as BRCA1/2 alterations are present in up to 12% and 25% of
mCRPC, respectively [
53
,
54
]. Based on a study from Royal Marsden hospital, tumor tissues
from 60 patients with mCRPC were analyzed for membranous PSMA expression (mPSMA)
and DDR aberrations with next generation sequencing. This study found that DDR aberra-
tions are associated with higher mPSMA expression [
55
]. PARP inhibitors such as olaparib
and rucaparib have been shown to be effective against mCRPC with BRCA1/2 mutations
and other DDR aberrations in prospective clinical trials [56–58]. As such, there is a strong
biological rationale for combining DDR inhibitors with PSMA-targeted radioligand therapy
in treatment of mCRPC.
Preclinical studies have shown synergistic anti-tumor effect of combination PARP
inhibitor and radiation, including radioligand therapy. PARP inhibitors appear to be es-
pecially effective in enhancing radiation-induced tumor cell death at low doses
[59,60]
.
LuPARP (NCT03874884) is an Australian phase 1 study examining the use of
177
Lu-PSMA-
617 with olaparib in men with mCRPC who have progressed on prior ARAT, and have
PSMA-avid disease on imaging.
177
Lu-PSMA-617 will be administered up to 6 cycles with
the dose of olaparib escalated from 50 mg to 300 mg, in six increments. The primary end-
points are to establish dose limiting toxicities, maximum tolerated dose and recommended
phase 2 dose. Secondary endpoints include safety and efficacy. Tissue and liquid biopsies
(circulating tumor cells and DNA) will be collected and analyzed to identify predictive
biomarkers of response and resistance.
Other DDR inhibitors that may have synergy with radioligand therapy include DNA-
PK inhibitor AZD7648, ATM inhibitor AZD0156, and RNA polymerase I inhibitor CX-5461.
Preclinical studies for these agents have shown synergy with radiation therapy [61–63].
3.3.6. Combination of 177 Lu-PSMA-617 with Immune Checkpoint Inhibitors
Anti-PD-1 monoclonal antibodies such as nivolumab and pembrolizumab, and anti-
CTLA-4 monoclonal antibodies, such as ipilimumab, together referred to as immune-
checkpoint inhibitors (ICI) are an important class of cancer therapies that have demon-
strated significant activity, including some durable responses, in a number of cancers,
including melanoma, non-small cell lung cancer, bladder cancer, and kidney cancer. These
agents are now used as single agents or in combination with chemotherapies as first or
second lines of treatment for approximately 50 cancer types with more than 3000 active
clinical trials as of 2020 [
64
]. In prostate cancer, these agents have had disappointing results,
suspected to be due to low levels of neo-antigens and immunogenic mutations seen in
the majority of prostate tumors [
65
–
67
]. Research is currently focusing on identifying
predictive biomarkers in prostate cancer, as well as strategies that will alter the tumor mi-
croenvironment which may lead to better response to ICIs. In particular, radiation is known
to have a variety of immunomodulatory effects. It has been observed that following radia-
tion of tumor sites can lead to shrinkage of other tumor sites that were not radiated. This
phenomenon is termed “abscopal effect”, in which it is hypothesized that radiation induces
immunogenic tumor cell death which leads to systemic antitumor immune response [
68
].
Various preclinical and clinical studies substantiated this hypothesis [69].
PRINCE (NCT03658447) is an Australian phase Ib/II study examining the combination
of pembrolizumab with
177
Lu-PSMA-617 in mCRPC patients who have progressed on
ARAT. Patients with PSMA-avid disease are enrolled to receive pembrolizumab up to
two years (35 cycles every three weeks) in combination with up to six cycles of
177
Lu-
PSMA-617 (six weeks apart). The primary endpoints include PSA response rate and safety.
Secondary endpoints include rPFS, PSA-PFS, and OS. The study aims to enroll 37 patients
with completion expected in October 2021.
3.3.7. Other 177 Lu PSMA Radioligand Therapy Trials in Prostate Cancer
Clinical trials are underway to examine the role of
177
Lutetium PSMA radioligand
therapy earlier in the prostate cancer natural history. The LuTectomy trial (NCT04430192)
Cancers 2021,13, 4023 9 of 17
is an Australian open label, phase I/II non-randomized study evaluating neoadjuvant
177
Lu-PSMA-617 (one or two cycles) followed by radical prostatectomy + pelvic lymph
node dissection in patients with high risk localized or locoregional advanced prostate
cancer and PSMA-avid disease. Accrual for this study has begun with estimated primary
completion date in August of 2022.
