Expert Review of Anticancer Therapy

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iery20

Emerging treatment options for prostate cancer

Mohammad Atiq, Elias Chandran, Fatima Karzai, Ravi A. Madan & Jeanny B.
Aragon-Ching

To cite this article: Mohammad Atiq, Elias Chandran, Fatima Karzai, Ravi A. Madan & Jeanny
B. Aragon-Ching (2023) Emerging treatment options for prostate cancer, Expert Review of
Anticancer Therapy, 23:6, 625-631, DOI: 10.1080/14737140.2023.2208352

To link to this article: https://doi.org/10.1080/14737140.2023.2208352

Published online: 02 May 2023.

Submit your article to this journal

Article views: 230

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=iery20
EXPERT REVIEW OF ANTICANCER THERAPY
2023, VOL. 23, NO. 6, 625–631
https://doi.org/10.1080/14737140.2023.2208352

REVIEW

Emerging treatment options for prostate cancer

Mohammad Atiqa, Elias Chandran a
, Fatima Karzaia, Ravi A. Madana and Jeanny B. Aragon-Ching b,c

a
Genitourinary Malignancy Branch, National Cancer Institute, Bethesda, MD, USA; bGU Medical Oncology, Inova Schar Cancer Institute, Fairfax, VA,
USA; cMedical Education, University of Virginia, Charlottesville, VA, USA

ABSTRACT ARTICLE HISTORY

Introduction: Prostate cancer treatment has rapidly evolved in the past few years. Androgen depriva­ Received 4 January 2023
tion therapy has been the backbone of treatment for locally advanced and metastatic prostate cancer, Accepted 25 April 2023
but incremental benefits in survival have been shown by adding androgen-receptor pathway inhibitors KEYWORDS
(ARPI) across various spectrums of disease state. In addition, docetaxel chemotherapy remains the first- Anti-androgen;
line chemotherapy regimen available with survival benefits shown with triplet therapy in those who are immunotherapy; metastatic
chemotherapy eligible. However, disease progression remains inevitable and novel agents such as prostate cancer;
radioligand therapy with lutetium have shown improvement in survival. radioligands; prostate cancer
Areas covered: This review discusses the pivotal trials that led to the U.S. FDA approval of agents
utilized in metastatic prostate cancer and explores the use of novel agents including prostate-specific
membrane antigen-targeting agents, radioligands, cell-based therapy, chimeric antigen receptor T-
cell, BiTE, and antibody drug conjugates.
Expert opinion: Treatment landscape for metastatic castrate-resistant prostate cancer (mCRPC) has
evolved beyond additional agents with ARPI and/or docetaxel, including other treatments with sipu­
leucel-T, radium, cabazitaxel, PARP inhibitors, and lutetium, which have specific indications and roles in
sequencing. Novel therapies remain critically needed after progression from lutetium.

1. Introduction
Prostate cancer remains the most common non-cutaneous
malignancy among American men. It is estimated to occur in
268,490 men and expected to result in 34,500 deaths in 2022
[1]. A review of over 3 million prostate cancer diagnoses from
2001 to 2017 revealed approximately 5% of new cases to be
metastatic at diagnosis with 5- and 10-year survivals of around
30% and 18%, respectively [2]. In addition, of patients defini­
tively treated for localized prostate cancer, 20–30% will have
recurrence in the form of rising prostate-specific antigen (PSA)
or disseminated disease that necessitates further treatment
[3]. The original backbone for treatment of metastatic prostate
cancer, androgen ablation or androgen deprivation therapy
(ADT), was discovered in the 1940s [4]. Since then, the treat­
ment landscape has evolved substantially. Many new FDA-
approved therapies within the past decade have been
oriented around the androgen receptor; however, multiple
novel avenues of treatment have emerged, demonstrating
promise for expansion of the therapeutic tools available to
treat this lethal disease.
2. Current treatment landscape
The current treatment landscape for metastatic prostate can­
cer includes chemotherapy, anti-androgens, radiopharmaceu­
tical therapy, immunotherapy, and targeted therapies. The
mainstay chemotherapies used in metastatic prostate cancer
are docetaxel and cabazitaxel, both used in combination with
ADT. In patients with metastatic castration-resistant prostate
cancer (mCRPC), docetaxel plus prednisone improved median
overall survival (OS) compared to mitoxantrone plus predni­
sone in the randomized phase III study TAX 327 (18.9 months
vs. 16.5 months) [5]. Docetaxel’s benefit when added to ADT in
metastatic castration-sensitive prostate cancer (mCSPC) was
demonstrated in two studies: CHAARTED and an arm of the
multiplatform study, STAMPEDE [6,7]. The first of these studies
yielded an improved OS of 57.6 months when docetaxel was
added to ADT versus 44.0 months with ADT alone. Patients
with mCSPC treated in the ADT plus docetaxel arm of
STAMPEDE had a median OS of 81 months while those given
ADT alone had a median OS of 71 months. Cabazitaxel only
carries an approval in mCRPC. When used with prednisone in
mCRPC patients who had progressed on docetaxel, it had
a 2.4-month improvement in OS over mCRPC patients treated
with mitoxantrone plus prednisone [8]. It has also been shown
to improve survival in patients with mCRPC post-docetaxel
and have received either abiraterone or enzalutamide, com­
pared to switching to the other of abiraterone or enzaluta­
mide in the CARD trial: median OS 13.6 versus 11.0 months
(HR 0.64; 95% CI, 0.46–0.89) [9].
Androgen receptor pathway inhibitors (ARPI) with indica­
tions for treatment of prostate cancer include the androgen
synthesis inhibitor, abiraterone, and the three androgen
receptor inhibitors: enzalutamide, apalutamide, and darolu­
tamide. Abiraterone in combination with low-dose predni­
sone was first shown to improve OS in mCRPC post-
docetaxel in the study COU-AA-301 [10,11]. Here, median
OS was 15.8 months with abiraterone plus low-dose

