TRECAN 00489 No.

of Pages 14

Trends in Cancer

Review

Advanced Prostate Cancer: Treatment

Advances and Future Directions
Umang Swami,1 Taylor R. McFarland,1 Roberto Nussenzveig,1 and Neeraj Agarwal1,*

Prostate cancer affects one in every nine men in the USA and is the second Highlights
leading cause of cancer-related death. The treatment landscape of advanced Three novel androgen axis inhibi-
prostate cancer is changing rapidly. Multiple agents including abiraterone, tors, abiraterone, apalutamide, and
enzalutamide, have recently been
enzalutamide, apalutamide, darolutamide, docetaxel, cabazitaxel, radium-223,
approved in metastatic castrate-
and sipuleucel-T have been approved for advanced prostate cancer. Appropriate sensitive prostate cancer.
drug selection remains crucial in this evolving landscape to derive maximum
benefit for the patients. We summarize clinical trials leading to recent drug Abiraterone, docetaxel, and enzalutamide
are the front-line treatments for metastatic
approvals and discuss optimal treatment selection. We also review recent castrate-resistant disease, as well as
advances in genomics including its evolving role in prognosis, in elucidating sipuleucel-T and radium-223 that are
mechanisms of treatment resistance, and in guiding treatment decisions. used in selected patients.

Advances in liquid genomics have the

Management of Advanced Prostate Cancer potential to guide the management of
Prostate cancer is the most common non-cutaneous malignancy among men in the USA and prostate cancer in the near future.
is the second most common cause of cancer-related death [1]. It is estimated to account for
Precision medicine such as treatments
191 930 (21%) new cases and 33 330 (10%) cancer-related deaths in 2020 [1]. The lifetime
directed towards specific mutations,
risk of developing prostate cancer is 11.6% [1]. Although localized prostate cancer has a N99% such as PARP inhibitors and prostate-
5 year survival rate, advanced prostate cancer is usually considered to be incurable [1,2]. The specific membrane antigen (PSMA)-
term 'advanced prostate cancer' is defined here as prostate cancer that has recurred after based radionucleotides, will soon open
new avenues for treatment of metastatic
definitive therapy (surgery and/or radiation), or that presents with metastatic disease without castrate-resistant prostate cancer.
prior local therapy. We focus here on the management of metastatic castrate-sensitive
prostate cancer (mCSPC, see Glossary), non-metastatic castrate-resistant prostate cancer
(M0CRPC), and metastatic castrate-resistant prostate cancer (M1CRPC). The 5 year survival
rate of metastatic prostate cancer is only 31% [1], and therefore effective novel agents and
combinations are urgently needed for treatment of this incurable disease. Since the 1940s,
suppression of gonadal production of testosterone via androgen deprivation therapy (ADT)
has been the backbone of the management of advanced prostate cancer [3–5]. However, we
are now witnessing a rapid transformation in the management of this cancer (Table 1) owing to
advances in our understanding of its evolution, signaling pathways, mutational landscape, and re-
sistance mechanisms (Figure 1, Key Figure). Currently approved agents in the management of
advanced prostate cancer either inhibit the androgen axis (abiraterone, enzalutamide,
apalutamide, darolutamide), target microtubules by inhibiting depolymerization or promoting
polymerization (docetaxel, cabazitaxel), utilize radioactive calcium mimetics targeting bone
metastases (radium-223), or involve immune mechanisms (sipuleucel-T)i. We discuss here how
appropriate drug selection can be made in this changing treatment landscape of prostate 1
Division of Oncology, Department of
adenocarcinoma, concisely review the results of practice-changing trials over the past 3 years, Internal Medicine, Huntsman Cancer
and discuss recent advances in relevant genomics tools. Finally, we briefly discuss how we Institute, University of Utah, Salt Lake
City, UT, USA
predict the field will evolve in the near future.

Metastatic Castrate-Sensitive Prostate Cancer

*Correspondence:
Historically, treatment decisions in the mCSPC setting have been made based on the criteria neeraj.agarwal@hci.utah.edu
developed in the CHAARTED trial for low- and high-volume disease (defined as the presence (N. Agarwal).

Trends in Cancer, Month 2020, Vol. xx, No. xx https://doi.org/10.1016/j.trecan.2020.04.010 1

© 2020 Elsevier Inc. All rights reserved.
Trends in Cancer

Table 1. FDA-Approved Systemic Therapies from 2017 to 2019v Glossary

Agent Approval indication Date of approval Trial name
Androgen deprivation therapy
(NCT number)
(ADT): treatment to suppress or block
Enzalutamide Metastatic castrate-sensitive 16 December 2019 ARCHES the production or action of male
prostate cancer (NCT02677896) hormones.
Apalutamide Metastatic castrate-sensitive 17 September 2019 TITAN Castrate-resistant prostate cancer
prostate cancer (NCT02489318) (CRPC): prostate cancer which
continues to progress even when
Darolutamide Non-metastatic castrate-resistant 30 July 2019 ARAMIS
testosterone is decreased to very low
prostate cancer (NCT02200614)
levels.
Enzalutamide Castrate-resistant prostate cancer 13 July 2018 PROSPER Castrate-sensitive prostate cancer
(NCT020032924) (CSPC): prostate cancer which can be
Apalutamide Non-metastatic castrate-resistant 14 February 2018 SPARTAN controlled by decreasing the amount of
prostate cancer (NCT01946204) testosterone in the body.
Hazard ratio (HR): ratio of risk of
Abiraterone acetate in Metastatic high-risk 7 February 2018 LATITUDE outcome in one group to risk of outcome
combination with prednisone castrate-sensitive prostate cancer (NCT01715285)
in another group occurring at a given
Cabazitaxel (20 mg/m2 every Metastatic castrate-resistant 14 September 2017 PROSELICA interval of time.
3 weeks) in combination with prostate cancer previously treated (NCT01308580) Novel hormonal therapies (NHTs):
prednisone with a docetaxel-containing second-generation androgen axis
treatment regimen inhibitors which can suppress prostate
cancer growth after it has become
castrate-resistant.
Overall survival (OS): length of time
of visceral metastases and/or at least four bone metastases, with at least one metastasis in any from either date of diagnosis or start of
bone structure outside the vertebral column and pelvis) [6]. At present, four agents – abiraterone, treatment for which the person with
apalutamide, enzalutamide, and docetaxel – are used in clinical practice for the treatment of disease (cancer) is still alive.
Progression-free survival (PFS):
mCSPCi. We discuss later how to best select these agents for treatment. The results of the length of time during or after treatment of
discussed trials since 2017 are summarized in Table 2. disease (cancer) in which a person is still
alive without the disease progressing
Docetaxel locally to a higher stage or spreading to a
distant site.
Docetaxel was the first systemic therapy to show improvement in overall survival (OS)
Radiographic progression-free
outcomes in men with mCSPC when added to ADT. This was demonstrated in two large survival (rPFS): time from random
randomized Phase III trials, E3805 CHAARTED [6] and STAMPEDE [7]. However, the results assignment to date when the first site of
from a smaller Phase III trial, GETUG-AFU15 [8] disagreed with these findings. This discrepancy disease is found to progress (using a
manifestation-specific definition of
was attributed to smaller sample size, lower statistical power, and a higher proportion of patients progression), or death, whichever
with low-volume disease [9]. In a meta-analysis of these three trials, addition of docetaxel to ADT occurs first.
was associated with improved progression-free survival (PFS) [hazard ratio (HR) = 0.63,
95% confidence interval CI 0.57–0.70, P b0.001] and OS (HR = 0.73, 95% CI 0.60–0.90,
P = 0.002) in mCSPC patients [10]. However, the OS benefit was driven by high-volume
disease. On subgroup analysis of the GETUG-AFU 15 and E3805 CHAARTED trials, the HR for
ADT plus docetaxel for patients with high-volume disease was 0.67 (95% CI 0.51–0.88), whereas
for low-volume disease it was 0.80 (95% CI 0.49–1.32) [10]. By contrast, in a post hoc analysis of
830 (76%) patients from the STAMPEDE trial with assessable metastatic disease burden, the
benefit with docetaxel was observed irrespective of disease volume (interaction P = 0.827) [11].
The HR was consistent in the low-volume (HR = 0.76, 95% CI 0.54–1.07, P = 0.107) and high-
volume (HR = 0.81, 95% CI 0.64–1.02, P = 0.064) subgroups [11]. Based on these results, the
combination of ADT plus docetaxel is recommended for men with high-volume mCSPCi [12],
whereas for low-volume disease its benefit is unclear. At present, the FDA has yet to approve
the use of docetaxel for mCSPC; nevertheless, its usage is recommended by guideline panelsi,ii.

