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Title
Celebrating the 80th anniversary of hormone ablation for prostate cancer.
Permalink
https://escholarship.org/uc/item/8946b7zn
Journal
Endocrine Related Cancer, 28(8)
ISSN
1351-0088
Authors
Zoubeidi, Amina
Ghosh, Paramita M
Publication Date
2021
DOI
10.1530/erc-21-0192
Peer reviewed
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Endocrine-Related
Cancer
A Zoubeidi and P M Ghosh
Hormone ablation treatment
in prostate cancer
28:8
T1–T10
THEMATIC REVIEW
Celebrating the 80th anniversary of hormone
ablation for prostate cancer
Amina Zoubeidi
1 and Paramita M Ghosh2,3,4
1Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
2Department of Urologic Surgery, School of Medicine, University of California Davis, Sacramento, California, USA
3Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, California, USA
4Department of Veterans Affairs, Northern California Health Care System, Mather, California, USA
Correspondence should be addressed to A Zoubeidi: azoubeidi@prostatecentre.com
This paper is part of a thematic review section celebrating 80 Years of Androgen Deprivation as a Treatment for Prostate Cancer. The guest editors for
this section were Amina Zoubeidi and Paramita Ghosh. They were not involved in the review or editorial process for this paper, on which they are
listed as authors.
Abstract
In this issue of Endocrine-Related Cancer, we are celebrating the 80th anniversary of
hormone ablation as treatment for metastatic prostate cancer. Our understanding
has evolved from the observation that androgen withdrawal, either surgical or
pharmacological, resulted in prostatic atrophy in animal models, to its application
in patients, to investigation of the mysterious way in which prostate cancer escapes
androgen dependence. We are now in an era of novel AR pathway inhibitors,
the combination of androgen ablation with chemotherapy, PARP inhibitors,
immunotherapies, guided radiotherapy, and novel drug application based upon genetic
testing of individual tumors. In this special issue, we bring together a collection of
eight reviews that cover not only the history of 80 years of progress after the initial
identification of androgen ablation as an effective treatment of prostate cancer,
but subsequent improvements in the understanding of the biology of the disease,
development of novel treatment paradigms, resistance to those treatments and disease
progression following that resistance.
Key Words
ff prostate
ff androgen
ff androgen receptor
ff endocrine therapy
Endocrine-Related Cancer
(2021) 28, T1–T10
Introduction
Localized prostate cancer can be treated with surgery;
however, metastasized prostate cancer is usually treated
with hormonal ablation. Improved diagnostic tools and
earlier diagnosis has helped increase the 10-year survival
of prostate cancer patients (Helgesen et al. 1996). By 1998,
the 10-year relative survival for patients diagnosed with
local and regional disease improved to 95% (Brawley 2012),
and is near 100% today. Five-year survival for distant-stage
prostate cancer improved to 32.3% by 2016 and remains at
that level today (Siegel et al. 2020).
https://erc.bioscientifica.com
https://doi.org/10.1530/ERC-21-0192
© 2021 Society for Endocrinology
Published by Bioscientifica Ltd.
Printed in Great Britain
In this special issue of Endocrine-Related Cancer,
we are celebrating the 80th anniversary of hormone
ablation as a treatment for metastatic prostate
cancer. Our understanding has evolved from the
observation that androgen withdrawal, either surgical
or pharmacological, resulted in prostatic atrophy in
animal models, to its application in patients, to the
investigation of the mysterious way in which prostate
cancer escapes androgen dependence. We are now in
an era of novel AR pathway inhibitors, the combination
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Endocrine-Related
Cancer
A Zoubeidi and P M Ghosh
of androgen ablation with chemotherapy, PARP
inhibitors, immunotherapies, guided radiotherapy,
and novel drug application based upon genetic testing
of individual tumors (Fig. 1). In this Anniversary Issue,
we bring together a collection of eight reviews that
cover not only the history of 80 years of progress after
the initial identification of androgen ablation as an
effective treatment of prostate cancer, but subsequent
improvements in the understanding of the biology of
the disease, development of novel treatment paradigms,
resistance to those treatments and disease progression
following that resistance.