CONTACT Jeanny B. Aragon-Ching jeanny.aragon-ching@inova.org GU Medical Oncology, Inova Schar Cancer Institute, Fairfax, VA, United States
This work was authored as part of the Contributor’s official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance
with 17 USC 105, no copyright protection is available for such works under US Law.
626 M. ATIQ ET AL.
Article highlights
● The treatment landscape for metastatic hormone-sensitive prostate
cancer has rapidly evolved with androgen deprivation therapy as
backbone and additional androgen-receptor pathway inhibitors
(ARPI) or docetaxel or combination as triplet therapy as first-line
treatment.
● Treatment sequencing in metastatic castrate-resistant prostate cancer
(mCRPC) remains an important issue upon failure from hormone-
based therapies.
● Lutetium has recently been approved for mCRPC after failure from
one ARPI and docetaxel, with improvements seen in radiographic
progression-free survival and overall survival.
● Emerging treatment options include radioactive ligand, antibody-
drug conjugates, chimeric antigen receptor T-cell, and cytokine-
based therapies.
prednisone compared to 11.2 months for placebo.
A subsequent study of pre-docetaxel patients (COU-AA-302)
showed improved median OS favoring those treated with
abiraterone-prednisone over patients treated with predni­
sone monotherapy (not reached vs. 27.2 months) [12].
Enzalutamide’s efficacy in mCRPC was shown as it improved
median OS compared to placebo in post-chemotherapy
mCRPC patients (18.4 months vs. 13.6 months) [13] and
then in the pre-chemotherapy mCRPC setting where there
was a radiographic progression-free survival (rPFS) and OS
benefit in the enzalutamide group compared to pla­
cebo [14].
In non-metastatic CRPC (nmCRPC), apalutamide, enzalu­
tamide, and darolutamide have all been shown to improve
metastasis-free survival as the primary endpoint. The
SPARTAN, PROSPER, and ARAMIS trials provided the sup­
port for approval of apalutamide, enzalutamide, and daro­
lutamide, respectively, in nmCRPC, specifically in patients
with PSA doubling times of ≤10 months [15–17]. All three
registrational studies demonstrated significant improve­
ments in OS as secondary endpoints.
ARPIs have also been widely adopted in mCSPC.
Abiraterone with prednisone added to ADT improved OS in
two separate randomized studies: LATITUDE and an arm of the
STAMPEDE trial [18,19]. In LATITUDE, the median OS was not
reached for the abiraterone group compared to 14.8 months
in the placebo group. The STAMPEDE study showed fewer
deaths in the ADT plus abiraterone group compared to ADT
alone: 184 versus 262 (HR 0.63; 95% CI, 0.52–0.76, P < 0.001).
The ENZAMET trial showed OS improvement in the enzaluta­
mide plus standard of care (SOC) arm compared to the SOC
arm (5-year OS 67% vs. 57%, HR 0.7; 95% CI, 0.58–0.84), with
docetaxel allowed as SOC [20,21]. Apalutamide with ADT also
yielded an OS advantage compared to ADT alone, with med­
ian OS not reached versus 52.2 months (HR 0.65, p < 0.0001) in
the TITAN trial [22,23]. In the last year, the needle has moved
further for mCSPC treatment, with data supporting the use of
ARPIs in combination with docetaxel and ADT, termed triplet
therapy. In the ARASENS trial, the addition of darolutamide
compared to placebo to docetaxel and ADT improved OS by
an HR of 0.68; 95% CI, 0.57–0.80 [24]. Similarly, the addition of
abiraterone with prednisone (vs. placebo) to docetaxel and
ADT in the PEACE-1 trial improved OS (HR 0.82, 95% CI,
0.69–0.98) [25].
Radiopharmaceutical therapy has largely been composed
of the alpha emitter Radium 223 dichloride. Radium 223
dichloride was the first-in-class alpha-emitting particle that
showed improvement in OS in the treatment of mCRPC
based on the ALSYMPCA trial [26]. Currently, Radium 223
dichloride is utilized in mCRPC patients with symptomatic
bone metastases. Beta emitters have been used in mCRPC
for many years in the form of samarium-153 and strontium-
89. However, their role had only been in palliation for painful
bone metastases as neither provided survival benefit [27,28].
The most recent advancement in radioligand therapy has
been with beta emitters, specifically lutetium-177 (177Lu),
which has been combined with prostate-specific membrane
antigen (PSMA), a type II transmembrane glycoprotein speci­
fically expressed in prostate cancer cells. TheraP, a phase II
study that compared 177Lu-PSMA-617 to cabazitaxel in
patients with mCRPC, showed a higher percentage of patients
with PSA responses (defined as reductions of at least 50%
from baseline) in the lutetium-treated group [29]. This sug­
gested that 177Lu-PSMA-617 may have a role as an alternative
to cabazitaxel in mCRPC. Adverse events (AEs) of particular
interest in this study include dry mouth, dry eyes, diarrhea,
thrombocytopenia, and neuropathy. Dry mouth and dry eyes
were seen in 60% and 30% of the patients treated with
lutetium as compared to 21% and 4%, respectively, of patients
treated with cabazitaxel. This was all grade 1–2 with no grade
3–4 events seen for either treatment with regard to these AEs.
Diarrhea was seen in approximately triple the percentage of
patients receiving cabazitaxel as compared to lutetium, but
again this was mostly grade 1–2. Thrombocytopenia was not
only more frequent in lutetium but also more severe as 11% of
patients treated with lutetium experienced this at grade 3–4
compared to none of the patients treated with cabazitaxel.
Neuropathy, a known possible AE of taxane chemotherapy,
occurred in 26% of patients treated with cabazitaxel as com­
pared to lutetium, which is important in a population that may
have residual neuropathy from prior taxane treatment. The
phase III VISION trial enrolled patients with mCRPC after failure
from at least one prior ARPI and one taxane treatment and
compared 177Lu-PSMA-617 to SOC therapy. The improvement
in OS in the 177Lu-PSMA-617 arm (median OS 15.3 vs. 11.3
months, HR 0.62, 95% CI, 0.52–0.74) led to U.S. FDA approval
in March 2022 in this setting [30].
Immunotherapy in prostate cancer has a limited role in the
setting of mCRPC. The only vaccine therapy in prostate cancer
to demonstrate an OS benefit thus far is sipuleucel-T, with
a median OS of 25.8 versus 21.7 months (HR 0.78, 95% CI,
0.61–0.98), although there was no improvement in PFS or
PSA response [31]. This treatment is reserved for asympto­
matic or minimally symptomatic mCRPC patients without visc­
eral metastases, and the magnitude of OS benefit was found
to be greater in patients with lower baseline PSA [32].
Pembrolizumab, a PD-1 inhibitor, currently carries approvals
only for prostate cancer patients with MSI-H and TMB-H dis­
ease [33,34]. These approvals were based on tissue-agnostic
solid tumor trials that did not have particularly large numbers

