Irish Journal of Medical Science (1971 -) (2023) 192:2643–2651

https://doi.org/10.1007/s11845-023-03303-y

ORIGINAL ARTICLE

Role of apalutamide in the treatment landscape for patients

with advanced prostate cancer: an expert opinion statement
of European clinical practice
Martin Bögemann1 · Gaetano Facchini2 · Thomas Bauernhofer3 · Richard Cathomas4 · Evanguelos Xylinas5 ·
Bertrand Tombal6

Received: 25 November 2022 / Accepted: 30 January 2023 / Published online: 22 March 2023
© The Author(s) 2023

Abstract
Background Patients with advanced prostate cancer have a poor prognosis, and well-tolerated new treatment strategies are
required to improve survival outcomes. Apalutamide is a novel androgen signalling inhibitor developed to be used in com-
bination with continuous androgen deprivation therapy (ADT) for the treatment of patients with advanced prostate cancer.
Based on evidence from two phase 3 pivotal clinical trials in non-metastatic castration-resistant (nmCRPC; SPARTAN)
and metastatic hormone-sensitive prostate cancer (mHSPC; TITAN), ADT plus apalutamide significantly extends overall
survival compared with the standard of care.
Aims To provide practical recommendations to guide optimal use in the real-world setting as the use of apalutamide in
clinical practice increases.
Methods Expert opinion from a group of European physicians is presented here to educate on the use of apalutamide in
combination with ADT in patients with mHSPC and patients with nmCRPC who are at risk of developing metastatic disease,
focusing on practical considerations such as patient selection, monitoring, and management of side effects.
Results In clinical practice, apalutamide in combination with ADT can be used in a broad patient population including
patients with high and low volume/risk mHSPC, patients with de novo metastatic disease or metastases following treatment
for localised disease, as well as older patients. Apalutamide in combination with ADT is well tolerated, with manageable
side effects which do not impact health-related quality of life compared to ADT alone.
Conclusions Real-world experience with apalutamide supports the efficacy and safety findings reported by the SPARTAN
and TITAN clinical trials.

Keywords Apalutamide · Metastatic hormone-sensitive prostate cancer · Non-metastatic castration-resistant prostate

cancer · Prostate cancer

4
* Martin Bögemann Division of Oncology/Hematology, Kantonsspital
[email protected] Graubünden, Chur, Switzerland
5
Department of Urology, Bichat-Claude Bernard Hospital,
1
Department of Urology, Münster University Medical Centre, Université Paris Cité, Paris, France
Münster, Germany 6
Division of Urology, Cliniques Universitaires St-Luc,
2
Oncology Complex Unit, “S. M. Delle Grazie” Hospital, Université Catholique de Louvain, Brussels, Belgium
ASL Napoli 2 Nord, Pozzuoli, Italy
3
Division of Clinical Oncology, Department of Internal
Medicine, Medical University of Graz, Graz, Austria

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2644 Irish Journal of Medical Science (1971 -) (2023) 192:2643–2651