The Bullseye trial (NCT04443062) is a Dutch randomized, open label, multi-center,
phase 2 study testing
177
Lu-PSMA-I&T in oligometastatic HSPC. Patients with PSMA-avid
disease with five or less metastatic lesions are randomized to either two cycles of
177
Lu-
PSMA-I&T given six weeks apart vs. standard of care. The estimated enrollment size is
58 patients with estimated primary completion in January 2023. The important clinical
rationale of this study is that many patients with oligometastatic prostate cancer do not
qualify for local MDT treatment such as surgery or EBRT due to tumor location or prior
therapy, in which targeted radioligand therapy for these lesions maybe beneficial.
UpFrontPSMA (NCT04343885) is an Australian phase 2 randomized clinical trial
comparing the efficacy of two cycles
177
Lu-PSMA-617 given every six weeks followed by
docetaxel chemotherapy every three weeks for six cycles, versus docetaxel chemotherapy
on its own in patients with newly-diagnosed high volume mHSPC, defined as PSMA-avid
visceral metastases, or
≥
4 PSMA-avid bone lesions with one or more outside the vertebral
column and pelvis as seen on
68
Ga-PSMA PET/CT. The study aims to enroll 140 patients
with estimated primary completion in April of 2024.
3.4. Other Notable Beta-Emitting PSMA-Targeted Radionuclide Therapy Agents
3.4.1. 131I-MIP-1095
Iodine-131(131I)-MIP-1095 is a PSMA-targeted small-molecule inhibitor radionuclide
therapy developed by Molecular Insight Pharmaceuticals, Inc. It was one of the first agents
used in radiopharmaceutical therapy against prostate cancer.
131
I is a beta-emitter having a
similar particle range and half-life as
177
Lu (eight vs. 6.7 days, respectively), but with much
more abundant gamma emission, which makes it less ideal from toxicity and radiation
safety perspectives [70].
A study testing a single cycle of
131
I-MIP-1095 in 28 mCRPC patients showed PSA
decrease of >50% in 60.7% of patients with median time to PSA progression of 126 days.
Seven of the 28 patients experienced transient xerostomia with all reported symptoms
resolved within 3–4 weeks. Although hematological toxicities were infrequent (two patients
with grade 3 thrombocytopenia, one patient was grade 3 leukopenia), thrombocytopenia
lasted multiple months [
70
]. In a subsequent study involving 36 mCRPC patients, 70.6%
experienced PSA decrease >50% with median PSA progression of 116 days. Patients
received an additional dose at PSA progression. However, only 65.2% experienced any PSA
decline with only much higher percentage grade 3 thrombocytopenia of 13%, compared
to 5.9% after first dose. Grade 3 xerostomia was observed in 13%, which was not seen
after the first dose [
71
]. ARROW (NCT03939689) is a randomized, multicenter, controlled
phase 2 study is currently underway to evaluate the safety and efficacy of
131
I-MIP-1095 in
combination with enzalutamide compared to enzalutamide alone in patients with PSMA-
avid mCRPC who have progressed on abiraterone.
3.4.2. 177Lu-PSMA-R2
177
Lu-PSMA-R2 is being developed by Advanced Accelerator Applications (a sub-
sidiary of Novartis). PSMA-R2 is a urea-based PSMA-targeting small molecule inhibitor. In
preclinical studies,
177
Lu-PSMA-R2 has rapid and specific uptake in mice bearing prostate
cancer tumors, with rapid elimination through urinary system [
72
]. A phase 1/2 dose
escalation study of
177
Lu-PSMA-R2 in patients with PSMA-avid mCRPC is currently being
conducted, with planned completion in June 2022 (NCT03490838).