of prostate cancer patients. Trials of immune checkpoint inhi­
bitors in unselected prostate cancer patients have failed to
demonstrate improvements in survival [35–37]. There is cur­
rently no indication beyond this biomarker-based population
especially given failure of phase III trials that included doce­
taxel in the mCRPC space (Keynote-921: NCT03834506) and
with enzalutamide (Keynote 641: NCT03834493) as well as
metastatic hormone-sensitive prostate cancer setting
(Keynote-991: NCT04191096).
Therapies targeting the DNA damage repair (DDR) path­
ways with poly-ADP ribose (PARP) inhibitors have also demon­
strated efficacy in selected patients with mCRPC. Olaparib and
rucaparib were examined in patients with mCRPC who pro­
gressed on prior ARPIs in the phase III, PROfound and phase II,
TRITON studies, respectively [38–40]. Olaparib was studied in
the phase III PROfound trial with the primary endpoint of
investigator-assessed imaging PFS in those who had at least
one homologous recombination repair (HRR) mutations that
included BRCA1, BRCA2, or ATM and failed prior ARPI in cohort
A. Other DDR mutations were included in cohort B.
Conversely, the TRITON study required progression on one
prior taxane and limited HRR mutations to BRCA1 and BRCA2.
Analysis from PROfound demonstrated a PFS and OS benefit in
favor of olaparib over ARPI in the BRCA1, BRCA2, and ATM
cohort (median OS 19.1 vs. 14.7 months, HR 0.69; 95% CI,
0.50–0.97), while that from TRITON showed antitumor activity
in the form of objective responses and PSA response in
patients treated with rucaparib. Another PARP inhibitor stu­
died in mCRPC was niraparib in the phase II GALAHAD trial,
which included 289 patients of whom overall response rates in
the BRCA cohort (n = 79) was 34.2% [41]. Collectively, these
aforementioned trials led to the eventual U.S. FDA approval of
olaparib in adult patients with deleterious or suspected dele­
terious germline or somatic HRR gene-mutated mCRPC, who
have progressed following prior treatment with enzalutamide
or abiraterone on May 19, 2020. While rucaparib was granted
U.S. FDA accelerated approval on May 15, 2020 and niraparib
was given a U.S. FDA breakthrough therapy designation
on October 4 2019, the approval was reserved only for
mCRPC patients with deleterious BRCA mutation (germline
and/or somatic) previously treated with ARPI and a taxane-
based chemotherapy.
3. Emerging treatment options
There are several treatment candidates with various mechanisms
of action being evaluated in prostate cancer. Most involve utiliz­
ing prostate-associated antigens and combining these with
other forms of treatment. The therapies discussed herein include
combination PARPi and oral anti-androgens, radioligands, mono­
clonal antibodies, small molecules, cell membrane receptors,
chimeric antigen receptor T-cell (CAR-T), cytokine-based thera­
pies, and antibody-drug conjugates (ADCs).
As noted above, PARPi are approved for treatment in select
mCRPC patients. More recent trials have begun to examine its
role in combination with oral anti-androgens in unselected
patients. The PROpel study is a phase III study combining
abiraterone and olaparib in unselected mCRPC as a first-line
EXPERT REVIEW OF ANTICANCER THERAPY 627
treatment [42]. This trial randomized patients to either abira­
terone and olaparib or abiraterone and placebo. The primary
endpoint of imaging-based progression-free survival (ibPFS)
favored the combination group over placebo (24.8 vs. 16.6
months, HR 0.66; 95% CI, 0.54–0.81, p < 0.001). A second study
looking at the combination of PARPi with oral anti-androgens
in mCRPC is TALAPRO-2. This phase III study randomized
patients to enzalutamide plus either talazoparib or placebo
in first-line mCRPC [43]. The primary endpoint was the same as
in PROpel: ibPFS. The median ibPFS again favored the oral
anti-androgen and PARPi combination arm over the anti-
androgen and placebo arm (NR vs 21.9 months, HR 0.63; 95%
CI, 0.51–0.78; p < 0.001). Importantly, neither study allowed for
patients on the placebo arm to receive PARPi at time of
progression, a comparison that would mirror a current
approach available to selected patients in the United States
who progress on abiraterone in the mCRPC setting.
There are many ongoing trials involving 177Lu-PSMA-617
that may expand its role further beyond mCRPC. PSMAfore
(NCT04689828) is a phase III trial in taxane-naive mCRPC
patients progressing on one line of ARPIs, and who are eligible
for a change to a different ARPI [44]. Patients in PSMAfore will
be randomized to either treatment with 177Lu-PSMA-617 or
an ARPI (abiraterone/enzalutamide) with the primary endpoint
for the trial being rPFS. Another trial, PSMAddition
(NCT04720157), is evaluating 177Lu-PSMA-617 in mCSPC
[45]. This trial will randomize patients to either 177Lu-PSMA
-617 added to SOC (defined as ADT+ARPI) versus SOC alone
with a primary endpoint of rPFS. A phase 1b trial (PRINCE)
investigating the benefits of immunogenic priming with
177Lu-PSMA-617 followed by pembrolizumab in chemother­
apy-naive mCRPC patients [46] demonstrated a promising
overall response rate of 44% in the 18 patients enrolled and
has led to further phase II trial testing (NCT03805594). PSMA-
based ligand forms are also being combined with lutetium in
phase III clinical trials for patients with mCRPC who have failed
prior ARPI but remain chemotherapy naive. The two studies
exploring this includes the following studies: SPLASH
(NCT04647526) and ECLIPSE (NCT05204927).
Alpha particles are attractive as these deliver high energy
with fewer particle tracks to effect cell kill, have a short depth
of penetration, and have shorter half-lives, potentially limiting
toxicity to normal tissues. Additionally, from a practical per­
spective, the easier production of alpha particles lends for
wider dissemination and use in the clinic [47]. The only
alpha emitter approved thus far in prostate cancer is radium
223 dichloride. One alpha emitter being evaluated is actinium-
225 (225Ac). A phase I study combining this with a PSMA-
localizing antibody, J591, was recently presented by Tagawa
et al. (NCT03276572) [48,49]. Thirty-two patients with mCRPC
who progressed on at least 1 ARPI and chemotherapy were
enrolled in the study. Interestingly, prior treatment with
radium 223 and lutetium was allowed, and PSMA PET positiv­
ity was not required for enrollment. There was only one
patient with dose-limiting toxicity (DLT) at all the planned
dose levels: grade 4 anemia and thrombocytopenia. Grade 3
or higher AEs were hematologic. Lower grade AEs included
fatigue, pain flare, nausea, and xerostomia (which occurred in
628 M. ATIQ ET AL.
8 patients – 5 previously treated with lutetium – and was
limited to grade 1). Clinical data presented included 22 out
