Prostate cancer (PCa) accounts for ~26,730 deaths
annually in the United States and remains the most
commonly diagnosed malignancy in men, despite recent
decreases in screening.1 The majority of new cases are
localized or locally advanced. Owing to early detection
and slow disease progression rates, the 5-year survival
rates for newly diagnosed localized/regional PCa
patients (Stages I-III) approach 100%. However, up to
one-third of early stage patients will develop
recurrence after curative intent therapy, often with
metastatic disease, and these Stage IV patients have
drastically lower 5-year survival rates.
Current treatment paradigm and unmet need
Primary treatments available for early stage PCa
patients include radical prostatectomy (RP),
radiotherapy (RT), and/ or appropriate androgen
deprivation therapy (ADT) with LHRH
agonist/antagonist or first-line antiandrogens with
or without chemotherapy. Treatments for progressive
castration-naïve local/metastatic disease include
orchiectomy or ADT. Although ADT remains the frontline gold standard in
treating advanced prostate cancer, resistance
develops with time, and the disease progresses to a
state of castration-resistance (metastatic
castrate-resistant prostate cancer (mCRPC)).
The last 7 years have seen a marked improvement in
the therapeutic options available for mCRPC with FDA
approvals for many agents. These include two
secondary hormone therapies – the antiandrogen
enzalutamide (2014) and the CYP17A1 inhibitor
abiraterone acetate (2012), a cytotoxic agent
cabazitaxel (2010), a radiopharmaceutical Radium-223
(2013), and the RANKL mAb denosumab (2010) for bone
metastasis, and sipuleucel-T (2010), the first
immunotherapy approved for the treatment of
asymptomatic or minimally symptomatic mCRPC.
Table 1: Patient segments and outcomes in PCa
Click Here to Enlarge
The median survival of CRPC patients with symptomatic
metastasis is ~2 years even with the available options.
New agents that can improve the quality of life for
patients with metastatic disease as well as those agents
that can improve overall survival (OS) and demonstrate
durability of response are still desirable in this
Newly diagnosed patients who present with metastasis
(bone or soft tissue) are currently treated with ADT,
with <1 year of median failure-free survival (FFS)*
and <2 years of median OS.2 A study
evaluating the pattern of care and outcomes among
patients newly diagnosed with metastatic prostate cancer
(from 2004 to 2013), reported that 5-year OS for
patients receiving local therapy (RP or RT) to treat the
primary disease was 45.7% versus 17.1% for those not
receiving local therapy,3 suggesting a
synergistic effect. Nevertheless, new therapies that
could delay progression to CRPC will continue to be
needed in this niche.
Patients with non-metastatic CRPC (M0CRPC) currently have
no approved therapies that may delay disease
and represent a large area of unmet need. M0CRPC is
defined by rising PSA level under ADT with a castrate
level of testosterone and in the absence of clinically
metastatic disease. Clinically, castrate
levels of androgens are maintained with ADT and these
are often referred to ongoing clinical trials. Among
patients with M0CPRC, about one-third will develop bone
metastasis within 2 years. In recent trials, denosumab
significantly prolonged bone metastasis free survival
(33.2 months compared with 29.5 months with placebo) but
there was no
in OS (median, 43.9 months with denosumab vs. 44.8 months with placebo) or
progression-free survival (PFS).4
There is some evidence that immunotherapy can be
successful in this patient segment – there was a trend
in M0CRPC patients randomized to initial treatment with
a poxvirus-based PSA vaccine compared to initial
treatment with the antiandrogen nilutamide (median 6.2
years vs. 3.7 years; p = 0.045; n = 20).5
This suggests a survival advantage for M0CRPC patients
if treated with an appropriate immunotherapy prior to
Early immunotherapy strategies in PCa and lessons
Immunotherapy designed to induce tumor-specific
immune responses capable of destroying tumor cells has
emerged as a promising treatment modality in solid
malignant tumors. Despite the modest outcomes seen with
checkpoint inhibitor monotherapies in prostate
much can be learned from clinical trial data and
correlative studies of these agents. Immunotherapy
studies so far in prostate cancer
have harnessed two main strategies: vaccination and
checkpoint blockade. Cancer vaccines aim to stimulate
immune cells to recognize malignant cells as foreign,
thus initiating an immune reaction. Cancer vaccines such
as Sipuleucel-T, PROSTVAC-VF, DCVAC/PCa, GVAX, ONY-P1,
etc. all employ this immune-stimulatory strategy.
Sipuleucel-T, an autologous cell vaccine, demonstrated a
survival advantage of 4.1 months in mCRPC and is
currently the only approved immunotherapy for
Sipuleucel-T appears to enhance multiple immune
functions and antigen spreading following treatment.
Evidence with sipuleucel-T in mCRPC patients
underscores the relevance of immune responses in
prostate cancer that can translate to clinical efficacy.