Novel Hormonal Therapies: Abiraterone, Apalutamide, Enzalutamide

In 2017, the LATITUDE trial and arm G of the STAMPEDE trial showed that the addition of
abiraterone acetate and prednisone to ADT significantly improved radiographic progression-
free survival (rPFS) and OS in men with newly diagnosed, high-risk mCSPC (Table 2) [13,14].

2 Trends in Cancer, Month 2020, Vol. xx, No. xx

Trends in Cancer

Key Figure

Overview of Androgen Signaling and Drug Resistance in Prostate Cancer

(A)
(B)

(C)

Trends in Cancer

Figure 1. (A) Androgen receptor (AR)-related signaling pathways in prostate cancer. AR is bound to heat-shock proteins (HSPs) in the cytosol until activated by either
testosterone (T) or dihydrotestosterone (DHT) causing it to localize to the nucleus via microtubules. Alternative signaling pathways such as receptor tyrosine kinase
(RTK) activation can induce cell growth as well as have direct effects on AR via phosphorylation (P). Drug efflux pumps such as multidrug-resistance 1 (MDR1) can
transport microtubule inhibitors out of cells. Constitutively active splice variants of AR (AR V7) are both microtubule- and ligand-independent. (B) Androgen

(Figure legend continued at the bottom of the next page.)

Trends in Cancer, Month 2020, Vol. xx, No. xx 3

Trends in Cancer

However, these trials differed significantly with regards to patient inclusion criteria. The LATITUDE
trial recruited only newly diagnosed mCSPC men with high-risk disease (≥2 of the following
criteria: Gleason score ≥8, ≥3 bone lesions, or measurable visceral metastasis) [13]. By contrast,
the STAMPEDE trial recruited non-metastatic (M0) and mCSPC without risk stratification [14].
Although the national guidelines recommend abiraterone for men with mCSPC regardless of
risk or volume status, currently ADT plus abiraterone is only approved for men with high-risk
mCSPCii. A post hoc subgroup analysis of the STAMPEDE trial showed that addition of
abiraterone to ADT improved OS (HR = 0.66, 95% CI 0.44–0.98) and 3 year failure-free survival
(HR = 0.25, 95% CI 0.17–0.33) compared with ADT alone in the low-risk group as well as in
the high-risk group (OS: HR = 0.54, 95% CI 0.41–0.70; 3 year failure-free survival: HR = 0.31,
95% CI 0.25–0.39) [15]. Based on these data, abiraterone can be recommended for men with
CSPC regardless of the risk status.

Recent successes with enzalutamide in the ENZAMET [16] and ARCHES [17] trials, and with
apalutamide in the TITAN trial [18], have generated more options for mCSPC patients (Table 2).
In the ENZAMET trial, the enzalutamide arm had a longer clinical PFS (rate of event-free survival
at 3 years: 68% vs 41%, HR = 0.40, 95% CI 0.33–0.49, P b0.001) and OS at 34 months
follow-up (HR = 0.67, 95% CI 0.52–0.86, P = 0.002) than the standard-of-care arm comprising
ADT with older nonsteroidal antiandrogen agents. A unique feature of the trial was to allow the
use of concurrent docetaxel based on the patient's and physician’s decision, which was also a
prespecified stratification factor. The results showed that early docetaxel use resulted in more
toxicities but no improvement in OS (HR = 0.90, 95% CI 0.62–1.31, P value for interaction
0.04, adjusted P value 0.14) [16]. In the ARCHES trial, rPFS, the primary endpoint, was signifi-
cantly improved in both low-volume (HR = 0.25, 95% CI 0.14–0.46) and high-volume disease
(HR = 0.43, 95% CI 0.33–0.57) [17]. ARCHES was the first trial to demonstrate rPFS benefit in
mCSPC men after prior docetaxel chemotherapy in the mCSPC setting [17]. In the TITAN trial,
the dual primary endpoints were OS and rPFS. At the time of first interim analysis, at the median
follow-up of 23 months, both dual OS and rPFS were significantly improved (OS: HR = 0.67, 95%
CI 0.51–0.89, P b0.005; rPFS: HR = 0.48, 95% CI 0.39–0.60, P N0.001). Overall, there was a
33% reduction in the risk of death and a 52% reduction in the risk of disease progression or
death. Remarkably, treatment with apalutamide improved survival outcomes while maintaining
the health-related quality of life [18,19]. These data show that the strategy of deeper androgen
blockade does not result in worsening of quality of life and fatigue, and will aid in counseling
patients presenting with mCSPC in the clinic [19].