Cancers 2021,13, 4023 10 of 17
3.5. Alpha-Emitting PSMA-617 Radioligand Therapy
3.5.1. Introduction
Alpha particle radiation is characterized by a significantly higher linear energy trans-
fer (LET) compared to beta particle radiation (50–230 keV/
µ
m vs. 0.2 keV/
µ
m), which
allows for a greater chance of inducing unrepairable DNA double-strand breaks in cancer
cell with increased cytotoxic potential. Furthermore, alpha particles have a shorter path in
tissue (50–100
µ
m) compared with beta articles (1000–10,000
µ
m) [
73
,
74
]. The short range of
alpha particles has the potential of minimizing cytotoxic damage in non-targeted cells, po-
tentially leading to less hematological toxicity, especially in patients with wide-spread bone
metastases with diffuse bone marrow infiltration [
75
]. This is exemplified by
223
Ra, which
is a first-in-class alpha particle-emitting agent approved for mCRPC with symptomatic
bone metastases [
27
]. However,
223
Ra treatment in mCRPC is limited by the fact that it
is a bone-seeking agent that does not target soft-tissue metastases, and even within bone
metastases the tumor cells are only reached via cross-fire radiation. The discovery of PSMA
allowed for the delivery of alpha-emitting radionuclides more selectively to the tumor.
3.5.2. 225Ac-PSMA-617
Actinium-225 (
225
Ac)-PSMA-617 has been the most studied PSMA-targeting alpha
particle therapy. Based on a preliminary report from a single-center study,
225
Ac-PSMA-617
(100 kBq/kg every two weeks) resulted in complete PSA and imaging response in two
patients who received greater than eight prior systemic therapies [
76
]. In the full report
including 14 patients, PSA response was seen in 75% of patients. All-grade hematological
AEs occurred in six patients and xerostomia occurred in eight patients. Xerostomia was the
dose-limiting toxicity with 100 kBq/kg considered the maximum tolerable dose [
77
].
225
Ac-
PSMA-617 is also active in mCRPC patients who have progressed after
177
Lu-PSMA-617.
In a group of 26 heavily pre-treated (median of six prior lines of systemic therapy) mCRPC
patients who have progressed on
177
Lu-PSMA-617, all of them received
225
Ac-PSMA-617
under a compassionate use program in Germany. This study reported substantial PSA
decline of >50% in 65% of patients with PFS and OS of 4.1 and 7.7 months, respectively. High
grade hematological toxicities were anemia (35%), leucopenia (27%), and thrombocytopenia
(19%). All patients experienced xerostomia, which led to treatment discontinuation in
about a quarter of patients [78].
225
Ac-PSMA-617 has also been reported to have good activity against CNS metastases.
Although rare in prostate cancer, brain metastases tend to occur in late stage CRPC and are
associated with very poor survival. Treatment is generally limited to surgical resection or
EBRT. In a case report,
225
Ac-PSMA-617 achieved complete molecular imaging response
on repeat
68
Ga-PSMA PET in an mCRPC patient with PSMA-avid cerebral metastases
after just 1 cycle of therapy. The patient had near complete PSA response after two cycles
(788.63
µ
g/L to 0.32
µ
g/L [
79
]. This case highlights the potential of
225
Ac-PSMA-617 being
an effective treatment for brain metastases as PSMA-617 crosses the blood–brain barrier.
However, no similar report has been seen yet with 177Lu-PSMA-617.
AcTION (NCT04597411) is a prospective phase 1, open-label, international, dose
escalation study to evaluate the safety of
225
Ac-PSMA-617 in men with PSMA-avid mCRPC.
The study has started in April of 2021. This study will hopefully help to address how best
to minimize xerostomia while still achieving an adequate response.
3.5.3. 213Bi-PSMA-617
Bismuth-213 (
213
Bi) is a mixed alpha and beta emitter with a short half-life of 45.6 min.
It demonstrated pre-clinical activity when tagged to PSMA-targeting antibody J591 [
80
,
81
].
Thus far, there has been only one clinical case report of
213
Bi-PSMA-617 in which one patient
with mCRPC was treated with two cycles. This patient achieved PSMA-imaging response
and biochemical response with decrease in PSA level from 237
µ
g/L to 43
µ
g/L [
82
].
Due to its short half-life, it is logistically challenging for therapeutic use. It also has an
inferior therapeutic index compared to
225
Ac-PSMA-617 based on a dosimetry study [
83
].