History
In an article in this special issue, 'Targeting androgen
receptor signaling: a historical perspective', Davies &
Zoubeidi (2021) outline the history of prostate cancer
treatment using androgen ablation. An 18th century
observation laid the foundation for the most important
discovery of the 20th century in prostate cancer. The
concept of androgen ablation was discussed as early as 1786
when John Hunter demonstrated that castration prevents
prostate development in young bulls while inducing
atrophy in adults (Hunter 1837). It was not until 1941 that
Charles Huggins and Clarence Hodge performed the first
castration surgically or by estrogen administration in eight
patients with metastatic prostate cancer (Huggins et al.
1941). They observed that castration resulted in a decrease
of serum acid-phosphatase and subsequently an increase
in patient quality of life.
Hormone ablation treatment
in prostate cancer
28:8
T2
Targeting adrenal androgen production
In early 1960s, multiple clinical trials provided evidence
that androgen ablation was merely palliative and not
sufficient to cure prostate cancer, as Huggins noted that
regression of the neoplasm is not complete (Huggins et al.
1941). Facing this challenge, new approaches of hormone
manipulation were developed between 1960s and 1980s
to block adrenal androgen production or androgen
interaction to androgen receptor (Pavone-Macaluso et al.
1986, 1997, Trachtenberg et al. 2002). This was possible
with the discovery of the structure of the hypothalamic
hormone known as luteinizing hormone (LH)-releasing
hormone (LHRH), which was shown to induce the
pituitary to produce LH. LH binds to its receptor on the
testes and activates testosterone production (outlined in
Messner et al. 2020). Schally and Guillemin investigated
ways to manipulate the hypothalamic–pituitary–gonadal
axis and developed the first synthetic peptide agonists
of LHRH (Tolis et al. 1982). Similarly, the antifungal
ketoconazole (non-specific inhibitor of several cytochrome
enzymes, involved in steroidogenesis including CYP17)
accomplished PSA responses in some patients (Small et al.
1997, Kruit et al. 2004, Peer et al. 2014), but did not improve
overall survival. This was traced to the fact that resistance to
the treatment was observed in the majority of the patients.
Targeting the androgen receptor
The discovery of androgen receptor (AR) in late 1960s
(Anderson & Liao 1968, Bruchovsky & Wilson 1968,
Mainwaring 1969) revolutionized how we treat prostate
Figure 1
Treatment evolution of metastatic prostate cancer.
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cancer today. The first AR antagonist targeting the AR
ligand binding domain (LBD) proved to be as effective as
castration (Pavone-Macaluso et al. 1986) and was approved
by the US Federal Drug Administration (FDA) in late 1980s,
which was followed by the development of non-steroidal
anti-androgens, such as flutamide in 1989 and biclutamide
in 1995, as treatment for prostate cancer (Wirth et al. 2007).
Similar to castration, LHRH agonist/antagonist or AR
inhibitors as monotherapy were shown to be ineffective,
which shaped the path for combination therapy (Labrie
et al. 1982, Lefebvre et al. 1982). Meta-analysis from 27
phase III clinical trials concluded that combined androgen
blockade improved 5-year survival by about 5% (Caubet
et al. 1997, Bennett et al. 1999, Schmitt et al. 2001, Klotz
2008, Mitsiades et al. 2011); however, it invariably led to the
development of castrate-resistant prostate cancer (CRPC)
(Sayyid et al. 2017).