Treatment Selection in mCSPC Patients

In a direct, randomized, comparative analysis from the STAMPEDE trial involving 566 mCSPC
patients (189, ADT + docetaxel; 377, ADT + abiraterone), no difference in PFS (HR = 0.65, 95%
CI 0.48–0.88) or OS (HR = 1.16, 95% CI 0.82–1.65) was observed [20]. It is to be noted that this
was not a formally powered comparison. Although the toxicity profile in both arms was different,
the worst toxicity grade over the entire time in both arms was similar [20]. Quality-of-life scores
have been analyzed in patients contemporaneously randomized to receive docetaxel or
abiraterone in the STAMPEDE trial. Global quality of life was significantly higher for the abiraterone
group in the first two years (+3.9, 95% CI 0.6–7.1, P = 0.021) compared with docetaxel, but did not
meet the predefined clinically meaningful threshold of ≥4 points [21]. In a network meta-analysis

synthesis pathway. In the case of chemical (or surgical) castration, intracellular synthesis of T/DHT by upregulation of key enzymes in the steroid biosynthetic pathway
is observed in prostate cancer. (C) The DNA damage response. In patients with BRCA1/2 mutations, treatment with PARP inhibitors can result in genotoxic stress
and apoptosis. Abbreviations: EMT, epithelial-mesenchymal transition; HRR, homologous recombination repair; NEPC, neuroendocrine prostate cancer; SSB,
single-strand break.

4 Trends in Cancer, Month 2020, Vol. xx, No. xx

 Trends in Cancer
Table 2. Pivotal Clinical Trials Evaluating Systemic Therapies Since 2017 for the Management of Advanced Prostate Cancera
Agent Trial name Important eligibility criteria Intervention Control Primary endpoint results (intervention versus control arm) Refs
(NCT number) (patient number) (patient number)
Primary endpoint Intervention Control HR
(follow-up time) (95% CI, P)
Metastatic castrate-sensitive prostate cancer (mCSPC)
Abiraterone LATITUDE Newly diagnosed mCSPC Abiraterone ADT (602) Median OS NR 34.7 0.62; 95% CI [13]
(NCT01715285) ≥2 of following high-risk factors: 1000 mg oral daily + (median months 0.51–0.76,
Gleason score ≥8, ≥3 bone prednisone 5 mg follow-up of 30.4 P b0.001
lesions, and measurable visceral daily + ADT (597) months)
metastasis
Median rPFS 33 months 14.8 0.47, 95% CI
months 0.39–0.55.
P b0.001
STAMPEDE Newly diagnosed metastatic Abiraterone acetate ADT (960) OS (3 year) 83% 76% 0.63, 95% CI [14]
(NCT00268476) (n = 941), node-positive (N1M0, 1000 mg oral daily + 0.52–0.76,
n = 369), or high-risk locally prednisolone 5 mg P b0.001
advanced (N0M0, ≥2 of following: daily + ADT (957)
Failure-free 75% 45% 0.29, 95% CI
T3 or T4, Gleason score ≥8, and
survival (3 year) 0.25–0.34,
PSA ≥40 ng/ml; n = 509), or
P b0.001
recurrent disease after local
therapy with high risk features or
metastasis (n = 98)
Enzalutamide ENZAMET mCSPC Testosterone Testosterone OS (3 years) 80% 72% 0.67, 95% CI [16]
(NCT02446405) suppression + suppression + 0.52–0.86,
enzalutamide standard P = 0.002
(160 mg oral daily) nonsteroidal (34 months
(563) antiandrogen follow-up)
therapy (562)
ARCHES mCSPC ADT + enzalutamide ADT + placebo rPFS (median) NR 19 0.39, 95% CI [17]
(NCT02677896) Prior ADT and docetaxel permitted (160 mg/day) (574) (576) months 0.30–0.50,
P b0.001
Apalutamide TITAN mCSPC ADT + apalutamide ADT + matched OS (24 months) 82.4% 73.5% 0.67, 95% CI [18]
(NCT02489318) Prior ADT for b6 months and (240 mg oral daily) placebo (527) 0.51–0.89,
docetaxel permitted (525) P = 0.005
rPFS (24 months) 68.2% 47.5% 0.48, 95% CI
0.39–0.60,
Trends in Cancer, Month 2020, Vol. xx, No. xx

P b0.001
Non-metastatic castrate-resistant prostate cancer (M0CRPC)
Apalutamide SPARTAN M0CRPC ADT + apalutamide ADT + matched MFS (median) 40.5 16.2 0.28, 95% CI [26]
(NCT01946204) PSADT ≤10 months (240 mg oral daily) placebo (401) months months 0.23–0.35,
(806) P b0.001
Enzalutamide PROSPER M0CRPC ADT + enzalutamide ADT + placebo MFS (median) 36.6 14.7 0.29, 95% CI [27]
(NCT02003924) PSADT ≤10 months (160 mg/day) (933) (468) months months 0.24–0.35,
P b0.001
Darolutamide ARAMIS M0CRPC ADT + darolutamide ADT + placebo MFS (median) 40.4 18.4 0.41, 95% CI [28]
(NCT02200614) PSADT ≤10 months (600 mg twice daily) (554) months months 0.34–0.50,
(955) P b0.001
(continued on next page)
5
 Trends in Cancer
6
Trends in Cancer, Month 2020, Vol. xx, No. xx

Table 2. (continued)
Agent Trial name Important eligibility criteria Intervention Control Primary endpoint results (intervention versus control arm) Refs
(NCT number) (patient number) (patient number)
Primary endpoint Intervention Control HR
(follow-up time) (95% CI, P)
Metastatic castrate-resistant prostate cancer (M1CRPC)
Cabazitaxel PROSELICA M1CRPC Cabazitaxel Cabazitaxel OS (median) 13.4 14.5 1.024, upper [34]
(NCT01308580) 20 mg/m2 IV every 25 mg/m2 IV every months months boundary of
3 weeks + 3 weeks + the HR CI
prednisone 10 mg prednisone 10 mg was 1.184
daily (598) daily (602) (less than the
1.214
noninferiority
margin)
CARD M1CRPC Cabazitaxel Abiraterone rPFS (median) 8 months 3.7 0.54, 95% CI [44]
(NCT02485691) Prior ≥3 cycles of docetaxel and 25 mg/m2 IV every (1000 mg orally months 0.40–0.73,
progression during 12 months of 3 weeks + once daily and oral P b0.001
treatment with abiraterone or prednisone 10 mg prednisone 5 mg
enzalutamide (before or after daily + primary twice daily) or
docetaxel) prophylactic enzalutamide
granulocyte-colony (160 mg orally once
stimulating factor daily) (126)
(129)

a
Abbreviations: ADT, androgen deprivation therapy; IV, intravenous; MFS, metastasis-free survival; NR, not reported; OS, overall survival; PSADT, prostate-specific antigen doubling time; rPFS, radiological
progression-free survival.
Trends in Cancer

using fixed-effects Bayesian methods, abiraterone was found to be at least as effective as

docetaxel in reducing the risk of death in newly diagnosed high-risk and/or high-volume mCSPC
patients [22]. Abiraterone was associated with improved quality of life compared with docetaxel
treatment for at least 1 year of therapy [22]. In another meta-analysis, the addition of docetaxel
or abiraterone to ADT statistically improved PFS but not OS in older men with mCSPC [23].