of 32 patients having any decline in PSA and 12 out of 32
patients experiencing ≥50% PSA reduction (PSA50 response).
CAR-T cell therapy is a new area of therapy being evaluated
in prostate cancer. A first-in-human phase I study of PSMA
CAR-T by Narayan et al. (NCT03089203) enrolled mCRPC
patients and treated them with a PSMA-directed armored
CAR-T cell that was modified with a dominant-negative trans­
forming growth factor (TGF)-beta receptor [50]. This study
utilized a 3+3 safety design with and without lymphodeple­
tion. Patients were dosed in four cohorts at a range of 10–­
30 million cells or 100–300 million cells with or without
lymphodepletion. Of the 13 patients treated, 4 had PSA reduc­
tions of at least 30%. It must be noted, however, that one of
the four patients died in the context of grade 4 cytokine
release syndrome (CRS) and sepsis, emphasizing the need for
continued vigilance regarding toxicity monitoring. A second
phase I study by Dorff et al. (NCT03873805) looked at CAR-T
cell therapy targeted to prostate stem cell antigen (PSCA) in
mCRPC after at least abiraterone or enzalutamide [51]. Patients
were also required to have disease that expressed PSCA as
confirmed by City of Hope’s Pathology Department. These
CAR-T cells are also using the 4-1BB costimulatory molecule.
Four cohorts were planned for treatment with cohort 1 receiv­
ing 100 million cells without lymphodepletion chemotherapy.
The other three cohorts were planned to receive lymphode­
pletion first followed by 100 million, 300 million, or 600 million
cells per each cohort, respectively. This first-in-human study
encountered two DLTs (grade 3 noninfective cystitis and fati­
gue in both) at a dose of 100 million cells after lymphodeple­
tion chemotherapy. However, upon amendment of the
lymphodepletion chemotherapy to reduce the cyclophospha­
mide portion, no DLTs were encountered in an additional
three patients. All three patients treated at the 100 million
cell dose level without lymphodepletion progressed, while
seven of the nine patients treated at the same cell number
but with lymphodepletion had stable disease. The data
acquired at this level allowed for escalation to the next dose
level of 300 million cells.
Another form of antibody-focused treatment in develop­
ment utilizes Bi-specific T-cell engagers (BiTEs). An example is
pasotuxizumab, which engages CD3 on T-cells and PSMA on
prostate cancer cells. A phase I trial enrolled 47 patients with
mCRPC post ≥1 taxane and either abiraterone or enzaluta­
mide, and escalated doses of pasotuxizumab in subcutaneous
(SC) and continuous intravenous infusion (cIV) routes [52]. It
demonstrated activity of the treatment, with dose-dependent
PSA reductions. Overall, PSA50 responses occurred in 9 out of
31 (29%) patients in the SC arm and 3 out of 16 (18.8%) in the
cIV arm. Common AEs in the SC and cIV arms, respectively,
included fever (25/31 [81%] and 15/16 [94%]), injection-site
reactions (24/31 [77%] and 0/16 [0%]), chills (7/31 [23%] and
11/16 [69%]), and fatigue (11/31 [36%] and 5/16 [31%]).
Despite promising activity, 30 out of 30 evaluable patients
developed anti-drug antibodies, prompting development of
an improved compound, AMG160 [52,53]. In turn, a phase
I trial of AMG160 monotherapy in mCRPC post ≥1 taxane
and ARPI enrolled 32 patients treated at 6 dose levels. PSA50
responses occurred in 6 out of 10 patients in dose levels 5 and
6 and 1 out of 18 patients had a RECIST response (at dose
level 4). CRS was the most common AE, occurring in 27 out of
32 (84.3%) patients, mostly in the first 2 cycles, presenting
with fever, transaminitis, and hypotension. DLTs included
rash and GI hemorrhage, both reversible [54]. An example of
another BiTE (with its tumor antigen) engaging CD3 on T-cells
in mCRPC clinical trials is AMG 509 (STEAP1)
(NCT04221542) [55].
Another mode of immunotherapy holding promise is cyto­
kine-based therapies, which may achieve a broader immuno­
logic impact beyond T-cells by having a pleiotropic effect on
the tumor microenvironment, including NK cells, myeloid-
derived suppressor cells, and tumor-associated macrophages
[56]. Clinical application of free cytokines has been largely
limited by significant toxicity, which often prevented delivery
of effective doses to the tumor [57–60]; however, develop­
ment of modified cytokines is hoped to improve tumor deliv­
ery and reduce toxicity. The multi-arm QuEST1 trial is
examining successive cumulative combinations of BNVax (a
poxviral-based vaccine against brachyury) and bintrafusp
alpha (a novel PD-L1 inhibitor with a TGF-β trap) with N-803
(an IL-15 superagonist) and epacadostat (an indoleamine 2,3
(IDO1) inhibitor). Preliminary results show four out of nine
(44%) patients in the BNVax plus bintrafusp alpha and N-803
arm having a PSA reduction by at least 30%, and two out of
three (66%) evaluable patients having a radiological response
(compared to 1/13 (7.8%) and 0/3, respectively, in the BNVax
and bintrafusp alpha only arm), possibly indicating activity of
N-803 [61]. NHS-IL12 is an immunocytokine composed of two
IL-12 heterodimers fused to an NHS76 antibody that targets
exposed DNA in areas of necrosis. A phase I/II trial combining
NHS-IL12 with docetaxel in mCSPC and mCRPC is ongoing
(NCT04633252) [62]. Preliminary data have established the
safety of the combination and the RP2D.
ADCs are another area being explored in prostate cancer.
These ADCs include antigen targets, such as six-
transmembrane epithelial antigen of prostate 1 (STEAP-1),
trophoblast antigen 2 (TROP2), PSMA, and B7 homolog 3 (B7-
H3). A phase I trial of an ADC (DSTP3086S) comprising
a humanized IgG1 STEAP-1 monoclonal antibody linked to
monomethyl-auristatin E was conducted in mCRPC [63]. The
3+3 dose escalation study treated 77 patients. DLTs included
transaminitis, hyperglycemia, and hypophosphatemia. Of the
62 patients who were treated at doses >2 mg/kg, 11 (18%) had
a PSA50 response. This evidence of antitumor activity compli­
mented the tolerable safety profile in this clinical trial
(NCT01283373). Sacituzumab govitecan (a humanized anti­
body to TROP2 combined with SN-38, the active portion of
irinotecan) is being evaluated in a phase II clinical trial of
mCRPC patients with progression on abiraterone or enzaluta­
mide (NCT03725761) [64]. This ongoing study will enroll
patients at a dose of 10 mg/kg and the primary endpoint will
be rPFS. PSMA-focused ADCs include one form, conjugated
with monomethyl-auristatin E, which has been tested in the
mCRPC setting in a phase II study (NCT01695044) [65]. In this
trial, 119 mCRPC patients who had progressed on abiraterone
or enzalutamide were treated with the PSMA ADC. PSA50
responses were seen in 14% of all treated patients. Grade 3