Reviving old concepts with potent inhibitors
In 'Androgen receptor signaling inhibitors: postchemotherapy, pre-chemotherapy and now in castrationsensitive prostate cancer', Mitsiades & Kaochar (2021) ask
'Can a more comprehensive approach targeting all sources
of androgenic stimulation delay emergence of resistance
to ADT?' The development of CRPC was proposed to be
caused by the low potency of AR antagonists and most
likely prone to 'antagonist-to-agonist' conversion which
was noticed in 15–30% CRPC treated patients (Kelly &
Scher 1993, Leone et al. 2018). This phenomenon was also
attributed to dysregulation of the AR complex via somaticacquired events, including AR LBD gain-of-function
mutations, AR amplification, overexpression, altered
recruitment of steroid receptor coactivators (Culig et al.
1999, Chen et al. 2004, 2009, Leone et al. 2018) as well as
de novo synthesis of androgen via cholesterol metabolism
(Locke et al. 2008, Cai et al. 2011). CYP17A1, a member
of the cytochrome P450 enzyme family, promotes the
synthesis of steroid hormones including testosterone and
dehydroepiandrosterone (DHEA), both precursors of the
strong AR ligand dihydrotestosterone (DHT) (outlined in
Messner et al. 2020). These findings provided the rationale
for drug discovery screens to identify novel anti-androgens
and novel CYP17 inhibitors with better pharmacodynamics
and more durable responses.
Despite the fact that ketoconazole itself did not show
a survival benefit, it did serve as a forerunner of CYP17
inhibitors. Abiraterone acetate (Abi) was developed as
a more effective inhibitor of CYP17 with significantly
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T3
higher potency and selectivity than ketoconazole (Barrie
et al. 1994, Potter et al. 1995, Rowlands et al. 1995, Haidar
et al. 2003). The first phase I study for Abi enrolled 21
men with chemotherapy-naïve CRPC and found that
Abi-treated patients experienced significant tumor
shrinkage and dramatic falls in prostate-specific antigen
(PSA) levels (Attard et al. 2008). In 2010, the pivotal phase
III COU-AA-301 trial showed survival benefit and was
approved in 2011 (de Bono et al. 2011).
Since CRPC was still driven by AR, second-generation
AR LBD inhibitors were developed, including enzalutamide,
apalutamide and darolutamide. Enzalutamide was initially
tested in men with metastatic CRPC previously treated
with docetaxel-based chemotherapy in the phase III
AFFIRM trial, showed positive survival benefits (Scher
et al. 2012) and was approved by the FDA in 2012 for latestage CRPC. Additional successful phase III clinical trials
on enzalutamide were conducted including PREVAIL in
men with asymptomatic metastatic CRPC without prior
chemotherapy (Beer et al. 2014), and the ARCHES trial
on men with high risk of metastatic progression or death
in the castration-sensitive (CSPC) setting (Armstrong
et al. 2019). It was later expanded to the setting of nonmetastatic CRPC (nmCRPC) in 2018 (Sternberg et al. 2020)
and metastatic CSPC in 2019 (Davis et al. 2019). In addition,
other AR inhibitors apalutamide and darolutamide which
have improved safety profiles compared to enzalutamide,
have also been approved for non-metastatic CRPC (Fizazi
et al. 2019, 2020) or for metastatic CSPC (Chi et al. 2019).
Following clinical integration of second-line hormone
therapy, growing evidence shows that CRPC patients
are progressing on CYP17 and AR inhibitors even when
they were administered sequentially (Loriot et al. 2013,
Noonan et al. 2013, Bianchini et al. 2014, Azad et al. 2015,
Attard et al. 2018, de Bono et al. 2018, Khalaf et al. 2019).
Cross-resistance between these two classes of AR pathway
inhibitors (ARPI) is not surprising, as several mechanisms
can provide resistance to both CYP17 inhibitors and
second generation anti-AR including constitutively active
AR variants (including ARv7).
Hormonotherapy and the
bone microenvironment
In 'Second-generation hormonotherapy in prostate
cancer and bone microenvironment', Bouleftour et al.
(2021) discuss the effect of androgen ablation and secondgeneration anti-androgens on the bone. Proper functioning
of the AR is essential both for bone development and for
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A Zoubeidi and P M Ghosh
bone mass maintenance (Bellido et al. 1995, Kawano et al.