Therefore, both docetaxel and novel hormonal therapies (NHTs; abiraterone, apalutamide, and
enzalutamide) are appropriate first-line choices for mCSPC patients with high-volume disease, and
the decision of one therapy over another depends on several factors. Docetaxel is given for a limited
duration of ~15 weeks (six cycles) [6,7] for the treatment of mCSPC, whereas the average duration
of NHTs is several months to years [13,14]. In many patients, docetaxel may not incur any of the
out-of-pocket costs commonly associated with NHTs but is associated with significantly more tox-
icities and more frequent visits to the providers during this time [24]. These agents have a different
side-effect profile, which can help to determine the treatment. Relevant toxicities with docetaxel are
neuropathy, febrile neutropenia, allergic reaction, and fatigue [7,25], whereas abiraterone toxicities
include hypertension, hypokalemia, elevated liver enzymes, and fluid retention [13,14]. Abiraterone
requires long-term concurrent use of corticosteroids, and this may be problematic in men with
diabetes, hypertension, osteopenia, or osteoporosis [13,14]. Apalutamide and enzalutamide
have none of the issues associated with docetaxel and abiraterone, and may be recommended
for all men with mCSPC regardless of age, performance status, risk or volume status, or comorbid-
ities such as diabetes, neuropathy, and osteoporosis, etc. Docetaxel may be most suitable for
those men who do not want to undergo a NHT or cannot afford the out-of-pocket cost associated
with NHTs, and are sufficiently healthy to tolerate docetaxel.

Important side effects with enzalutamide are seizures, cognitive impairment, fractures, ischemic
heart disease, and hypertension, and these can impact the decision to choose it as a treatment
[16,17]. On the other hand, the major toxicities of apalutamide are hypothyroidism and transient
rash [18].

Non-Metastatic Castrate-Resistant Prostate Cancer

Three large, placebo-controlled, randomized Phase III trials, SPARTAN [26], PROSPER [27], and
ARAMIS [28], have shown improved metastasis-free survival with apalutamide, enzalutamide,
and darolutamide, respectively, in patients with prostate-specific antigen (PSA) N2 ng/ml and
PSA doubling time of ≤10 months, and no evidence of metastatic disease based on conventional
bone and computerized tomography (CT) scans. Results from these trials have led to FDA approval
of these three drugs in this indication (Tables 1 and 2). Recent updates from these trials have also
reported OS improvementiii,iv [29]. However, many of these patients, hitherto diagnosed with non-
metastatic CRPC, are being detected to have metastatic CRPC with increasing utilization of novel
and more sensitive imaging modalities such as prostate-specific membrane antigen positron emis-
sion tomography (PSMA-PET), choline PET, fluorodeoxyglucose PET, and FDA-approved
fluciclovine (18F) PET. In these patients, the practical application of the results from these three trials
may be challenging. Indeed, results from a recent retrospective study of 200 men with M0CRPC
with clinical and imaging characteristics resembling the patients from the three Phase III trials
described earlier, and who underwent imaging by PSMA-PET, showed metastasis in either the
pelvis (44%) and/or in distant sites (55%) in the vast majority of these men [30].

Metastatic Castrate-Resistant Prostate Cancer

Approved Agents for Treatment of M1CRPC
In 2004, docetaxel received approval for treatment of M1CRPC patients after demonstrating
superior OS in two Phase III trials compared with mitoxantrone [31,32]. In 2010 the TROPIC

Trends in Cancer, Month 2020, Vol. xx, No. xx 7

Trends in Cancer

trial demonstrated improved median OS with cabazitaxel (25 mg/m2) compared with
mitoxantrone (15.1 months vs 12.7 months; HR = 0.70, 95% CI 0.59–0.83, P b0.0001) in
patients previously treated with docetaxel, leading to its approval in this patient population [33].
In 2017, the PROSELICA trial showed that 20 mg/m2 of cabazitaxel was noninferior to 25 mg/m2
in post-docetaxel treated men, leading to approval of the reduced dose (Table 1) [34]. However,
neither dose of cabazitaxel was superior to docetaxel in chemotherapy-naïve patients in the
FIRSTANA trial [35].

Treatment with abiraterone in randomized placebo-controlled trials demonstrated a median OS

benefit in chemotherapy naïve (34.7 months vs 30.3 months; HR = 0.81, 95% CI 0.70–0.93,
P = 0.0033) [36] and post-docetaxel M1CRPC men (14.8 months vs 10.9 months; HR = 0.65,
95% CI 0.54–0.77, P b0.001) [37]. Similarly, enzalutamide compared with placebo demonstrated
a median OS benefit in chemotherapy-naïve (32.4 months vs 30.2 months; HR = 0.71, 95% CI
0.60–0.84, P b0.001) [38] and post-docetaxel M1CRPC patients (18.4 months vs 13.6 months;
HR = 0.63, 95% CI 0.53–0.75, P b0.001) [39].

Other agents that demonstrated OS improvement in M1CRPC patients are radium-223, an α-

emitter radiopharmaceutical [40], and sipuleucel-T, a dendritic cell vaccine which is prepared
from patient peripheral blood mononuclear cells obtained by leukapheresis [41]. In the Phase III
ALSYMPCA trial, patients treated with radium-223 had an improved median OS compared
with placebo (14.9 months vs 11.3 months; HR = 0.70, 95% CI 0.58–0.83, P b0.001) in
M1CRPC patients [40]. In minimally symptomatic M1CRPC patients, sipuleucel-T also had an
improved median OS compared with placebo (25.8 months vs 21.7 months; HR = 0.78, 95%
CI 0.61–0.98, P = 0.03). However, no effect on disease-progression parameters was observed
[41]. It is important to remember that both radium-223 and sipuleucel-T trials excluded patients
with visceral disease, and therefore these agents should not be used in the subset of patients
who have metastatic disease in sites beyond bone and lymph nodes [40,41].

Pembrolizumab has a tissue-agnostic approval for patients with microsatellite instability (MSI)-
high and mismatch repair-deficient (dMMR) tumors who have progressed following prior treat-
ment and have no satisfactory alternative optionsv. However, b3% of prostate cancer patients
have MSI-H or dMMR tumors, and only ~50% respond to treatment, although the responses
are durable [42].

Treatment Sequencing and Selection

A few studies are looking at treatment sequencing. In a crossover Phase II prospective trial of 202
newly diagnosed M1CRPC patients, abiraterone followed by enzalutamide provided greater
benefit than vice versa [43]. In this study, time to PSA progression was longer in abiraterone
followed by enzalutamide than for enzalutamide followed by abiraterone (median 19.3 months
vs 15.2 months; HR = 0.66, 95% CI 0.45–0.97, P = 0.036).