Overview of the role of apalutamide in the metastases) or may develop after treatment for localised
management of advanced prostate cancer disease (metachronous metastases). The exact proportion
of each of these types of disease stages is not known and
Prostate cancer disease burden varies by country or clinical practice setting. In addition,
metastatic hormone-sensitive prostate cancer (mHSPC)
Worldwide, prostate cancer is the second most common can be classified as either high/low volume or high/low
cancer diagnosed in men; it is responsible for approxi- risk [5, 6]. Using definitions from the CHAARTED trial,
mately 7% of all male cancers and is the fifth most com- high-volume mHSPC disease is defined as the presence of
mon cause of cancer-related death among men [1]. In more visceral metastases and/or ≥ 4 bone lesions with ≥ 1 outside
than half of all the countries of the world, it is the most of the spine or pelvis [5]. Alternatively, mHSPC can be
frequently diagnosed cancer in men, and approximately defined as either high or low risk using the definitions used
1.4 million new cases of prostate cancer are diagnosed in the LATITUDE trial which considered high-risk disease
annually [1]. Incidence rates vary from 6.3 to 83.4 cases to be the presence of at least two of the following: Gleason
per 100,000 men with the highest rates observed in North- Score ≥ 8, ≥ 3 bone metastases (independent of location),
ern and Western Europe, North America, Australia and and/or visceral metastases [7]. Importantly, high-volume
New Zealand, and Southern Africa [1]. The prognosis of (or high-risk) disease and de novo metastatic diagnosis
prostate cancer is highly variable and dependent on the have been shown to be independently associated with a poor
tumour grade and stage at initial diagnosis; patients diag- prognosis in mHSPC [8], and there is a significant clinical
nosed early with localised disease confined to the prostate need for novel treatment regimens to improve outcomes in
can have a life expectancy of 99% over 10 years, whereas these patients.
patients diagnosed with late stage, advanced disease with For patients with mHSPC, intensification of ADT with
distant metastases have poor survival of only approx- different agents including docetaxel [5, 9], abiraterone ace-
imately 30% at 5 years [2]. Due to its prevalence, and tate plus prednisone (AAP) [7, 10, 11], enzalutamide [12,
the increase in diagnosis of early-stage tumours through 13], or apalutamide [14, 15] has been shown to improve
screening, many patients live with prostate cancer for years overall survival (OS) and is currently recommended for
or even decades, and it is estimated that at least 10 mil- mHSPC patients (Table 1; [16]).
lion men are living with prostate cancer of whom 700,000 The treatment landscape for mHSPC continues to evolve
have metastatic disease [3]. Metastatic prostate cancer rapidly. Triplet combinations of ADT plus docetaxel and
is responsible for > 400,000 cancer-related deaths annu- either abiraterone acetate plus prednisone [17] or darolu-
ally, and a similar number of patients live with treatment- tamide [18] demonstrated superior OS when compared to
related morbidity 10 years after diagnosis [3, 4]. Andro- ADT plus docetaxel alone. This triplet approach can be
gen deprivation therapy (ADT) is the backbone systemic considered for patients with de novo high-volume/risk dis-
treatment for advanced prostate cancer, although patients ease who are fit to receive chemotherapy treatment [19].
with aggressive disease will eventually relapse and expe- At the time of this article, triplet combinations were not
rience disease progression. Effective, well-tolerated new yet evaluated by the EAU guidelines committee [16] for the
treatments that delay the development of metastases and treatment of patients with mHSPC. If these two trials are
improve survival outcomes for patients with advanced dis-
ease are therefore needed to reduce the global burden of
disease caused by prostate cancer.
Table 1  2022 EAU recommendations for nmCRPC and mHSPC
Indication Recommendation Trial

nmCRPC ADT + apalutamide SPARTAN [21]

Current treatment approaches and unmet ADT + enzalutamide PROSPER [23]
needs for patients with advanced ADT + darolutamide ARAMIS [25]
prostate cancer mHSPC ADT + apalutamide TITAN [15]
ADT + docetaxel STAMPEDE [9]
Metastatic hormone‑sensitive prostate cancer CHAARTED [5]
ADT + abiraterone LATITUDE [7]
acetate + prednisone STAMPEDE [10]
Patients who present with metastatic prostate cancer are a ADT + enzalutamide ± docetaxel ENZAMET [13]
heterogeneous population. Metastases, usually in the lymph ADT + enzalutamide ARCHES [12]
nodes, bone, or lung and liver, can be present at the ini- ADT antigen deprivation therapy, mHSPC metastatic hormone-sensitive
tial diagnosis of prostate cancer (de novo or synchronous prostate cancer, nmCRPC non-metastatic castration-resistant prostate cancer