2003, Chen et al. 2019). As a result, androgen ablation is
significantly associated with bone loss and increased risk
of bone fractures (Abu et al. 1997, Notelovitz 2002). In
addition, most prostate cancer patients weare older, and
naturally undergo age-related decline in hormonal levels
and are highly prone to bone loss (Manolagas et al. 2013).
The receptor activator of NF-κB ligand (RANKL) gene,
which encodes a major osteoclastogenesis inducer, was
found to be a major regulator of bone density regulated
by androgens (Kawano et al. 2003). Denosumab, a fully
human MAB against RANKL, is used to improve bone
mineral density and fractures in men receiving androgendeprivation therapy for non-metastatic prostate cancer
(Smith et al. 2009). Despite this, prostate cancer patients,
especially those who are older, suffer significantly from
bone loss and related side effects. Bouleftour et al. (2021)
argue that currently, specific recommendations for bone
health management in prostate cancer patients are lacking,
and prospective studies assessing bone mineral density
in patients treated with second-generation hormone
therapy has not been conducted. It may be hoped that the
collection of information provided in this issue would pave
the way for such a study.
Emergence of aggressive variant
prostate cancer
Two articles in this special issue, 'The heterogeneity of
prostate cancers lacking AR activity will require diverse
treatment approaches' by Labrecque et al. (2021) and
'Therapy considerations in neuroendocrine prostate
cancer: what next?' by Beltran & Demichelis (2021) describe
the advent of aggressive variant prostate cancers. Labrecque
et al. describes AR indifferent and AR inactive prostate
cancer and identify the role of SOX2, nBAF and LSD1 in the
development of neuroendocrine prostate cancer. Beltran
and Demichelis focus mainly on therapeutic aspects of
neuroendocrine prostate cancer and identify numerous
biomarkers that can predict its outcome.
With drugs targeting the AR pathway used in earlier
disease settings, patients are living longer with longer
exposure to systemic therapies. However, systemic therapies
are not curative, and the treatment-resistant state remains
a major medical problem. With the integration of potent
ARPI, the archetypal course of prostate cancer was altered
by the emergence of aggressive variants of prostate cancer
with activated lineage programs. This includes amphicrine
(expresses AR activity and neuroendocrine (NE) markers,
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retains luminal differentiation programs); AR-low (expresses
low AR, high level of PSA and lacks NE markers); doublenegative prostate cancer (DNPC: lacks AR expression and
activity and lacks NE markers) (Labrecque et al. 2019) and the
treatment-induced neuroendocrine prostate cancer (NEPC: loss
of AR signaling, expresses neuroendocrine markers) (Beltran
et al. 2011, 2016). The complexity surrounding the transition
from an AR-dependent to an AR-indifferent phenotype has
made it difficult to define histological or molecular features
that consistently associate with the emerging CRPC
phenotypes. Currently, no morphological characteristics
have been described in clinical specimens to delineate an
AR-active from an AR-inactive phenotype in AR-expressing
CRPC. Furthermore, it is not yet clear that morphological
features associate with the full spectrum of molecular
phenotypes of NEPC (Beltran et al. 2011, 2016, Aggarwal
et al. 2018, Labrecque et al. 2019). With exception of loss of
PTEN, RB1 and TP53, genomic analyses have not clarified
genomic features that reliably distinguish these phenotypes
or that can be used to predict risk of conversion to AR-null
or NE-positive states. Epigenetic alterations, including
changes in DNA methylation, chromatin accessibility,
SWI/SNF, and histone markers are distinguishing features
of NEPC, suggesting a key role of epigenetics in driving
prostate cancer adenocarcinoma to NEPC (Dardenne et al.
2016, Cyrta et al. 2020, Baca et al. 2021). Activation and
coordination of lineage determining transcription factors
(e.g. ASCL1, BRN2, ONECUT2, MYCN, FOXA1) (Lee et al.