The CARD trial enrolled 255 M1CRPC patients previously treated with docetaxel and whose
M1CRPC had progressed within 12 months while receiving an androgen axis inhibitor
(abiraterone or enzalutamide). Patients were randomized 1:1 to cabazitaxel or an alternative
androgen axis inhibitor (Table 2). In this study, cabazitaxel showed a superior median rPFS
(primary endpoint, 8 months vs 3.7 months; HR = 0.54, 95% CI 0.40–0.73, P b0.001), and OS
(secondary endpoint, 13.6 months vs 11 months; HR = 0.64, 95% CI 0.46–0.89, P = 0.008)
when compared with an alternative NHT (enzalutamide or abiraterone) [44]. The median PFS
(defined as the first occurrence of any of the following: rPFS, symptomatic or pain progression,
death) was also improved by 1.7 months with cabazitaxel versus the alternative NHT. Notably,

8 Trends in Cancer, Month 2020, Vol. xx, No. xx

Trends in Cancer

the results of this trial may only apply to those patients who have a relatively short duration of
response to the first NHT (≤12 months), and not to the general patient population with mCRPC
where the median PFS with first NHT was in the range of 15 months [38,45].

At present, there are multiple options for M1CRPC patientsi. However, three of these agents
(NHTs and docetaxel) have moved to the frontline mCSPC setting and the benefit of rechallenge
with these agents is currently unknown. Docetaxel may be considered in chemotherapy-naïve
patients with good performance status and in patients harboring biomarkers predicting poor
response to an NHT, for example the androgen receptor splice variant 7 (AR-V7). Docetaxel
retreatment can also be considered in M1CRPC patients who did not have definitive
progression during docetaxel therapy in the mCSPC settingi . Treatment with abiraterone,
enzalutamide, or docetaxel may be based on patient wishes, comorbidities, and affordability
of the out-of-pocket cost of NHTs. Cabazitaxel may be preferred in patients who have
progressed on docetaxel and had a PFS of ≤12 months on abiraterone or enzalutamide
based on the CARD trial [44]. Cabazitaxel (20 mg/m2) had a lower risk of peripheral sensory
neuropathy compared with docetaxel (11.7% vs 25.1%), and may be preferred in patients
who are intolerant or refuse docetaxel owing to prior toxicities such as neuropathy, or who
have underlying diabetes mellitus of long duration and are thus at high risk of developing
neuropathy [35]. Radium-223 may be considered in men with symptomatic bone metastasis,
no visceral disease, and who are not candidates for chemotherapy or have had prior chemo-
therapy [40].

Dawning of Precision Medicine in M1CRPC

Olaparib, a poly ADP-ribose polymerase (PARP) inhibitor, is soon expected to garner FDA
approval for the treatment of homologous recombination repair-deficient M1CRPC. The
Phase III PROfound trial investigated olaparib versus abiraterone or enzalutamide in M1CRPC
patients who had progressed on a prior NHT and had a qualifying tumor mutation in one of the
15 predefined genes involved in the homologous recombination repair (HRR) pathway. Cohort
A included patients with alterations in ATM, BRCA1, and BRCA2, whereas cohort B included
patients with alterations in any one of the 12 other HRR genes (BRIP1, BARD1, CDK12,
CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L). In
total, 245 patients were randomized to cohort A, and 142 were randomized to cohort B. In cohort
A, olaparib demonstrated a significant improvement in the primary endpoint of rPFS (7.39 months
vs 3.55 months; P b0.0001) compared with abiraterone or enzalutamide [46]. Similarly, rucaparib
has shown promising preliminary results in the Phase II TRITON2 study, which is enrolling
M1CRPC patients who have progressed on at least one NHT and taxane, and who harbor a
deleterious germline or somatic alteration in BRCA1, BRCA2, ATM, or in other prespecified
HRR genes. Rucaparib showed a response rate of 47.5% in BRCA1/2 altered patients [47].
Talazoparib, another PARP inhibitor, showed a response rate of 50% in BRCA1/2 mutated,
docetaxel- and NHT-pretreated mCRPC patients. The ORR was 25.6% in the overall cohort
with DNA damage repair mutations that are predicted to sensitize to PARP inhibitors [48].

Advances in Molecular Profiling

Prostate cancer mostly metastasizes to bone, which makes it hard to biopsy and follow tumor
evolution. Recent advances in our understanding of liquid biomarkers such as circulating tumor
cells (CTC), tumor-educated platelets (containing tumor RNA), exosomes (containing tumor
RNA), and cell-free nucleic acids such as DNA, mRNA, miRNA, and lncRNA have helped bridge
this gap and have improved our understanding of the evolution and development of resistance of
prostate cancer [49]. CTC counts of ≥5 CTC/7.5 ml of blood have been shown to be an indepen-
dent adverse prognostic factor for survival in mCRPC patients [49,50]. PCWG3 criteria suggest

Trends in Cancer, Month 2020, Vol. xx, No. xx 9

Trends in Cancer

CTC enumeration as an outcome measure for clinical trials [50]. At present, CellSearch® is the Outstanding Questions
only FDA-approved CTC assay [49,50]. How to select the ideal agent
from available options (abiraterone,
apalutamide, enzalutamide, and
AR-V7 lacks the C-terminal ligand-binding domain of full-length AR, and this leads to its
docetaxel) for ADT intensification in
constitutive activation [51,52]. AR-V7 has been implicated as an independent mechanism of men with mCSPC?
de novo and acquired resistance to NHTs [53]. Detection of AR-V7 CTCs is a predictive
biomarker for resistance to NHTs and is associated with poorer PFS and OS with these How to best sequence the available
systemic therapy options for the
agents [54]. At present, AdnaTest and Oncotype DX are two Clinical Laboratory Improvement
treatment of metastatic prostate
Amendments (CLIA)-certified tests used to detect AR-V7 [49]; however, discrepancies in cancer?
AR-V7-positive results between the two platforms have been noted [54]. In addition, as
noted in a recent study, CTC counts should be included when evaluating the prognostic What is the role of definitive treatment
(radical prostatectomy or radiation
role of CTC AR-V7 [55]. therapy) in addition to systemic therapy
in the mCSPC setting?
Cell-free DNA (cfDNA) is DNA derived from malignant (circulating tumor DNA, ctDNA) and non-
What is the role of genomic biomarkers
malignant cells as a result of apoptosis, necrosis, or active secretion, and can be detected in
in treatment selection and sequencing?
peripheral blood [49]. In a preplanned analysis of the FIRSTANA and PROSELICA trials, baseline
cfDNA was an independent prognostic variable for rPFS and OS in both first- and second-line What are the best ways to improve
chemotherapy settings [56]. In addition, post-treatment changes in cfDNA concentration were the efficacy of immunotherapy in
metastatic prostate cancer?
shown to correlate with PSA PFS but not with rPFS or OS [56]. In addition to quantitating
cfDNA, sequencing of ctDNA may provide valuable information about genomic alterations asso-
ciated with tumor evolution and help to elucidate mechanisms of resistance. Figure 1 summarizes
some of the known mechanisms of resistance to NHT. Bone is the only site of metastatic disease
in a large proportion of men with mCRPC, and is often difficult to biopsy for genomic profiling of
the tumors. Given this, ctDNA may soon become a more common tool over tissue biopsy for
obtaining tumor genomic information, especially as novel biomarker-driven therapies receive
approval.