Three other vaccine platforms, PROSTVAC (PSA-TRICOM),
DCVAC/PCa, and ProstAtak are in advanced stages of
development in the metastatic (PROSTVAC and DCVAC/PCa)
and localized neo-adjuvant (ProstAtak) settings.
second class of agents is immune checkpoint
inhibitors which are antagonist monoclonal antibodies
that act as immunomodulators and potentiate antitumor
immunity by targeting checkpoint regulatory proteins.
CTLA-4, PD-1, and PD-L1 are the most well-studied
checkpoint proteins, while B7-H3, LAG-3, and CD38 are
being targeted in many Phase I trials. Immune checkpoint
blockade affects interactions between several immune
components and the tumor, which in turn could modulate
the tumor microenvironment. Tumors employ inhibitory
checkpoint signals to prevent stimulating T-cell
activation, thus checkpoint blockade enables the immune
response to proceed uninterrupted against tumor cells.
Ipilimumab, pembrolizumab, nivolumab, atezolizumab are
examples of a few checkpoint blockade agents being
tested in various PCa trials, mostly in advanced stage
disease (Table 2).
our current understanding of checkpoint blockade
immunotherapy in prostate cancer
comes from trials with ipilimumab, a humanized
monoclonal antibody against CTLA-4.
Ipilimumab was studied in seven Phase I and II
clinical trials that evaluated various doses, schedules,
and combinations across the spectrum of patients with
advanced prostate cancer. Early trials of ipilimumab in
CRPC suggested that the agent is active in prostate
cancer as monotherapy or in combination with RT/
docetaxel/ other immunotherapeutics. But two large Phase
III clinical trials (NCT01057810, NCT00861614) with
ipilimumab in chemo-naïve or post-chemo CRPC patients
failed to show statistically improved OS, although in
both trials an improved PFS and a reduction in PSA were
observed.6,7 In the post-chemo trial,
although short-term OS did not differ between the
ipilimumab and placebo arms, survival curves began to
diverge after 5 months.7 The data suggest
that extended patient follow-up is necessary for the
emergence of the OS benefit associated with checkpoint
inhibitors to become evident. Additionally from the same
trials, there is evidence that two ipilimumab-treated
CRPC patients are in long-term complete remission for 4
and 5 years as of 2017.8 Prespecified subset
analyses also suggest that ipilimumab improves
survival in patients with more favorable prognostic
factors such as no visceral metastasis, lower levels of
alkaline phosphatase, and elevated hemoglobin.7
Anti-PD-1 therapies have demonstrated sporadic
responses as single agents in unselected patients.
Studies are assessing whether biomarker analysis
of tumor cells can provide clues as to who will respond
to immunotherapy. Pembrolizumab is currently being used
in the US for mismatch repair (MMR) deficient prostate
cancer. MMR-deficient PCa is known to have higher levels
of PD-L1 positivity and immune cell infiltrates. Early
evidence is also available showing that PD-1 blockade
produces anticancer activity in trial patients selected
for advanced PD-L1-positive CRPC.9 This trial
with pembrolizumab (KEYNOTE-028) elicited durable
responses even among heavily pretreated patients.9
A currently recruiting Phase II trial will stratify
mCRPC patients by tumor PD-L1 status and presence of
bone metastases before treating them with pembrolizumab
New peripheral biomarkers are also being sought to aid
in the prediction and measurement of response to
immunotherapy treatment, as well as markers that
would enable the prediction of toxicity. This
would allow targeted therapy for individuals most likely
to benefit from immunotherapy, providing a rationale for
the use of such high-cost treatments and a basis on
which truly individualized treatment plans could be
formulated. To date, immunotherapy has been investigated
predominantly in advanced disease, where the immune
system may have been suppressed and impaired by previous
treatments, disease burden, and associated comorbidities.
Immunotherapy could potentially be more effective when
administered early in the course of the disease and many
current trials are focused on this possibility. A better
understanding of the natural history of changes within
tumors treated with immunotherapy is also needed.
Combinations with IO agents in PCa
Although immune checkpoint inhibitors appear to have
modest activity as monotherapy in the broader PCa
population, preclinical and clinical data suggest that
they may synergize with other agents. Several clinical
studies that combine these therapies are currently
underway (Table 2). Tumors with poor T-cell infiltration
such as PCa (traditionally considered a ‘cold tumor’)
may require a stimulus to get the immune system to seek,
recognize, and destroy the tumor (Fig 1). This can be
achieved by combining IO with agents that can boost
tumor antigen release and mobilize key immune players.
Evidence suggests that immune checkpoint inhibitors may
be more active in inflamed tumors characterized by
immune cell infiltrates. Combination strategies that
both direct the immune players to the tumor and allow
effector cells to infiltrate and remain functional
within the tumor microenvironment will be optimal.