Cancers 2021,13, 4023 11 of 17
Currently, this PSMA radioligand therapy agent has not been explored much further in its
clinical application against prostate cancer.
4. Anti-PSMA Radioimmunotherapy
4.1. Lutetium-177-J591 Antibody
The extracellular domain of PSMA also makes an accessible target for antibodies. Anti-
PSMA radioimmunotherapy actually predates the development of small molecule-based
radioligand therapy. A notable example is J591 antibody, which was initially characterized
in 1997, and it has been the most explored antibody for PSMA-targeted radioimmunother-
apy to date [
84
].
177
Lu-J591 was initially tested in a phase I study in 2005 in 35 mCRPC
patients who received up to three doses. Myelosuppression was dose limiting and the
maximum-tolerated dose was 70 mCi/m2. Biological activity was seen with four patients
experiencing >50% declines in PSA lasting up to eight months with 46% of patients have
PSA stabilization for a median of 60 days [
85
]. In a phase 2 study investigation single doses
of
177
Lu-J591, median OS was 21.8 months in mCRPC patients who received a single dose
of 70 mCi/m
2
, compared to 11.9 months in those who received 65 mCi/m
2
. However,
higher dose led to higher grade 4 thrombocytopenia and neutropenia (53% vs. 27%, and
48% vs. 0%, respectively) [86].
Dose-fractionation of
177
Lu-J591 appears to be a promising strategy to increase cumu-
lative radiation in order to improve anti-tumor activity while mitigating hematological
toxicity. In a phase 1/2 study, 49 mCRPC patients received fractionated doses of
177
Lu-J591
ranging from 20 to 45 mCi/m
2×
2 two weeks apart. The recommended phase 2 doses
were 40 mCi/m
2
and 45 mCi/m
2×
2. At the higher dose, median OS was 42.3 months
vs. 19.6 months in patients who received lower dose. The higher dose led to higher grade
4 thrombocytopenia and neutropenia than lower dose (58.8% vs. 43.8%, and 35.3% vs.
31.3%, respectively), with no high-grade hemorrhagic episodes in any of the patients [87].
4.2. Actinium-225-J591 Antibody
The cause of higher hematological toxicity for
177
Lu-J591 is likely attributed to mono-
clonal antibodies being large molecules with slower clearance from the circulation com-
pared to small molecules such as PSMA-617 [
84
]. However, compared to PSMA-617, J591
does not demonstrate uptake in the salivary gland or kidneys [
7
]. Based on this feature, it
is hypothesized that
225
Ac-J591 could mitigate the xerostomia and nephrotoxicity seen in
225
Ac-PSMA-617. In a phase 1 trial, 22 mCRPC heavily-pretreated patients were treated
with seven dose levels of 225Ac-J591. The treatment was very well tolerated and the MTD
was not reached. Only one patient treated with 80 KBq/kg had grade 4 anemia and
thrombocytopenia. There were no DLT reported in 6 patients that were treated at the
highest planned dose of 93.3 KBq/kg. Xerostomia was only seen in patients with prior
177
Lu-PSMA-617 therapy. PSA decline was seen in 64% of patients with 41% of patients
experienced
≥
50% PSA decline. Enrollment in the expansion cohort is currently being
completed [
88
]. Given the above-mentioned success of the dose-fractionation strategy with
177
Lu-J591, a phase I/II dose-escalation study of fractionated and multiple dose
225
Ac-J591
is currently ongoing for mCRPC patients (NCT04506567).
4.3. Thorium-227-PSMA-TTC Antibody
Thorium-227 (
227
Th) is an alpha-particle emitter with a long half-life of 18.7 days,
which allows for ease of transportation and preparation of the radiopharmaceutical.
227
Th
can be efficiently complexed with octadenate 3, 2-hydroxypryridinone (3,2-HOPO) chelator
convalently linked to antibodies at ambient room temperature.
227
Th-PSMA-TTC is a novel,
fully human antibody attached to
227
Th, which has recently been developed by Bayer and
has demonstrated very strong antitumor efficacy in animal models with prostate cancer [
89
].
Currently, it is being tested in a large multi-center, international, phase 1, open-label study
in mCRPC pre-treated mCRPC patients. The study is active with a planned enrollment of
157 participants and estimated completion in July 2024 (NCT03724747).