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however suggesting that ADT plus docetaxel alone should High‑risk nmCRPC
not be considered a standard of care, they do not provide
clarity on which patients needs docetaxel when ADT plus In the SPARTAN trial, 1207 patients with high-risk
one of the available androgen receptor-targeted agents is nmCRPC diagnosed using conventional imaging were ran-
the chosen treatment. domised in a 2:1 ratio to receive apalutamide 240 mg/day
plus ADT or matched placebo plus ADT [21, 26]. Patient
demographics were well balanced between the two treat-
Non‑metastatic castration‑resistant prostate cancer ment groups; approximately 16% of patients in the apaluta-
mide and placebo groups had malignant pelvic lymph nodes
Patients treated with ADT for biochemical relapse who pro- that measured less than 2 cm in the short axis (classified as
gress with three consecutive rises in prostate-specific anti- N1), the median patient age in both treatment groups was
gen (PSA) levels, a PSA of > 2 ng/mL, and a castrate serum 74 years, and the median PSA doubling time was < 5 months.
testosterone level (< 50 ng/dL or 1.7 nmol/L) are consid- In patients treated with apalutamide plus ADT, the risk of
ered by definition to have castration-resistant prostate cancer metastasis or death was 72% lower than for patients on ADT
(CRPC) by EAU guidelines [16]. In the absence of detect- alone (hazard ratio [HR] for metastasis or death 0.28, 95%
able metastases on conventional imaging, these patients confidence interval [CI] 0.23–0.35; p < 0.001), and the
are classified as having non-metastatic CRPC (nmCRPC). median MFS was more than 2 years longer with apalutamide
Patients with nmCRPC are considered to have high-risk dis- plus ADT (median MFS 40.5 vs 16.2 months, respectively).
ease when their PSA doubling time is ≤ 10 months, as this Based on the data from the SPARTAN trial, apalutamide
has been associated with a higher risk of metastatic progres- became the first US Food and Drug Administration (FDA)
sion and death [20]. Due to the fact that high-risk nmCRPC and European Medicines Agency (EMA) approved treat-
is an asymptomatic disease, treatment aims to delay devel- ment for high-risk nmCRPC. In SPARTAN, a total of 19%
opment of metastases and increase OS, while maintaining of patients crossed over to apalutamide after the trial was
health-related quality of life (HRQoL). Delaying or prevent- unblinded when the primary endpoint of MFS was met. In
ing the progression to metastatic disease and prolonging OS the final OS analysis, the median OS was significantly longer
are an important goal of management in patients with high- with apalutamide versus ADT alone (73.9 vs 59.9 months),
risk nmCRPC, along with preserving QoL. The develop- and apalutamide plus ADT was associated with a 22% reduc-
ment of effective treatment options for these patients has tion in the risk of death compared standard ADT only (HR
long been an unmet need. Until recently, treatment options 0.78, 95% CI 0.64–0.96; p = 0.016) despite the crossover
for patients with high-risk nmCRPC were ADT alone until [26]. Compared with placebo, there was a higher incidence
the development of metastatic disease. However, several key of skin rash (24.8/14.3% vs 5.5/0.3%), hypothyroidism
clinical trials (SPARTAN, PROSPER, ARAMIS) have dem- (8.0/0% vs 2.0/0%), bone fracture (11.7/2.7% vs 6.5/0.8%),
onstrated that an early introduction of apalutamide, enza- fatigue (30.0/0.9% vs 21.1/0.3%), and falls (15.6/1.7% vs
lutamide, or darolutamide in high-risk nmCRPC patients 9.0/0.8%) with apalutamide plus ADT for all grades and for
significantly extends metastasis-free survival (MFS) and Grade 3/4 adverse events (AEs), respectively [21].
OS [18, 21–25]. Current EAU guidelines recommend that
patients with high-risk nmCRPC (i.e. PSA doubling time mHSPC
≤ 10 months) should receive treatment with ADT plus either
apalutamide, enzalutamide, or darolutamide to delay metas- The double-blind, randomised phase 3 TITAN trial evalu-
tasis and prolong life (Table 1; [16]). ated the efficacy and safety of apalutamide in combination
with standard ADT in a broad population of patients with
low- and high-volume/risk mHSPC, the majority of whom
had newly diagnosed metastatic disease, but the population
Apalutamide key clinical data also included patients with metachronous mHSPC [14, 15].
Overall, 1052 patients with mHSPC were randomised in a
Apalutamide is a novel androgen signalling inhibitor devel- 1:1 ratio to treatment with apalutamide 240 mg once daily
oped for the treatment of advanced prostate cancer. Two key or matched placebo in addition to standard ADT. Patients
registrational phase 3 clinical trials provided clinical evidence that did not experience disease progression in the placebo
for the efficacy and safety of apalutamide in combination with arm were permitted to cross over to apalutamide after the
ADT: SPARTAN in patients with high-risk nmCRPC [21, 26] trial was unblinded; 39.5% of patients crossed over to apal-
and TITAN in patients with mHSPC [14, 15]. utamide after unblinding. Patient demographics were well