2016, Bishop et al. 2017, Guo et al. 2019, Baca et al. 2021) and
pluripotency factors (e.g. SOX2) (Bishop et al. 2017) and
downregulation of REST (Zhang et al. 2015) appear to drive
lineage programming. This lineage reprogramming may be
mediated by an intermediary, de-differentiated ‘stem like’
state before cells differentiate toward a NE-like phenotype
with loss of AR dependence. Patient with aggressive variants
of prostate cancer is treated with systemic therapy regimen.
The combination of cabazitaxel and carboplatin is now
supported by NCCN guidelines as an option for patients
with aggressive variant clinical features or unfavorable
genomics (loss of function alterations involving at least two
of PTEN, TP53, and RB1) (Suzuki et al. 2020).
Beyond hormone therapy DNA repair
machinery targeting
While AR-dependent transcriptional activity is the main
driver of prostate cancer progression, genomic instability
is a major feature of prostate cancer. This phenomenon is
described by Díaz-Mejía et al. (2021) in this special issue
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in the article entitled 'PARP inhibitors in prostate cancer:
when to use them?'. This genomic instability is related
to AR pathway and chronic inflammation leading to
increased DNA damage (Godwin et al. 2013, Polkinghorn
et al. 2013). These alterations in double-strand break repair
genes will lead to impairment of error-free homologous
recombination-mediated repair, favoring genomic
instability and replicative stress. In prostate cancer,
mutations of genes of the homologous recombination
repair (HRR) and double strand break (DSB) pathways,
mainly BRCA2, FANCA, RAD51 or PALB2; ATM, CHEK2 or
CDK12, were observed 20–30% of patients with advanced
prostate cancer (Abida et al. 2017, Chung et al. 2019). Some
of these mutations arise in the germline DNA and are
hereditary and were found in other cancers, including
pancreatic, ovarian and breast cancer (Sokolova et al.
2020), suggesting patients with prostate cancer can benefit
from genetic testing and selected therapy beyond ARPI
using PARP inhibitors. Hence PARP inhibitors were tested
in multiple clinical trials, including the PROFOUND study
(de Bono et al. 2020). This trial was structured around two
cohorts: cohort A included 245 patients with mutations in
BRCA1, BRCA2 or ATM; cohort B included 142 patients with
alterations in any of the 12 other prespecified genes (BRIP1,
BARD1, CDK12, 363 CHEK1, CHEK2, FANCL, PALB2,
PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L). The
trial met the predefined threshold for overall survival
and the PARP inhibitor olaparib was approved by FDA in
2020 for men with mCRPC and different DNA repair gene
mutations offering a new treatment for these patients.
Immunotherapy
Although the effects of DNA repair defects and genetic/
epigenetic aberrations on the cell division machinery
are increasingly well-defined, it has become evident that
the tumor microenvironment (TME), including stroma,
endothelial and immune cells, plays an important role
in prostate cancer disease progression and survival
(Hinshaw & Shevde 2019). In this special issue, Kwon,
Bryant and Parkes describe the role of immunotherapy
in prostate cancer treatment in the article 'The tumor
microenvironment and immune responses in prostate
cancer' (Kwon et al. 2021). Large phase III clinical trials
have failed to show improvement in overall survival with
ipilimumab (a CTLA-4 inhibitor) (Kwon et al. 2014, Beer
et al. 2017). However, these trials did demonstrate an
acceptable toxicity profile, improved PFS with ipilimumab,
and PSA response. Because of the limited benefit of
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monotherapy in the general setting, it was suggested
that investigators select patients based on high genomic
instability or mismatch repair efficiency that is known
to increase neoantigen load with increased immune
infiltration (Graham et al. 2020). Analysis of five clinical
trials revealed that patients harboring genomic instability
who received pembrolizumab reach objective response
rate (Marcus et al. 2019). Because of the limited benefit of
monotherapy, ongoing trials are investigating combination
immunotherapy. For instance, the CheckMate trial
evaluated ipilimumab and nivolumab for patients with
mCRPC. Initial results have shown a response rate of 26%
in the chemotherapy-naïve cohort and 10% in the group
who failed taxane-based therapy (Sharma et al. 2020).