Concluding Remarks
With the rapid strides in genomics, imaging, theranostics, and treatment modalities, the manage-
ment of advanced prostate cancer will continue to change rapidly over the next decade. In the
near future, results from the PROfound [46] and VISION [57] trials will see PARP inhibitors and
177
Lu-PSMA-617, respectively, become new players in the treatment landscape of prostate
cancer. Multiple studies are investigating novel agents such as rhenium-188-HEDP, HC-1119,
masitinib, and DCVAC, as well as exciting combinations, in Phase III studies. Table 3 summarizes
important ongoing Phase III trials in advanced prostate cancer. Recent results of cohort 6 in the
COSMIC-021 study, which showed a 32% response rate and 80% disease-control rate with
cabozantinib in combination with atezolizumab in mCRPC, has rekindled enthusiasm in the
immunotherapy of this disease [58]. Pembrolizumab is being tested in several registration trials
in combination with enzalutamide, olaparib, and docetaxel in the mCRPC setting, with encouraging
data from earlier trials (Table 3). Next-generation PSMA targeting radioisotope conjugates such as
actinium-225, bismuth-213, thorium-227, iodine-131, and lutetium-177 can give rise to a whole
new era of theranostics [59]. In addition to these interesting developments, the role of
CTCs (NCT03327662) and biomarkers (NCT03903835) in treatment optimization is also being
investigated in Phase III trials.

Management of metastatic prostate cancer has changed dramatically with the approval of
multiple new agents. However, more focus needs to be placed on optimal and effective ways
to sequence and combine these agents to delay resistance, decrease toxicities, and improve
OS (see Outstanding Questions). In addition, the identification and validation of informative
biomarkers is urgently needed and should be prioritized in future prospective clinical trials.

10 Trends in Cancer, Month 2020, Vol. xx, No. xx

Trends in Cancer

Table 3. Selected Ongoing Phase III Studies in Advanced or Metastatic Prostate Cancer
Number NCT Number Title Acronym Target Primary completion Expected
enrollment date completion date
1 NCT03748641 Abiraterone + prednisone ± niraparib in mCRPC MAGNITUDE 1000 21 July 2022 25 February 2025
2
2 NCT02961257 Cabazitaxel 25 mg/m on day 1 of 3 week cycle, CABASTY 170 1 May 2021 1 July 2022
plus daily prednisone or cabazitaxel 16 mg/m2 on
day 1 and day 15 of 4 week cycle, plus daily
prednisone in elderly men (aged ≥65 years) with
mCRPC previously treated with docetaxel
3 NCT03458559 Rhenium-188-HEDP versus Radium-223-chloride RaRe 402 16 May 2022 16 May 2024
in mCRPC
4 NCT03850795 HC-1119 versus enzalutamide in mCRPC . 430 1 May 2021 1 December 2021
5 NCT03072238 Abiraterone + prednisone/prednisolone ± IPATential150 1101 12 May 2020 11 October 2023
ipatasertib in mCRPC
6 NCT01957436 ADT (+ docetaxel) ± local radiotherapy ± PEACE1 1173 1 May 2019 1 December 2032
abiraterone and prednisone
7 NCT03678025 Standard systemic therapy ± definitive treatment in 1273 1 April 2028 1 October 2031
mCSPC
8 NCT01949337 Enzalutamide ± abiraterone and prednisone in 1311 2 November 2018
mCRPC
9 NCT03327662 Utilizing CTC counts to optimize systemic therapy CTC-STOP 1178 1 January 2021 1 January 2022
with docetaxel in mCRPC
10 NCT01809691 ADT + TAK-700 versus ADT + bicalutamide in S1216 1313 1 March 2022 1 October 2027
mCSPC
11 NCT03732820 Olaparib ± abiraterone in mCRPC 720 13 April 2021 17 August 2022
12 NCT03761225 Docetaxel ± masitinib in mCRPC 580 1 March 2020 1 September 2020
13 NCT04139772 Docetaxel or hormone therapy as second-line 900 1 September 2024 1 July 2025
treatment in asymptomatic or oligosymptomatic
mCRPC progressing after abiraterone or
enzalutamide.
14 NCT02111577 Docetaxel ± DCVAC in mCRPC VIABLE 1170 16 December 2019 1 June 2020
15 NCT02975934 Rucaparib versus physician's choice of therapy in TRITON3 400 1 February 2022 1 April 2022
mCRPC and homologous recombination gene
deficiency
16 NCT04191096 Enzalutamide + ADT ± pembrolizumab in mCSPC MK-3475-991/ 1232 2 July 2026 1 September 2026
KEYNOTE-991
17 NCT03903835 Biomarker-driven study in mCRPC ProBio 750 1 December 2026 1 December 2026
18 NCT02288247 Efficacy and safety of continuing enzalutamide in PRESIDE 690 1 June 2020 1 September 2021
chemotherapy-naïve mCRPC treated with
docetaxel + prednisolone who have progressed
on enzalutamide alone
19 NCT03879122 ADT + docetaxel ± nivolumab, or nivolumab + 135 31 July 2021 31 December 2023
ipilimumab in mCSPC
20 NCT02799602 ADT + docetaxel ± darolutamide in mCSPC ARASENS 1303 1 August 2022 1 August 2022
21 NCT03511664 177Lu-PSMA-617 ± best supportive/standard of VISION 750 1 August 2020 1 May 2021
care in mCRPC
22 NCT03834493 Enzalutamide ± pembrolizumab in mCRPC MK-3475-641/ 1200 12 November 2023 30 April 2024
KEYNOTE-641
23 NCT03834506 Docetaxel ± pembrolizumab in MK-3475-921/ 1000 12 September 28 February 2023
chemotherapy-naïve mCRPC KEYNOTE-921 2021
24 NCT02257736 Abiraterone ± apalutamide in chemotherapy-naive 983 19 March 2018 24 August 2021
mCRPC
(continued on next page)

Trends in Cancer, Month 2020, Vol. xx, No. xx 11

Trends in Cancer

Table 3. (continued)
Number NCT Number Title Acronym Target Primary completion Expected
enrollment date completion date
25 NCT03834519 Pembrolizumab + olaparib versus abiraterone or MK-7339-010/ 780 12 October 2021 30 September
enzalutamide in mCRPC KEYLYNK-010 2022
26 NCT04237584 12 weeks lead-in androgen receptor blocker ESCALATE 499 1 July 2024 1 July 2024
(darolutamide or enzalutamide) followed by ±
radium-223 or placebo in mCRPC
27 NCT02194842 Enzalutamide ± radium 223 in mCRPC PEACE III 560 1 December 2024 1 December 2025
28 NCT03016312 Enzalutamide ± atezolizumab in mCRPC after IMbassador250 771 21 March 2020 21 March 2020
failure of an androgen synthesis inhibitor and
failure, ineligibility or refusal of a taxane regimen
29 NCT03851640 HC-1119 versus placebo in mCRPC who failed 255 1 January 2021 1 February 2021
abiraterone and docetaxel
30 NCT03574571 Docetaxel ± radium 223 in mCRPC 738 1 June 2022 1 June 2023
31 NCT04100018 Docetaxel ± nivolumab in advanced CRPC CheckMate 7DX 984 20 February 2023 14 May 2024
32 NCT03395197 Enzalutamide ± talazoparib in mCRPC TALAPRO-2 1037 22 August 2021 25 November 2024

Conflicts of interest
Neeraj Agarwal has received consultancy fees from Astellas, Astra Zeneca, Bayer, Bristol Myers
Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen,
Merck, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics and institutional research
funding from Astra Zeneca, Bavarian Nordic , Bayer, Bristol Myers Squibb, Calithera, Celldex, Clo-
vis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Janssen,
Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche,
Sanofi, Seattle Genetics, Takeda, and Tracon. Roberto Nussenzveig has received advisory fees
for Tempus Labs Inc. Umang Swami and Taylor McFarland do not report any conflict of interest.