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balanced between apalutamide and placebo cohorts [14]. groups in TITAN, but rate of AEs of interest was increased
Median age was 69 years of age in the apalutamide arm, and with the addition of apalutamide skin rash (24.4/2.9% vs
a total of 38% had low-volume and 62% high-volume dis- 8.3/0.6%), bone fracture (6.1/1.5% vs 1.3/0.8%), falls
ease. Previous treatment with docetaxel had been received (4.6/0.7% vs 6.8/0.6%), ischemic heart disease (5.9/3.1% vs
by 11% of patients, and 18% had received prior therapy 2.1/0.8%), ischemic cerebrovascular disorder (2.5/1.6% vs
for localised prostate cancer and therefore presented with 1.5/0.2%), and seizure (0.6/0.2% vs 0.4/0%) for all grades
metachronous disease. All patients had bone metastases and for Grade 3/4 AEs, respectively [15].
by conventional imaging at study entry; the proportion of
patients with bone-only disease was 55% in the apalutamide
arm, and the proportion of patients with visceral and bone Expert opinion: role of apalutamide
metastases was 11%. in clinical practice
At the first interim analysis of TITAN data, with a median
follow-up of 22.7 months, apalutamide in combination with Apalutamide is now an integral part of the clinical arma-
ADT significantly improved OS (HR 0.67, 95% CI 0.51 to mentarium for treating advanced prostate cancer and has
0.89; p = 0.005). The final survival analysis from TITAN been approved for use in combination with ADT in patients
demonstrated that the use of apalutamide was associated with high-risk nmCRPC and those with mHSPC. Real-world
with significant improvement in OS and delayed disease pro- clinical experience needs to be added to clinical trial data to
gression despite 39.5% of patients crossed over from placebo guide clinicians using apalutamide to optimally treat their
to apalutamide once the study was unblinded [15]. The risk patients with prostate cancer. The second part of this review
of death was reduced by 35% (median OS not reached vs is therefore based upon the expert opinion of the authors, a
52.2 months; HR 0.65, 95% CI 0.53–0.79; p < 0.0001) and group of European urologists and medical oncologists, who
48% after adjusting for crossover of patients from the pla- summarised their clinical experience with apalutamide in
cebo arm (median OS not reached vs 39.8 months; HR 0.52, the treatment of prostate cancer.
95% CI 0.42–0.64; p < 0.0001) [15]. Apalutamide plus ADT
also delayed the median time to second progression-free sur-
vival (PFS2) compared to placebo plus ADT (not reached Which patients are suitable for treatment
vs 44 months; HR 0.62, 95% CI 0.51–0.75; p < 0.0001), and with apalutamide?
the time to castration resistance (not reached vs 11.4 months;
HR 0.34, 95% CI 0.29–0.41; p < 0.0001). Apalutamide is an oral treatment, administered as four
Notably, the benefit of apalutamide plus ADT on OS 60-mg tablets given at the same time (total daily dose
was seen in patients with high-volume (not reached vs 240 mg), with or without food, and is prescribed in addi-
14.9 months; HR 0.53, 95% CI 0.49–0.67) and low-volume tion to standard continuous ADT. In current EAU guide-
(not reached vs 30.5 months; HR 0.36, 95% CI 0.22–0.57) lines, apalutamide plus continuous ADT is recommended
disease. HRQoL was maintained throughout, up to 4 years as a first-line treatment option for men with mHSPC [16,
of follow-up in patients with mHSPC [27]. Rapid declines 30]. Importantly, apalutamide was evaluated in a popula-
of > 90% in PSA levels (PSA90) were observed in 14% of tion of mHSPC “all comers”, meaning that all subpopula-
patients treated with apalutamide plus ADT in TITAN, and tions within mHSPC were included. That is, apalutamide has
patients who achieved PSA90 or a PSA nadir of ≤ 0.2 ng/mL demonstrated efficacy including mHSPC patients who have
had a reduced risk of radiographic progression and synchronous or metachronous disease that has metastasised
extended MFS [28]. A total of 15% of patients achieved a following initial treatment for a localised tumour [31] and
PSA decline of > 50% (PSA50 response), and median time including patients with both high- and low-volume as well
to PSA50 was 1 month [28]. Deep and rapid PSA declines in as both high- and low-risk disease. In patients with mHSPC
patients treated with apalutamide have been associated with treatment with apalutamide plus ADT should be early, ide-
prolonged time to deterioration in HRQoL in the TITAN and ally within 1 month of diagnosis of metastatic disease as
SPARTAN trials [29]. In the TITAN and SPARTAN studies, early treatment intensification with apalutamide has been
deep and rapid PSA responses with apalutamide were associ- shown to be key to optimising outcomes. In the TITAN
ated with prolonged time to deterioration in HRQoL, Func- trial, PFS2 was longer in patients treated with apalutamide
tional Assessment of Cancer Therapy – Prostate (FACT-P) in combination with ADT, which was also noted in patients
physical wellbeing, Brief Pain Inventory-Short Form (BPI- who crossed over from the placebo arm to the apalutamide
SF) worst pain intensity, and Brief Fatigue Inventory (BFI) arm, which supports the early use of apalutamide in mHSPC
worst fatigue intensity in patients with advanced prostate [14, 15]. In contrast to treatment intensifications with doc-
cancer [29]. The overall incidence of treatment-emergent etaxel and abiraterone acetate plus prednisone, that is mainly
AEs was similar between the apalutamide and placebo beneficial in high-volume disease, and with abiraterone that