AEs that were the most common included fatigue, neuropa­
thy, anemia, neutropenia, and electrolyte imbalance. Another
B7-H3 monoclonal antibody, DS-7300, which has a exatecan
derivative payload, has been explored in a phase I/II study of
advanced solid tumors, including mCRPC (NCT04145622). The
mCRPC subset included a heavily pretreated population of 29
patients [66]. No patients had a treatment-emergent AE lead­
ing to discontinuation. Besides establishing an RP2D, prelimin­
ary results from this study regarding the mCRPC cohort
demonstrated 6 patients with partial responses and 15 with
stable disease. MGC018, which also targets B7-H3, but has
a duocarmycin payload, was studied in a phase I multicohort
expansion that included 26 out of 40 patients with prostate
cancer [67]. At the last follow-up, 11 out of 22 patients with
mCRPC had ≥50% PSA reduction and 4 out of 7 patients had
radiographic tumor response and reduction from 13% to 35%.
4. Conclusion
Emerging treatments are moving beyond the mostly andro­
gen-focused regimens that have dominated the approved
therapeutic strategies for years. There is a large focus on
utilizing more therapies targeted to tumor antigens by explor­
ing rational combinations. As has been practiced in the past,
most novel treatments are first evaluated in mCRPC and only
brought into earlier disease states if efficacy is proven; how­
ever, this need not be the case as long as the risk-to-benefit
ratio for use in earlier disease stages can be scientifically
justified. New therapeutics bring the promise of expanding
options and improving survival for patients in the most
advanced stages of disease. There are many practical chal­
lenges that can arise in the face of this, and creative strategies
will need to be implemented to overcome them.
5. Expert opinion
With a multitude of potential options arising in the arma­
ment of prostate cancer therapy, the future of treatment is
promising. In light of the current approach to treatment
focusing on the androgen receptor, alternative mechanisms
of action looking beyond this are crucial to move the field
forward. Moreover, in light of a trend of intensification of
treatment as an approach to the mCSPC state, having more
treatment options may allow for greater latitude in dein­
tensification of existing treatment regimens, consequently
allowing for improved quality of life. On the other hand,
multiple factors need to be considered regarding the elig­
ibility for treatment intensification for patients with mCSPC
including volume of disease (high volume or low volume),
risk of disease (high risk vs. low risk), and even use of
stereotactic radiotherapy or primary radiotherapy in the
prostate area in patients with oligometastatic disease. One
of the criteria for triplet therapy, beyond volume or high-
risk disease, includes whether patients are considered che­
motherapy-fit and likely remain to be the appropriate can­
didates for intensification therapy. Current trials continue to
further elucidate the appropriate population of patients
EXPERT REVIEW OF ANTICANCER THERAPY 629
who are deemed to benefit. For instance, further subgroup
analysis of the ARASENS trial has shown no major difference
between OS outcomes in either high-volume or low-volume
disease or in high-risk or low-risk disease, benefiting all
equally. However, as with any new treatment, there are
challenges that will need to be dealt with. One ongoing
challenge is the sequencing of therapies. Treatments with
overlapping toxicities or somewhat similar mechanisms
comprise many of the currently approved as well as the
developing options discussed above. Understanding what
appropriate sequence of treatments to maximize survival
benefits while optimizing the quality of life will be key to
utilizing the treatments in a meaningful way. Additionally,
as treatments may share overarching mechanisms, cross-
resistance may emerge that could reduce the utility of
some of the available options. Sequencing of different treat­
ment options in the mCRPC space includes prioritization of
PARPi use over ARPIs or chemotherapy in those who harbor
DNA repair gene (DDR) mutations especially BRCA1 and
BRCA2. However, there is also emerging benefit in combi­
nation therapy with ARPI and PARPi irrespective of DDR
mutations given synergistic responses and likely will
become approved soon, though not yet as of this writing.
Logistical challenges cannot be ignored as was already seen
with the issues regarding the use of lutetium in 2022, with
ongoing shortage. Utilization of such an agent on a broader
scale would require increases in capacity for production;
a principle that should be considered with regard to many
of the emerging treatments mentioned above [68]. Finally,
economic factors which have always been a significant chal­
lenge in the implementation of new treatments will be
another variable that is important to consider. However,
despite advances in therapy for mCRPC, treatment
responses lack durability especially when progression
ensues. Therefore, a search for other novel therapies with
unique mechanism of action and better understanding of
mechanisms of resistance to newer treatment options such
as lutetium must be sought.
Funding
This paper received no funding.
Declaration of interest
JAC serves on Speakers’ Bureau of Astellas/Seagen, BMS, and Pfizer/
EMD Serono; Consulting/Advisory Board Role for Bayer, Janssen,
Astellas, Sanofi/Genzyme, Merck, Pfizer/EMD Serono, AVEO, and
Immunomedics.
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
Reviewer disclosures
A reviewer on this paper is an occasional advisory board member for
Merck Sharp & Dohme, AstraZeneca, Ipsen, and Pfizer.
630 M. ATIQ ET AL.
ORCID
Elias Chandran http://orcid.org/0000-0002-0150-7765
Jeanny B. Aragon-Ching http://orcid.org/0000-0002-6714-141X
References
1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA
Cancer J Clin. 2022 Jan;72(1):7–33.
2. Siegel DA, O’Neil ME, Richards TB, et al. Prostate cancer incidence
and survival, by stage and race/ethnicity - United States,
2001-2017. MMWR Morb Mortal Wkly Rep. 2020 Oct 16;69
(41):1473–1480.
3. Han M, Partin AW, Zahurak M, et al. Biochemical (prostate spe­
cific antigen) recurrence probability following radical prostatect­
omy for clinically localized prostate cancer. J Urol. 2003 Feb;169
(2):517–523.
4. Huggins C, Stevens RE Jr., Hodges CV. Studies on prostate cancer: iI.
The effects of castration on advanced carcinoma of the prostate
gland. Arch Surg. 1941;43(2):209–223.
5. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer.
N Engl J Med. 2004 Oct 7;351(15):1502–1512.
6. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy
in metastatic hormone-sensitive prostate cancer. N Engl J Med.
2015 Aug 20;373(8):737–746.
7. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel,
zoledronic acid, or both to first-line long-term hormone therapy
in prostate cancer (STAMPEDE): survival results from an adaptive,
multiarm, multistage, platform randomised controlled trial. Lancet.
2016 Mar 19;387(10024):1163–1177.
8. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazi­
taxel or mitoxantrone for metastatic castration-resistant prostate
cancer progressing after docetaxel treatment: a randomised
open-label trial. Lancet. 2010 Oct 2;376(9747):1147–1154.
9. De Wit R, De Bono J, Sternberg CN, et al. Cabazitaxel versus
abiraterone or enzalutamide in metastatic prostate cancer. N Engl
J Med. 2019;381(26):2506–2518. DOI:10.1056/NEJMoa1911206
10. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and
increased survival in metastatic prostate cancer. N Engl J Med.
2011 May 26;364(21):1995–2005.
11. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment
of metastatic castration-resistant prostate cancer: final overall sur­
vival analysis of the COU-AA-301 randomised, double-blind,
placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13
(10):983–992.
12. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic
prostate cancer without previous chemotherapy. N Engl J Med.
2013 Jan 10;368(2):138–148.
13. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzaluta­
mide in prostate cancer after chemotherapy. N Engl J Med. 2012
Sep 27;367(13):1187–1197.
14. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in meta­
static prostate cancer before chemotherapy. N Engl J Med. 2014 Jul
31;371(5):424–433.
15. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and
metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr
12;378(15):1408–1418.
16. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmeta­
static, castration-resistant prostate cancer. N Engl J Med. 2019 Mar
28;380(13):1235–1246.
17. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with non­
metastatic, castration-resistant prostate cancer. N Engl J Med. 2018
Jun 28;378(26):2465–2474.
18. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in
metastatic, castration-sensitive prostate cancer. N Engl J Med.
2017 Jul 27;377(4):352–360.
19. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate
cancer not previously treated with hormone therapy. N Engl J Med.
2017 Jul 27;377(4):338–351.
20. Davis ID, Martin AJ, Zielinski RR, et al. Updated overall survival
outcomes in ENZAMET (ANZUP 1304), an international, cooperative
group trial of enzalutamide in metastatic hormone-sensitive pros­
tate cancer (mHSPC). J Clin Oncol. 2022;40(17_suppl):LBA5004–
LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004.
21. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard
first-line therapy in metastatic prostate cancer. N Engl J Med.
2019;381(2):121–131. DOI:10.1056/NEJMoa1903835
22. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic,
castration-sensitive prostate cancer. N Engl J Med. 2019 Jul 4;381
(1):13–24.
23. Chi KN, Chowdhury S, Bjartell A, et al. Final analysis results from
TITAN: a phase III study of apalutamide (APA) versus placebo (PBO)
in patients (pts) with metastatic castration-sensitive prostate cancer
(mCSPC) receiving androgen deprivation therapy (ADT). J Clin Oncol.
2021;39(6_suppl):11–11. doi:10.1200/JCO.2021.39.6_suppl.11.
24. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in
metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022
Mar 24;386(12):1132–1142.
25. Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone
added to androgen deprivation therapy and docetaxel in de
novo metastatic castration-sensitive prostate cancer (PEACE-1):
a multicentre, open-label, randomised, phase 3 study with a 2 × 2
factorial design. Lancet. 2022;399(10336):1695–1707. DOI:10.1016/
S0140-6736(22)00367-1
26. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and
survival in metastatic prostate cancer. N Engl J Med. 2013 Jul
18;369(3):213–223.
27. Pandit-Taskar N, Batraki M, Divgi CR. Radiopharmaceutical therapy
for palliation of bone pain from osseous metastases. J Nucl Med.
2004 Aug;45(8):1358–1365.
28. Seider MJ, Pugh SL, Langer C, et al. Randomized phase III trial to
evaluate radiopharmaceuticals and zoledronic acid in the palliation
of osteoblastic metastases from lung, breast, and prostate cancer:
report of the NRG Oncology RTOG 0517 trial. Ann Nucl Med. 2018
Oct;32(8):553–560.
29. Hofman MS, Emmett L, Sandhu S, et al. [(177)lu]lu-PSMA-617 versus
cabazitaxel in patients with metastatic castration-resistant prostate
cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet.
2021 Feb 27;397(10276):797–804.
30. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for
metastatic castration-resistant prostate cancer. N Engl J Med.
2021 Sep 16;385(12):1091–1103.
31. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunother­
apy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul
29;363(5):411–422.
32. Schellhammer PF, Chodak G, Whitmore JB, et al. Lower baseline
prostate-specific antigen is associated with a greater overall survi­
val benefit from sipuleucel-T in the immunotherapy for prostate
adenocarcinoma treatment (IMPACT) trial. Urology. 2013 Jun;81
(6):1297–1302.
33. Marcus L, Lemery SJ, Keegan P, et al. FDA approval summary:
pembrolizumab for the treatment of microsatellite instability-high
solid tumors. Clin Cancer Res. 2019 Jul 1;25(13):3753–3758.
34. Marabelle A, Fakih M, Lopez J, et al. Association of tumour muta­
tional burden with outcomes in patients with advanced solid
tumours treated with pembrolizumab: prospective biomarker ana­
lysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
Lancet Oncol. 2020 Oct;21(10):1353–1365.
35. Beer TM, Kwon ED, Drake CG, et al. Randomized, double-blind,
phase iii trial of ipilimumab versus placebo in asymptomatic or
minimally symptomatic patients with metastatic
chemotherapy-naive castration-resistant prostate cancer. J Clin
Oncol. 2017;35(1):40–47. DOI:10.1200/JCO.2016.69.1584
36. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after
radiotherapy in patients with metastatic castration-resistant pros­
tate cancer that had progressed after docetaxel chemotherapy
(CA184-043): a multicentre, randomised, double-blind, phase 3
trial. Lancet Oncol. 2014;15(7):700–712. DOI:10.1016/S1470-
2045(14)70189-5