Radiation therapy
Throughout the advances in the last several decades,
radiotherapy (RT) has remained a pillar of treatment in
localized advanced disease. Importantly, the addition of
hormone therapy to adjuvant RT resulted in a significant
improvement in progression-free survival (Pilepich et al.
2005). Sandoval, Dohm and Yamoah, in this special
issue, describe the role of radiotherapy, with or without
immunotherapy in 'Management of early-stage metastatic
prostate cancer: appraisal of locoregional treatments and
radiation therapy, with or without immunomodulation'
(Sandoval et al. 2021). Analysis of the RTOG 9408 study
showed that the benefit of hormone therapy was seen mostly
in intermediate-risk disease and was likely insufficient for
men with high-risk disease (Jones et al. 2011). In a large
retrospective analysis of over 1300 post-prostatectomy
patients who were either placed under observation or given
hormone therapy ± adjuvant RT showed significant increase
in overall survival using androgen deprived therapy plus RT
(Touijer et al. 2018). However, the HORRAD trial showed no
difference in the overall survival in patient that received
hormone therapy to those that received RT + hormone
therapy (Boeve et al. 2019). Radium-223 is an alpha
emitter that has been shown to target highly proliferative
bone metastases (Bruland et al. 2006, Gomez-Veiga et al.
2018). Development of advanced assays and genomic risk
stratification has increased the spectrum of using RT in
prostate cancer. However, the use of RT in biochemicalrecurrent disease was challenging because of the lack of
sensitive modalities to detect positive nodes. Recently
a very sensitive approach was developed based on the
prostate-specific membrane antigen (PSMA) PET/CT
imaging and become the recommended imaging
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modality in the setting of rising PSA (Gillessen et al. 2020).
Interestingly, PSMA can be used beyond imaging not only
for PET imaging but in the linking to the beta emitter
lutetium-177, which has provided a novel approach to treat
prostate cancer patients showing an average PSA decline
in 75% of patients, which was supported by radiographic
evidence of objective responses and stable disease (Yadav
et al. 2019).
Current perspectives
Over 80 years, tremendous advances were achieved
leading to changes in clinical practice. We built
on observations from 19th and 20th centuries and
developed potent AR pathway inhibitors, discovered and
validated novel markers, established novel modalities
for imaging and treatment and innovated on how to
run clinical trials. We accepted that prostate cancer is
not one disease. Today, we stratify patients and employ
genetic testing. Yet, metastatic prostate cancer patients
still die with treatment-resistant aggressive disease. We
are advancing our understanding of mechanisms of
treatment resistance, identifying targets and novel drugs.
However, the only way we can save lives is to conduct
clinical studies, which will be challenging, especially
for rare phenotypes. We recommend embracing the
concept of the STAMPEDE trial to tackle this problem.
Briefly, STAMPEDE was initiated in 2005, and it is an
ongoing multi-arm, multistage randomized clinical
trial conducted in the United Kingdom and Switzerland
testing various treatment in newly diagnosed or relapsing
high risk, node-positive, or metastatic prostate cancer
patients initiating long term hormone therapy. The
unique trial design permits for test arms to be added
over time and compared with contemporary standard
of care single ongoing control arm. Overall, STAMPEDE
has established docetaxel, abiraterone, and radiotherapy
as new first-line treatment options. 4000 patients have
experienced a survival benefit on the completed arms
in STAMPEDE (James et al. 2017, Parker et al. 2018,
Clarke et al. 2019, 2020). We hope that with this series
of reviews in this issue of Endocrine-Related Cancer, future
investigators will better understand the scope of the work
needed to make such a trial easier to implement.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of this review.
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Funding
The authors did not receive any specific grant from any funding agency in
the public, commercial or not-for-profit sector for this work.
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