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is licenced only in high-risk disease, the disease’s volume of a number of other medications that may be prescribed
of metastatic disease does not restrict treatment selection concomitantly. This includes a number of drugs used to treat
for apalutamide. Indeed, TITAN shows that all patients, or prevent cardiovascular and thromboembolic disease (e.g.
irrespective of the volume, risk status, or the timing of the simvastatin, quinidine, amiodarone, gemfibrozil, clopidogrel,
metastases, benefit from early addition of apalutamide. dabigatran etexilate, warfarin), blood pressure–lowering
Apalutamide should also be considered for the treatment drugs (e.g. felodipine), anti-anxiety medications (e.g. mida-
of men with high-risk nmCRPC since apalutamide plus zolam, diazepam), certain antibiotics (e.g. clarithromycin,
ADT does delay the time to metastasis and improves OS in moxifloxacin), and antiviral drugs (e.g. ritonavir). It is there-
these patients [21, 22]. As described previously, high-risk fore important to carry out a full review of patient’s current
nmCRPC relates to patients on continuous ADT who have medications before prescribing apalutamide, particularly as
developed castration resistance with a rapidly rising PSA many patients with advanced prostate cancer are older and
level defined as a PSA-doubling time of ≤ 10 months. may be taking medications for several comorbid conditions.

