EURURO Vol. 72 No. 3

412 476

1. Introduction
Immune checkpoint inhibitors (ICIs) have shown efficacy in
the treatment of a variety of solid tumors, including
advanced urological cancers Historically, the treatment
of urological malignancies included immune modulating
agents. In high-risk non–muscle-invasive bladder cancer
(NMIBC), adjuvant treatment with intravesical Bacille
Calmette Gue´rin (BCG), a therapy that uses mycobacterial
components to activate the immune system, provides a 32%
risk reduction in recurrence compared with intravesical
chemotherapy . In addition, 10–20% of patients with
metastatic renal cell cancer (mRCC) experience durable
responses upon treatment with high-dose interleukin-2
The first commercially available autologous cell-based
vaccination therapy, sipuleucel-T, was found to be effective
in metastatic castration-resistant prostate cancer (mCRPC)
Although immune modulating therapies have shown
efficacy in these specific cases, systemic treatment of
advanced and metastatic urological cancers thus far mainly
comprises chemotherapy (for urothelial cell cancer [UCC]
and prostate cancer [PC]), vascular endothelial growth
factor (VEGF) pathway inhibitors (for mRCC), and androgen
deprivation therapy (for PC).
Over the past 20 yr, standard first-line treatment for
advanced and metastatic UCC has been cisplatin-based
chemotherapy However, up to 50% of patients are
unfit for cisplatin, mainly due to age-associated impaired
renal function, cardiovascular comorbidities, and perfor-
mance status Furthermore, no effective second-line
treatment is available for patients with disease progression
after first-line chemotherapy. Single-agent chemotherapy
(paclitaxel, docetaxel, or vinflunine) is commonly applied,
but only 10% of patients experience a tumor response, and
the median overall survival (OS) is around 7 mo .
In contrast with UCC, RCC is highly resistant to
chemotherapy and, until the introduction of VEGF pathway
inhibitors (eg, sunitinib and sorafenib) in 2005–2006,
systemic treatment consisted of interferon-alpha and
high-dose interleukin-2 Although VEGF pathway
inhibitors, together with mammalian target of rapamycin
(mTOR) inhibitors (eg, everolimus), have significantly
improved the perspectives of mRCC patients , the median
OS for mRCC patients remains only 12.5 mo after first-line
targeted therapy .
In metastatic PC, androgen deprivation therapy is the
backbone of treatment and frequently results in durable
responses. Nevertheless, eventually all patients experience
progression to mCRPC For the treatment of mCRPC,
chemotherapy (docetaxel and cabazitaxel ),
second-generation antiandrogens such as abiraterone
and enzalutamide , and radionuclides such as radium-
223 have been approved. These agents have improved
the survival in mCRPC patients; however, the median OS
seems to plateau at about 3 yr .
The current lack of efficacious treatment options for
advanced UCC, mRCC, and mCRPC underscores the clinical
need for new well-tolerated treatment modalities that
improve the outcome of patients with urological cancers.
ICIs may expand the treatment armamentarium for patients
with urological malignancies. Currently available ICIs
include monoclonal antibodies that block the function of
inhibitory receptors on T cells, resulting in a release of T-cell
inhibition. Some tumors manage to escape immune
surveillance by expressing the programmed cell death
receptor ligand 1 (PD-L1) activating the inhibitory receptors
on T cells and thereby preventing clearance by the immune
system . Interference with this receptor–ligand inter-
action by ICIs reinvigorates the T-cell–mediated antitumor
immune response . Thus far, blocking antibodies
against programmed cell death 1 (PD-1; eg, nivolumab and
pembrolizumab), PD-L1 (eg, atezolizumab), and cytotoxic
T-lymphocyte–associated protein 4 (CTLA-4; eg, ipilimu-
mab) have been introduced in the clinic .
The first hint of antitumor activity of ICIs in urological
cancers came from phase I clinical trials, reporting durable
responses in metastatic UCC and RCC . Since then,
several pivotal clinical trials evaluating the efficacy of ICIs in
urological cancers have been initiated. In this systematic
review, we analyzed the efficacy and safety of ICIs in
patients with advanced urological cancers, including UCC,
RCC, and PC.
2. Evidence acquisition
2.1. Search strategy
Up to March 16, 2017, an electronic search of the Medline,
Embase, and Cochrane databases, and relevant websites
(Web of Science and Google Scholar) was performed by an
expert librarian. The search was conducted per Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines . Search terms included the
following: ‘‘urinary tract cancer, bladder cancer, kidney
cancer, prostate cancer, immune checkpoint inhibitors,
atezolizumab, avelumab, durvalumab, ipilimumab,
nivolumab, pembrolizumab, tremelimumab, anti-PD1,
anti-PD-L1, and anti-CTLA-4’’ (see Supplementary materials
for details). The search was completed by manual screening
of reference lists from included studies.
2.2. Inclusion criteria
The study population consisted of patients (>18 yr of age),
diagnosed with advanced or metastatic UCC, RCC, or PC,
who were treated with one of the ICIs targeting PD-1
(nivolumab and pembrolizumab), PD-L1 (atezolizumab,
avelumab, and durvalumab), and CTLA-4 (ipilimumab and
tremelimumab). The search was limited to studies executed
in humans. No restrictions in publication date or language
were imposed. During the systematic review process, only
prospective, randomized, phase 1, 2, and 3 clinical trials
were included, whereas nonrandomized clinical trials (non-
RCTs), case reports, editorials, letters, review articles, and
conference abstracts were excluded. If multiple analyses of
the same clinical study were performed, the most recent or
most relevant publication was selected. Primary outcome
measures included OS, progression-free survival (PFS), and
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