37. Sweeney CJ, Gillessen S, Rathkopf D, et al. Abstract CT014:
iMbassador250: a phase III trial comparing atezolizumab with enza­
lutamide vs enzalutamide alone in patients with metastatic
castration-resistant prostate cancer (mCRPC). Cancer Res. 2020;80(16
Supplement):CT014–CT014. doi:10.1158/1538-7445.AM2020-CT014.
38. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic
castration-resistant prostate cancer. N Engl J Med. 2020 May
28;382(22):2091–2102.
39. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with
metastatic castration-resistant prostate cancer harboring a BRCA1
or BRCA2 gene alteration. J Clin Oncol. 2020 Nov 10;38
(32):3763–3772.
40. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in meta­
static castration-resistant prostate cancer. N Engl J Med. 2020;383
(24):2345–2357. DOI:10.1056/NEJMoa2022485
41. Smith MR, Scher HI, Sandhu S, et al. Niraparib in patients with
metastatic castration-resistant prostate cancer and DNA repair
gene defects (GALAHAD): a multicentre, open-label, phase 2 trial.
Lancet Oncol. 2022 Mar;23(3):362–373.
42. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and
olaparib for metastatic castration-resistant prostate cancer. NEJM
Evi. 2022;1(9):EVIDoa2200043.
43. Agarwal N, Azad A, Carles J, et al. TALAPRO-2: phase 3 study of
talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) +
ENZA as first-line (1L) treatment in patients (pts) with metastatic
castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41
(6_suppl):LBA17–LBA17. doi:10.1200/JCO.2023.41.6_suppl.LBA17.
44. Sartor AO, Morris MJ, Chi KN, et al. Psmafore: a phase 3 study to
compare 177Lu-PSMA-617 treatment with a change in androgen
receptor pathway inhibitor in taxane-naïve patients with metastatic
castration-resistant prostate cancer. J Clin Oncol. 2022;40(6_suppl):
TPS211–TPS211. doi:10.1200/JCO.2022.40.6_suppl.TPS211.
45. Sartor AO, Tagawa ST, Saad F, et al. Psm addition: a phase 3 trial to
compare treatment with 177Lu-PSMA-617 plus standard of care
(SOC) versus SOC alone in patients with metastatic
hormone-sensitive prostate cancer. J Clin Oncol. 2022;40(6_suppl):
TPS210–TPS210. doi:10.1200/JCO.2022.40.6_suppl.TPS210.
46. Aggarwal RR, Sam SL, Koshkin VS, et al. Immunogenic priming with
177Lu-PSMA-617 plus pembrolizumab in metastatic castration
resistant prostate cancer (mCRPC): a phase 1b study. J Clin Oncol.
2021;39(15_suppl):5053–5053. doi:10.1200/JCO.2021.39.15_suppl.
5053.
47. Targeted Alpha Therapy Working G, Parker C, Lewington V,
Shore N, et al. Targeted alpha therapy, an emerging class of cancer
agents: a review. JAMA Oncol. 2018 Dec 1;4(12):1765–1772. doi: 10.
1001/jamaoncol.2018.4044.
48. Tagawa ST, Osborne J, Fernandez E, et al. Phase I dose-escalation
study of PSMA-targeted alpha emitter 225Ac-J591 in men with
metastatic castration-resistant prostate cancer (mCRPC). J Clin
Oncol. 2020;38(15_suppl):5560–5560. doi:10.1200/JCO.2020.38.15_
suppl.5560.
49. Tagawa ST, Sun M, Sartor AO, et al. Phase I study of 225Ac-J591 for
men with metastatic castration-resistant prostate cancer (mCRPC).
J Clin Oncol. 2021;39(15_suppl):5015–5015. doi:10.1200/JCO.2021.
39.15_suppl.5015.
50. Narayan V, Barber-Rotenberg JS, Jung IY, et al. PSMA-targeting
TGFbeta-insensitive armored CAR T cells in metastatic
castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022
Apr;28(4):724–734.
51. Dorff TB, Blanchard S, Martirosyan H, et al. Phase 1 study of
PSCA-targeted chimeric antigen receptor (CAR) T cell therapy for
EXPERT REVIEW OF ANTICANCER THERAPY 631
metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol.
2022;40(6_suppl):91–91. doi:10.1200/JCO.2022.40.6_suppl.091.