What other considerations are important

when prescribing apalutamide for a patient?
The role of imaging in treatment decisions
It is necessary to look at the patient’s overall physical condi-
tion and assess all potential patients for their level of frailty, Imaging is important to guide apalutamide treatment; how-
existing cognitive impairment, and overall life expectancy. ever, the imaging method used can affect staging and varies
Apalutamide is effective in older as well as younger patients by country. Computed tomography (CT) and bone scans are
with high-risk nmCRPC and mHSPC. Post hoc analyses of the traditional standard methods of imaging, but the avail-
data from SPARTAN and TITAN trials have shown that ability of prostate-specific membrane antigen-guided posi-
apalutamide improves radiographic PFS (rPFS) and OS in tron emission tomography (PSMA-PET) scanning is grow-
patients ≥ 65 and 65–79 years of age [32]. Although rates ing, and this method is used in several European countries
of AEs, particularly rash, were increased in older patients, to assess prostate cancer patients because PSMA-PET can
HRQoL was maintained in the population of older patients, detect metastases earlier and at a smaller size. Current EAU
and they did not report increased bother from treatment side guidelines acknowledge that PSMA-PET/CT is more accu-
effects [32]. However, patients who are very frail with lim- rate for staging prostate cancer than CT and bone scans, but
ited life expectancy or with significant comorbidities may currently there are no outcome data to guide/inform clini-
not be suitable for treatment with any regimen beyond stand- cians on disease management in relation to PSMA-PET/CT
ard ADT. This is an important clinical decision that must be findings [16]. The heterogeneity of daily clinical practice
taken on an individual basis following thorough evaluation in European cancer treatment centres and in different coun-
of patient history, physical condition, and patient treatment tries does not allow any conclusions to be drawn on opti-
preferences. mal imaging strategy. Many patients with mHSPC, who are
When prescribing apalutamide, comorbidities of rel- classified as having low-volume disease using conventional
evance include dementia, severe organ insufficiency (i.e. imaging with CT and bone scan, may be stage migrated if
heart, lung) leading to a life expectancy < 12 months and PSMA-PET imaging was used; and the same issue may also
patients with an Eastern Cooperative Oncology Group affect high-risk nmCRPC, when PSMA-PET is used [34].
(ECOG) performance status > 2. However, in the real-world Data from the pivotal SPARTAN and TITAN clinical trials
setting, it is feasible and may be clinically reasonable to treat were produced based on conventional imaging leading to
patients with cardiovascular disease, moderate renal insuffi- the question of whether PSMA-PET scans are truly needed
ciency, and moderate liver impairment—this decision should in a situation when high-risk nmCRPC is diagnosed using
be based upon individual patient history and their ability conventional imaging. Neither apalutamide nor daroluta-
to tolerate the treatment. Cardiovascular contraindications mide are approved for the treatment of mCRPC; therefore,
include clinically significant cardiovascular disease within increased use of PSMA-PET scans might lead to an earlier
the past 6 months including myocardial infarction, severe/ diagnosis of mCRPC in most patients, thereby missing an
unstable angina, symptomatic congestive heart failure, or opportunity to use apalutamide or darolutamide in nmCRPC
thromboembolic events [33]. Considerations for patients and leaving these patients with fewer treatment choices to
with renal impairment include an estimated glomerular fight their disease. The consensus of this group of authors
filtration rate < 30 mL/min; and with hepatic impairment was that disease staging should be carried out using con-
include elevated bilirubin or liver transaminase levels. ventional CT and bone scans, but it is important to note
Apalutamide is a potent enzyme inducer cytochrome P450 that clinical practice is evolving faster than clinical trial
(CYP)2C8 and CYP3A4 and as such may affect the efficacy protocols with respect to next-generation imaging, and it is