Trials of immune checkpoint inhibitors in combination
with other MoAs and in Phase II or III clinical
development are ongoing (Table 2).
Combinations of IO agents with ADT
Combining immunotherapy with an antiandrogen can
possibly improve treatment efficacy compared to
monotherapy. ADT has been suggested to function by
potentiating the DNA damage induced by ionizing
radiation, and by reducing androgens that enhance PCa
growth.10 Castration can lead to improved
T-cell number and diversity by limiting thymic
involution and contributing to peripheral T-cell
homeostasis.11 Multiple preclinical studies
demonstrate that androgen deprivation can enhance the
function of T cells12–14 and similar findings
have been seen in human trials as well. Enzalutamide and
abiraterone have both demonstrated that they sensitize
AR-expressing PCa cell lines to cytotoxic T-cell lysis
in preclinical studies.15 In a recent report
from a Phase II trial, patients with mCRPC progressing
on enzalutamide received anti-PD-1 (pembrolizumab) with
enzalutamide; 4 of 20 patients had PSA reductions ≥ 50%
and reached a serum PSA < 0.1 ng/mL that was durable for
16-61 weeks.16 This is proof of principle
that the immunomodulatory properties of ADT can render
human prostate carcinomas more sensitive to
immune-mediated attack. Two patients with measurable
disease in liver and lymph nodes had ongoing partial
responses after 61 and 22 weeks of follow-up,
respectively. Tumor biopsies from both patients were
PD-L1+, and one showed microsatellite instability. The
authors suggest that PD-L1 expression on tumor cells may
be a unique mechanism of non-AR driven resistance to enzalutamide in CRPC. Progression on enzalutamide is
associated with increased frequency of PD-L1/PD-L2 (and
to a lesser extend CTLA-4) expression on the tumor(s) as
well as in circulating immune cells. ADT in PCa patients
may also induce additional immunoinhibitory compensatory
mechanisms, including VISTA expression.17
Taken together, there is a strong biological basis for
immunotherapy in the treatment of prostate cancer in
combination with ADT, but the particulars remain
ambiguous. For instance, are all methods of attaining
androgen scarcity the same in terms of inducing
immunogenicity? Even though there is a consensus
that ADT has immune modulatory effects, the impact of
the different agents of ADT (LHRH antagonists/agonist,
antiandrogens, abiraterone, etc.) on T-cell function,
antigen-presenting function, and immune recognition
needs to be defined separately and more clearly. This
information will help guide the optimal ADT(s) to be
used in combination with a specific IO.
Figure 1: The role of combinations in enhancing
immune checkpoint efficacy in prostate cancer
Click Here to Enlarge
*FFS was defined as time from
randomization to evidence of at least one of the
following: biochemical failure; progression either
locally, in lymph nodes, or in distant metastases; or
death from PCa.
Combinations of IO agents with targeted therapy
Observational studies have shown that a
significant proportion of mCRPC patients
(19.3%) harbor somatic mutations in
BRCA1/BRCA2 or ATM (DNA damage repair
genes). This suggests that targeting DNA
repair enzymes such as PARP (poly
[ADP-ribose] polymerase) may propel the
tumor cells into a state of distress and
antigen shedding. Olaparib is a PARP
inhibitor that received breakthrough
designation from the FDA for PCa patients
with BRCA 1/2 or ATM germline mutations.
Findings from a study that examined mCRPC
patients treated with olaparib suggest that
the drug is highly active in this
subpopulation of patients.18
Combination studies of PARP inhibitors with
PD-1 blockade in prostate cancer are ongoing
(Table 2). Other targeted agents being
combined with PD-1 blockade include the VEGF
receptor inhibitor cediranib and an AR
antisense oligonucleotide (Table 2).
Combinations of IO agents with
Exploratory preclinical studies focusing on
the effect of chemotherapy (oxaliplatin) in
combination with IO (anti-PD-1 treatment)
found that oxaliplatin stimulated the
immunogenic potential and established a
pro‑immune microenvironment in CRPC cells
and enhanced the response of prostate cancer
to anti-PD-1 treatment.19 This
combination may be another option for CRPC
Combinations of various checkpoint blockade
therapies are also being tried in the clinic
for prostate cancer.
Anti-CTLA-4 and anti-PD-1
therapies affect the immune system in
different ways, offering the potential for
synergy when given in combination. But any
improvements in immune response will need to
be reconciled with the increased toxicity
expected with this approach. One such Phase
I trial of ipilimumab with nivolumab had a
>50% PSA decline in 1 of 15 ARV7+ mCRPC
patients.20 This combination has
progressed to Phase II for mCRPC patients
with the immunogenic signature of defective
DNA repair or MMR as identified by IHC/targeted
sequencing panel (NCT03061539).