Cancers 2021,13, 4023 12 of 17
5. PSMA-Targeted Bispecific T-Cell Engager (BiTE) Immunotherapy
BiTE (bispecific T-cell engager) therapy is a novel targeted immunotherapy approach
that engages the patient’s own T cells to kill cancer cells. The BiTE molecule binds to a
tumour-associated antigen on targeted cells and CD3 on T cells which leads to T-cell prolif-
eration, cytokine production, and T-cell-mediated killing of cancer cells. The advantage of
this treatment approach over conventional ICI is such that it can bypass the conventional
pathway of T-cell receptor activation and may be active, independent of the tumour’s
genetic background [
90
]. BiTE therapy has shown great efficacy for treatment of certain
hematological cancers [
91
,
92
]. The emergence of this novel therapy has renewed hope for
immunotherapy in prostate cancer, where efficacy for ICI have been disappointing, owing
to the suboptimal immunogenic microenvironment seen in prostate tumours [65–67].
Pasotuxizumab (AMG 212) is a 55 kDa BiTE molecule that binds to CD3 on T cells
and also PSMA on prostate cancer cells, thereby activating the patient’s own T cells to
eliminate PSMA-expressing prostate cancer cells. Preclinical studies have demonstrated
delayed tumour growth and shrinkage in human cancer xenograft models [
91
]. A phase
I dose-escalation study of once daily subcutaneous (SC) pasotuxizumab in patients with
multi-treated mCRPC demonstrated remarkable safety, with only 16% drug-related AEs
reported. The SC maximum tolerated dose was 172
µ
g/d. PSA responders (>50% PSA
decline) occurred in 29%, including two long-term responders. One such patient achieved
near-complete radiological response, having received six prior therapies including 177Lu-
PSMA-617 prior to commencing with pasotuxizumab, and then had 500 days to tumor
progression [
93
]. Despite the encouraging results, further studies are required to fully
elucidate the role of BiTE therapy in the treatment of mCRPC. Whether this treatment
only works for PSMA-avid disease, as well as the exact specificity for PSMA, remain to
be addressed.
6. Conclusions
Based on extensive research conducted thus far, PSMA theranostics represents a
rapidly emerging strategy in the management of prostate cancer. PSMA-targeted imaging
has demonstrated excellent sensitivity and specificity for the detection of prostate cancer
compared to conventional imaging, with preliminary evidence demonstrating that the
result impacts clinical practice. There are many potential clinical applications of PSMA-
targeted imaging, with the most encouraging being the earlier detection of disease, leading
to earlier therapeutic interventions. However, the impact on survival of an earlier initiation
of therapy based on PSMA-targeted imaging is not yet apparent. Furthermore, PSMA-
targeted radioligand therapy is a highly promising way to treat advanced prostate cancer,
with recent evidence of rPFS and OS benefits. More research is underway to validate
efficacy as well as improve safety and outcomes at earlier stages of the disease. Future
research directions include the development of standardized methods for patient selection,
response assessment, cost–benefit analysis, and the optimization of production and supply
of radiopharmaceuticals. Considering that PSMA theranostics will soon become a standard
of care in the management of prostate cancer, it will be crucial to integrate nuclear medicine
physicians into the multidisciplinary team alongside medical oncologists, radiation on-
cologists, urologists, and radiologists in order to optimize the care of patients with this
complex malignancy.
Author Contributions:
Writing—original draft preparation, H.Z.; writing—review and editing,
H.Z., S.K., F.P., J.-M.B. and M.K. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Conflicts of Interest:
H.Z. has received an honorarium from Merck. S.K. declares no conflict of
interest. F.P. has received honoraria and/or consulting fees from Abbvie, Amgen, Astellas, Bayer,
Genzyme, Jenssen, Pfizer, Progenics, and Sanofi; and research funding from Astellas, Bayer, Janssen,
Sanofi, and Tersera. J.M.B. has received honoraria and/or consulting fees from Ipsen and Novartis.
Cancers 2021,13, 4023 13 of 17
M.K. has received honoraria and/or consulting fees from Astellas, AstraZeneca, Bayer, BMS, Eisai,
Ipsen, Janssen, and Merck; and research funding from AstraZeneca and Janssen.
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