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important to carry out clinical studies that use PSMA-PET cost of treatment. Although not mandated in the prescribing
imaging to assess disease stage at baseline and at follow-up information for apalutamide, laboratory tests should be car-
assessments. ried out before starting treatment and at regular intervals to
check liver, renal, and thyroid function.
Additionally, imaging should be performed initially
Real‑world clinical experience after 3 to 6 months and then every 6 months using CT and
with apalutamide bone scans to confirm the patient’s disease stage and assess
for metastases. In line with the HRQoL evidence from the
PSA levels are an important clinical marker for response SPARTAN and TITAN trials, clinical experience in Europe
to treatment in prostate cancer. In the apalutamide pivotal confirms that patients are generally very well able to tolerate
clinical trials, rapid and deep declines in PSA levels (> 90%) the ADT plus apalutamide treatment regimen, maintaining
have been reported in patients with high-risk nmCRPC and a favourable QoL. The recommendations of the authors for
in those with mHSPC [28], and they are correlated with monitoring patients being treated with apalutamide in com-
improved rPFS and MFS, improved OS [15], and improved bination with ADT are summarised in Table 2.
HRQoL in patient-reported outcomes [29]. These findings
are supported by the clinical experience of the authors with
apalutamide, as well as emerging evidence from clinical Management of AEs with apalutamide
practice. Published real-world evidence is very limited, but
a recent study analysed data from patients with mHSPC The most common AEs associated with apalutamide in
treated with ADT plus either apalutamide or enzalutamide in clinical trials were skin rash (29.2% of any grade), fatigue
69 urology clinics in the USA. PSA responses were observed (20.4%), hypertension (19.5%), hot flush (23.1%), arthralgia
with both treatment regimens, but initiation of apalutamide (19.7%), and increased fracture risk (10.3%) [15].
in addition to ADT was associated with significantly faster
and deeper PSA declines than enzalutamide [35]. Skin rash
Regular patient monitoring is important during treat-
ment with apalutamide plus ADT. While there is still some A mild macular or maculopapular skin rash is a common
debate on the frequency of PSA monitoring, if feasible, side effect associated with apalutamide treatment that usually
patients should be seen monthly for the first 3 months and occurs early in the treatment course [22, 36]. In the clinical
then on a 3-monthly basis thereafter to monitor effective- trials of apalutamide, the median time until the first manifes-
ness of treatment and to ensure patient compliance. Patients tation of skin rash was 83 days, and in 78% of patients, the
on long-term treatment regimens visit the oncology clinic rash disappeared after a median of 78 days [33]. Grade 1 skin
every 3 months for their injection of ADT, and this can be rash (< 10% body surface area [BSA]) associated with apalu-
linked to their PSA monitoring. As described previously, tamide can be successfully controlled through careful moni-
PSA levels are key indicators of treatment efficacy in pros- toring and dose adaption. The use of antihistamine tablets or
tate cancer, which is particularly important given the high topical corticosteroids is also recommended. The notion that

Table 2  Expert panel recommendations for clinical assessment and management of patients receiving apalutamide in combination with ADT
Clinical assessment/tests Notes

Before initiating treatment Clinical history—review for cardiovascular events and If patient has a history of cardiovascular disease
concomitant medications or cardiovascular events in past 6 months, refer to
Assessment of comorbidities/patient frailty cardiologist before starting treatment
Assess fracture/fall risk Patients with a history of osteopenia/previous
Consider baseline thyroid function test fractures/frailty need careful management
(physiotherapy, vitamin D and/or calcium/
antiresorptive agents) due to potential impact of
apalutamide plus ADT on BMD
Each clinic visit (monthly Check PSA level
initially, then every Assessment of liver, kidney, and thyroid function
3 months) Review of any patient-reported side effects (fatigue,
skin rash)
Every 6 months CT imaging and bone scan OR PSMA-PET
ADT antigen deprivation therapy, BMD bone mineral density, CT computed tomography, PSA prostate-specific antigen, PSMA-PET prostate-
specific membrane antigen-positron emission tomography