Resources
i
www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
ii
www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications
iii
www.pfizer.com/news/press-release/press-release-detail/xtandi_enzalutamide_demonstrates_significant_improvement_
in_overall_survival_in_phase_3_prosper_trial_of_patients_with_nmcrpc
iv
www.investor.bayer.de/en/nc/news/investor-news/investor-news/darolutamide-plus-androgen-deprivation-therapy-
significantly-increased-overall-survival-in-men-with/
v
www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications

References
1. Siegel, R.L. et al. (2020) Cancer statistics, 2020. CA Cancer
J. Clin. 70, 7–30
2. Moul, J.W. (2004) The evolving definition of advanced prostate
cancer. Rev. Urol. 6, S10–S17
3. Huggins, C. and Hodges, C.V. (1941/2002) Studies on prostatic
cancer. I. The effect of castration, of estrogen and of androgen
injection on serum phosphatases in metastatic carcinoma of
the prostate. Cancer Res. 1, 293–297 reprinted in J. Urol.
168, 9–12
4. National Comprehensive Cancer Network (2019) Clinical
Practice Guidelines in Oncology for Prostate Cancer (Version
4.2019), NCCN
5. US Food and Drug Administration (2020) Hematology/Oncology
(Cancer) Approvals & Safety Notifications (05/01/2020), FDA
6. Kyriakopoulos, C.E. et al. (2018) Chemohormonal therapy in
metastatic hormone-sensitive prostate cancer: long-term sur-
vival analysis of the randomized phase III E3805 CHAARTED
trial. J. Clin. Oncol. 36, 1080–1087
7. James, N.D. et al. (2016) 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 387,
1163–1177
8. Gravis, G. et al. (2013) Androgen-deprivation therapy alone or
with docetaxel in non-castrate metastatic prostate cancer
(GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet
Oncol. 14, 149–158
9. Gravis, G. et al. (2016) Androgen deprivation therapy (ADT) plus
docetaxel versus ADT alone in metastatic non castrate prostate
cancer: impact of metastatic burden and long-term survival
analysis of the randomized phase 3 GETUG-AFU15 trial. Eur.
Urol. 70, 256–262
10. Tucci, M. et al. (2016) Addition of docetaxel to androgen depri-
vation therapy for patients with hormone-sensitive metastatic
prostate cancer: a systematic review and meta-analysis. Eur.
Urol. 69, 563–573