Preclinical and clinical data also suggest
that PD-1/L1 blockade
may synergize with other IO agents
such as epacadostat, an indole-amine
2,3-dioxygenase-1 (IDO1) inhibitor.21
A recent study reported objective responses
in 18/30 treatment-naïve patients with
advanced melanoma (2 CR, 16 PR) who received
epacadostat plus pembrolizumab.22
Although these data are from early phase
trials, the improvement in response rate
provides rationale for testing epacadostat
in combination with PD-1/L1 agents
in prostate cancer. In addition,
primary and metastatic CRPC preclinical
models showed robust synergistic responses
when immune checkpoint blockade was combined
with myeloid-derived suppressor cell (MDSC)
targeted therapy, thus forming the basis for
other combination trials in the future.23
Table 2: Immune checkpoint blockade
agents in prostate cancer trials
(Phase II and III trials only)
Click Here to Enlarge
* Trial combines PROSTVAC with nivolumab
^ Cediranib and/or olaparib combination with
** In combination with multiple agents (ADT,
targeted, or chemotherapy)
Combinations of IO agents with cancer vaccine
Seminal clinical data from Dr. James L. Gulley (NIH) sheds
light on novel combination approaches that offer good
promise for improving outcomes for PCa patients – combining
cancer vaccines with immune checkpoint inhibitors. Antitumor
immune responses seen with cancer vaccines such as
sipuleucel-T and PROSTVAC may be a way to permeate the tumor
microenvironment with lymphocytes, creating a framework in
which immune checkpoint inhibitors can be effective.24
In one such case, a 95% PSA decline was observed in 1 of 4
mCRPC patients treated with PROSTVAC followed by 3 doses of
nivolumab. (NCT02933255; unpublished work from James L.
The relatively modest success
with immune checkpoint monotherapy in prostate cancer could
have been due to the absence of effector T cells within the
tumor microenvironment. Immune checkpoint inhibitors may
still be viable as therapeutics for prostate cancer when
used in combination with other agents. Currently, ADT is the
primary treatment for all stages of prostate cancer and is
ideally suited to be used in combination with immunotherapy
treatments for prostate cancer. The various agents used for
ADT also differ in their effects on immune function.
Although there is no doubt that ADT has immunomodulatory
effects, there is no comprehensive comparison of the various
agents on the synergistic effects or lack thereof when
combined with IO therapy.
It is clearly important to understand the impact of ADT
agents on T-cell function, antigen-presenting cell function,
and immune recognition of prostate tumor cells. In addition,
the timing and sequencing of ADT might affect the efficacy
of immunotherapy; for example, a preferred sequence in one
study was determined to be cancer vaccine (sipuleucel-T)
prior to ADT in mCRPC patients.25,26 Immune
therapies (other than vaccines) might best be used following
the start of ADT as demonstrated in a recent clinical trial
with advanced PCa patients responding to pembrolizumab when
delivered with concurrent enzalutamide, despite having
Single-agent immune checkpoint inhibitors appear to have a
modest activity and potential utility only in select
patients. The lack of clinically meaningful immune response
endpoints has been partly attributed to an increased
understanding of tumor heterogeneity and polyclonality
during the progression of prostate cancer to late-stage
disease (even treatment-induced polyclonality).27
Each metastatic site in CRPC patients could be composed of
subclones harboring distinct driver mutations, which may
promote both disease progression and tumor immune evasion.
Moving forward, effective therapeutic combinations in CRPC
patients may have to be driven by the analysis of
tumor-specific genomic and gene expression alterations in
distinct clonal populations.
Physicians and scientists are also considering the potential
for immunotherapy in earlier patient disease settings in
which immune responsiveness may be greater.28
Clinical trials of immunotherapy, if pursued in earlier
disease states with appropriate immune monitoring, may
improve OS. For example, a retrospective evaluation showed
that a lower PSA level at the start of treatment correlates
with longer OS in the IMPACT trial with sipuleucel-T
suggesting that patients with less advanced disease may
benefit the most.29
In conclusion, while the treatment landscapes of
melanoma, NSCLC, urothelial carcinoma, and hematological
malignancies have been transformed by immune checkpoint
inhibitors, they appear to have had only modest activity as
monotherapy in prostate cancer. Evaluating previous and
ongoing immune checkpoint clinical trials in prostate cancer
have led us to some key forward-looking questions: How can
we leverage the information we have about the MoAs of
emerging agents, to guide rational combinations with
immunotherapy that will result in meaningful therapeutic
outcomes? Can we identify the factors involved in the
successful IO responses observed in a few patients and
replicate them in the larger population of PCa patients?
Answers to these questions will permit the successful
development and approval of IO agents which will add another
useful tool in the therapeutic armamentarium for prostate
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