52. Hummel HD, Kufer P, Grüllich C, et al. Pasotuxizumab, a BiTE( ) ®
immune therapy for castration-resistant prostate cancer: phase I,
dose-escalation study findings. Immunotherapy. 2021 Feb;13
(2):125–141.
53. Kamat NV, Yu EY, Lee JK. BiTE-ing into prostate cancer with bispe­
cific T-cell engagers. Clin Cancer Res. 2021;27(10):2675–2677.
54. Tran B, Horvath L, Dorff T, et al. 609O results from a phase I study of
AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific
®
T-cell engager (BiTE ) immune therapy for metastatic castration-
resistant prostate cancer (mCRPC). Ann Oncol. 2020;31:S507.
55. Danila DC, Waterhouse DM, Appleman LJ, et al. A phase 1 study of
AMG 509 in patients (pts) with metastatic castration-resistant pros­
tate cancer (mCRPC). J Clin Oncol. 2022;40(16_suppl):TPS5101–
TPS5101. doi:10.1200/JCO.2022.40.16_suppl.TPS5101.
56. Chandran E, Meininger L, Karzai F, et al. Signaling new therapeutic
opportunities: cytokines in prostate cancer. Expert Opin Biol Ther.
2022 Oct 03;22(10):1233–1243.
57. Ruef C, Coleman DL. Granulocyte-macrophage colony-stimulating
factor: pleiotropic cytokine with potential clinical usefulness. Rev
Infect Dis. 1990;12(1):41–62.
58. Cohen J. IL-12 deaths: explanation and a puzzle. Science. 1995;270
(5238):908–908. DOI:10.1126/science.270.5238.908.a.
59. Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol. 1991;9
(4):694–704.
60. Maas RA, Dullens HFJ, Den Otter W. Interleukin-2 in cancer treat­
ment: disappointing or (still) promising? A review. Cancer Immunol
Immunother. 1993;36(3):141–148.
61. Redman JM, Madan RA, Karzai F, et al. 616MO efficacy of BN-brachyury
(BNVax) + bintrafusp alfa (BA) + N-803 in castration-resistant prostate
cancer (CRPC): results from a preliminary analysis of the quick efficacy
seeking trial (QuEST1). Ann Oncol. 2020;31:S511.
62. Atiq MO, Chandran EBA, Meininger L, et al. Safety evaluation of M9241
in combination with docetaxel in metastatic prostate cancer. J Clin
Oncol. 2022;40(6_suppl):93–93. doi:10.1200/JCO.2022.40.6_suppl.093.
63. Danila DC, Szmulewitz RZ, Vaishampayan U, et al. Phase I study of
DSTP3086S, an antibody-drug conjugate targeting six-transmembrane
epithelial antigen of prostate 1, in metastatic castration-resistant prostate
cancer. J Clin Oncol. 2019 Dec 20;37(36):3518–3527.
64. Lang JM, Kyriakopoulos C, Slovin SF, et al. Single-arm, phase II
study to evaluate the safety and efficacy of sacituzumab govitecan
in patients with metastatic castration-resistant prostate cancer who
have progressed on second generation AR-directed therapy. J Clin
Oncol. 2020;38(6_suppl):TPS251–TPS251. doi:10.1200/JCO.2020.38.
6_suppl.TPS251.
65. Petrylak DP, Vogelzang NJ, Chatta K, et al. PSMA ADC monotherapy
in patients with progressive metastatic castration-resistant prostate
cancer following abiraterone and/or enzalutamide: efficacy and
safety in open-label single-arm phase 2 study. Prostate. 2020;80
(1):99–108. DOI:10.1002/pros.23922
66. Patel MR, Johnson ML, Falchook GS, et al. DS-7300 (B7-H3
DXd-ADC) in patients (pts) with metastatic castration-resistant
prostate cancer (mCRPC): a subgroup analysis of a phase 1/2 multi­
center study. J Clin Oncol. 2022;40(6_suppl):87–87. doi:10.1200/
JCO.2022.40.6_suppl.087.
67. Shenderov E, Mallesara GHG, Wysocki PJ, et al. 620P MGC018, an
anti-B7-H3 antibody-drug conjugate (ADC), in patients with
advanced solid tumors: preliminary results of phase I cohort
expansion. Ann Oncol. 2021;32:S657–659.
68. Chandran E, Figg WD, Madan R. Lutetium-177-PSMA-617: a vision
of the future. Cancer Biol Ther. 2022 Dec 31;23(1):186–190.