12 Trends in Cancer, Month 2020, Vol. xx, No. xx

Trends in Cancer
11. Clarke, N.W. et al. (2019) Addition of docetaxel to hormonal
therapy in low- and high-burden metastatic hormone sensitive
prostate cancer: long-term survival results from the STAMPEDE
trial. Ann. Oncol. 30, 1992–2003
12. Morris, M.J. et al. (2018) Optimizing anticancer therapy in meta-
static non-castrate prostate cancer: American Society of Clinical
Oncology clinical practice guideline. J. Clin. Oncol. 36,
1521–1539
13. Fizazi, K. et al. (2017) Abiraterone plus prednisone in metastatic,
castration-sensitive prostate cancer. N. Engl. J. Med. 377,
352–360
14. James, N.D. et al. (2017) Abiraterone for prostate cancer not
previously treated with hormone therapy. N. Engl. J. Med. 377,
338–351
15. Hoyle, A.P. et al. (2019) Abiraterone in 'high-' and 'low-risk' meta-
static hormone-sensitive prostate cancer. Eur. Urol. 76, 719–728
16. Davis, I.D. et al. (2019) Enzalutamide with standard first-line therapy
in metastatic prostate cancer. N. Engl. J. Med. 381, 121–131
17. Armstrong, A.J. et al. (2019) ARCHES: a randomized, phase iii
study of androgen deprivation therapy with enzalutamide or pla-
cebo in men with metastatic hormone-sensitive prostate cancer.
J. Clin. Oncol. 37, 2974–2986
18. Chi, K.N. et al. (2019) Apalutamide for metastatic, castration-
sensitive prostate cancer. N. Engl. J. Med. 381, 13–24
19. Agarwal, N. et al. (2019) Health-related quality of life after
apalutamide treatment in patients with metastatic castration-
sensitive prostate cancer (TITAN): a randomised, placebo-
controlled, phase 3 study. Lancet Oncol. 20, 1518–1530
20. Sydes, M.R. et al. (2018) Adding abiraterone or docetaxel to
long-term hormone therapy for prostate cancer: directly
randomised data from the STAMPEDE multi-arm, multi-stage
platform protocol. Ann. Oncol. 29, 1235–1248
21. Rush, H.L. et al. (2020) Comparative quality of life in patients ran-
domized contemporaneously to docetaxel or abiraterone in the
STAMPEDE trial. J. Clin. Oncol. 38, 14
22. Feyerabend, S. et al. (2018) Survival benefit, disease progression
and quality-of-life outcomes of abiraterone acetate plus predni-
sone versus docetaxel in metastatic hormone-sensitive prostate
cancer: a network meta-analysis. Eur. J. Cancer 103, 78–87
23. Landre, T. et al. (2019) Is there a benefit of addition docetaxel,
abiraterone, celecoxib, or zoledronic acid in initial treatments
for patients older than 70 years with hormone-sensitive
advanced prostate cancer? A meta-analysis. Clin. Genitourin.
Cancer 17, e806–e813
24. Ramamurthy, C. et al. (2019) Cost-effectiveness of abiraterone
versus docetaxel in the treatment of metastatic hormone naive
prostate cancer. Urol. Oncol. 37, 688–695
25. Sweeney, C.J. et al. (2015) Chemohormonal therapy in metasta-
tic hormone-sensitive prostate cancer. N. Engl. J. Med. 373,
737–746
26. Smith, M.R. et al. (2018) Apalutamide treatment and metastasis-
free survival in prostate cancer. N. Engl. J. Med. 378,
1408–1418
27. Hussain, M. et al. (2018) Enzalutamide in men with
nonmetastatic, castration-resistant prostate cancer. N. Engl.
J. Med. 378, 2465–2474
28. Fizazi, K. et al. (2019) Darolutamide in nonmetastatic, castration-
resistant prostate cancer. N. Engl. J. Med. 380, 1235–1246
29. Small, E.J. et al. (2019) Apalutamide and overall survival in non-
metastatic castration-resistant prostate cancer. Ann. Oncol.
30, 1813–1820
30. Fendler, W.P. et al. (2019) Prostate-specific membrane antigen
ligand positron emission tomography in men with nonmetastatic
castration-resistant prostate cancer. Clin. Cancer Res. 25,
7448–7454
31. Tannock, I.F. et al. (2004) Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer.
N. Engl. J. Med. 351, 1502–1512
32. Petrylak, D.P. et al. (2004) Docetaxel and estramustine com-
pared with mitoxantrone and prednisone for advanced refractory
prostate cancer. N. Engl. J. Med. 351, 1513–1520
33. de Bono, J.S. et al. (2010) Prednisone plus cabazitaxel or
mitoxantrone for metastatic castration-resistant prostate cancer
progressing after docetaxel treatment: a randomised open-label
trial. Lancet 376, 1147–1154
34. Eisenberger, M. et al. (2017) Phase III study comparing a
reduced dose of cabazitaxel (20 mg/m2) and the currently
approved dose (25 mg/m2) in postdocetaxel patients with
metastatic castration-resistant prostate cancer – PROSELICA.
J. Clin. Oncol. 35, 3198–3206
35. Oudard, S. et al. (2017) Cabazitaxel versus docetaxel as first-line
therapy for patients with metastatic castration-resistant prostate
cancer: a randomized phase III trial – FIRSTANA. J. Clin. Oncol.
35, 3189–3197
36. Ryan, C.J. et al. (2015) Abiraterone acetate plus prednisone
versus placebo plus prednisone in chemotherapy-naive men
with metastatic castration-resistant prostate cancer (COU-AA-
302): final overall survival analysis of a randomised, double-
blind, placebo-controlled phase 3 study. Lancet Oncol. 16,
152–160
37. de Bono, J.S. et al. (2011) Abiraterone and increased survival in
metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005
38. Beer, T.M. et al. (2014) Enzalutamide in metastatic prostate
cancer before chemotherapy. N. Engl. J. Med. 371, 424–433
39. Scher, H.I. et al. (2012) Increased survival with enzalutamide in
prostate cancer after chemotherapy. N. Engl. J. Med. 367,
1187–1197
40. Parker, C. et al. (2013) Alpha emitter radium-223 and survival in
metastatic prostate cancer. N. Engl. J. Med. 369, 213–223
41. Kantoff, P.W. et al. (2010) Sipuleucel-T immunotherapy for
castration-resistant prostate cancer. N. Engl. J. Med. 363,
411–422
42. Abida, W. et al. (2019) Analysis of the prevalence of microsatellite
instability in prostate cancer and response to immune check-
point blockade. JAMA Oncol. 5, 471–478
43. Khalaf, D.J. et al. (2019) Optimal sequencing of enzalutamide
and abiraterone acetate plus prednisone in metastatic
castration-resistant prostate cancer: a multicentre, randomised,
open-label, phase 2, crossover trial. Lancet Oncol. 20,
1730–1739
44. de Wit, R. et al. (2019) Cabazitaxel versus abiraterone or
enzalutamide in metastatic prostate cancer. N. Engl. J. Med.
381, 2506–2518
45. Ryan, C.J. et al. (2013) Abiraterone in metastatic prostate can-
cer without previous chemotherapy. N. Engl. J. Med. 368,
138–148
46. Hussain, M. et al. (2019) LBA12_PRPROfound: phase III study of
olaparib versus enzalutamide or abiraterone for metastatic
castration-resistant prostate cancer (mCRPC) with homologous
recombination repair (HRR) gene alterations. Ann. Oncol. 30,
v881–v882
47. Abida, W. et al. (2019) Preliminary results from the TRITON2
study of rucaparib in patients (pts) with DNA damage repair
(DDR)-deficient metastatic castration-resistant prostate can-
cer (mCRPC): updated analyses. Ann. Oncol. 30, v327–v328
48. Bono, J.S.D. et al. (2020) TALAPRO-1: A phase II study of
talazoparib (TALA) in men with DNA damage repair mutations
(DDRmut) and metastatic castration-resistant prostate cancer
(mCRPC) – first interim analysis (IA). J. Clin. Oncol. 38, 119
49. Boerrigter, E. et al. (2019) Clinical utility of emerging bio-
markers in prostate cancer liquid biopsies. Expert. Rev. Mol.
Diagn. 1–12
50. Scher, H.I. et al. (2016) Trial design and objectives for castration-
resistant prostate cancer: updated recommendations from the
Prostate Cancer Clinical Trials Working Group 3. J. Clin. Oncol.
34, 1402–1418
51. Dehm, S.M. et al. (2008) Splicing of a novel androgen receptor
exon generates a constitutively active androgen receptor that
mediates prostate cancer therapy resistance. Cancer Res. 68,
5469–5477
52. Hu, R. et al. (2009) Ligand-independent androgen receptor
variants derived from splicing of cryptic exons signify hormone-
refractory prostate cancer. Cancer Res. 69, 16–22
53. Antonarakis, E.S. et al. (2014) AR-V7 and resistance to
enzalutamide and abiraterone in prostate cancer. N. Engl.
J. Med. 371, 1028–1038
54. Armstrong, A.J. et al. (2019) Prospective multicenter validation of
androgen receptor splice variant 7 and hormone therapy resis-
tance in high-risk castration-resistant prostate cancer: the
PROPHECY study. J. Clin. Oncol. 37, 1120–1129
Trends in Cancer, Month 2020, Vol. xx, No. xx 13
Trends in Cancer
55. Sharp, A. et al. (2019) Clinical utility of circulating tumour cell
androgen receptor splice variant-7 status in metastatic
castration-resistant prostate cancer. Eur. Urol. 76, 676–685
56. Mehra, N. et al. (2018) Plasma cell-free DNA concentration and
outcomes from taxane therapy in metastatic castration-
resistant prostate cancer from two phase III trials (FIRSTANA
and PROSELICA). Eur. Urol. 74, 283–291
57. Sartor, A.O. et al. (2019) VISION: an international, prospective,
open-label, multicenter, randomized phase 3 study of 177Lu-
14 Trends in Cancer, Month 2020, Vol. xx, No. xx
PSMA-617 in the treatment of patients with progressive
PSMA-positive metastatic castration-resistant prostate cancer
(mCRPC). J. Clin. Oncol. 37, TPS5099
58. Agarwal, N. et al. (2020) Cabozantinib (C) in combination with
atezolizumab (A) in patients (pts) with metastatic castration-
resistant prostate cancer (mCRPC): results of cohort 6 of the
COSMIC-021 Study. J. Clin. Oncol. 38, A139
59. De Vincentis, G. et al. (2019) Advances in targeted alpha therapy
for prostate cancer. Ann. Oncol. 30, 1728–1739