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apalutamide-associated skin rash is being attributed to off- and fractures. By itself, ADT is associated with decreased
target pharmacological reactions [37, 38] suggests that moni- bone mineral density and increased fracture risk [20], and
toring and dose adaption interventions are crucial for rash apalutamide may further increase this risk [21]. In the piv-
management. For Grade 2 skin rash (10–30% BSA), patients otal clinical trials, when apalutamide was added to ADT, the
should interrupt apalutamide treatment for a few days until the prevalence of bone fractures was 18% in SPARTAN [26] and
rash is resolved using antihistaminics, topical corticosteroids, 10.3% in TITAN [15]. All patients who are on ADT, and even
or a short course of oral corticosteroids. When apalutamide more for those considered for treatment intensification with
treatment is resumed after a Grade 2 skin rash, a dose reduc- apalutamide, should be carefully evaluated for fracture risk
tion should be considered, restarting treatment at either 180 or using dual energy X-ray absorptiometry (DEXA) measure-
120 mg of previous dose. If the rash does not recur, the dose ment and prediction tools such as the FRAX (Fracture Risk
can be re-escalated to 240 mg. In the clinical experience of the Assessment Tool, Centre for Metabolic Bone Diseases, Uni-
authors, Grade 2 skin rash does not recur frequently and is rarely versity of Sheffield, UK) score and should receive appropriate
seen after 6 months of treatment. Grade 3 skin rash (> 30% interventions to mitigate their risk such as physiotherapy and
BSA) on apalutamide should always be managed by interrupt- vitamin D/calcium supplementation and/or bone-targeting
ing treatment and controlled using a topical corticosteroid, oral agents such as denosumab, zoledronic acid, or alendronate as
antihistaminics, antihistamine, and a systemic corticosteroid. preventive measures for the development at the osteoporosis
Patients who are receiving apalutamide should be seen in the prevention dose as well [16].
clinic regularly and should be educated about the likelihood
of skin rash before starting and advised to see their doctor Fatigue
without delay if it occurs. Clinicians may consider counselling
patients that the onset of skin rash typically occurs within the In clinical practice, increased fatigue is reported by some
first 3 months of treatment; if a rash has not manifested after patients during treatment with apalutamide plus ADT,
6 months of treatment, then it is highly unlikely to develop. but the level of fatigue related to apalutamide is difficult
to assess separately from the impact of advanced prostate
Hypothyroidism cancer per se and the effect of ADT—both of which are
known to increase fatigue [2]. In the TITAN trial, the addi-
As a potent enzyme inducer, apalutamide may induce uri- tion of apalutamide to ADT did not worsen fatigue to a clini-
dine 5′-diphospho-glucuronosyltransferase (UGT). Thyroid cally relevant degree in patients with mHSPC; energy levels
hormone (T4) is metabolised by UGT, and consequently were maintained at each treatment cycle in 78% of patients
induction of UGT may promote faster metabolism and clear- [24]. In the experience of the expert panel to date, the dose
ance of T4, with subsequent increases in the level of thyroid- of apalutamide rarely needs to be reduced due to fatigue,
stimulating hormone (TSH) [36]. In clinical practice, it is although fatigue can be an issue for elderly and frail patients.
advised that patients’ thyroid function should be checked Practical recommendations to manage fatigue associated
before start of treatment and at each clinic visit to detect with treatment include taking apalutamide tablets before
hypothyroidism. In case of occurrence of hypothyroidism, bedtime and keeping levels of daytime physical activity
hormonal substitution is advised. high. Dose reduction can also be helpful for some elderly or
frail patients; the authors suggest considering a 60 mg reduc-
Cardiovascular events tion in dose tapering to a 120 mg dose reduction if needed.

Cardiovascular events are not common with apalutamide,

but every patient requires a thorough clinical history and Quality of life
evaluation of comorbidities which should include a history
of cardiovascular events 6 months prior to starting apaluta- Most asymptomatic and high-risk nmCRPC patients
mide. If a patient is known to have active cardiovascular dis- are very focussed on their PSA levels, and their QoL is
ease, a cardiology consultation is needed before prescribing strongly related to having declining/low PSA at follow-
apalutamide. In such cases, treatment can be initiated with up visits. They are often willing to live with other, rela-
ADT alone, and apalutamide can be added once the patient tively mild, adverse effects of apalutamide treatment, such
has approval by the cardiologist. as skin rash, as a “trade-off” for steep declines in PSA.
Overall, very little adverse effect management or support
Fractures is needed with apalutamide for both mHSPC and high-
risk nmCRPC patients, which is considered a very well-
Prostate cancer patients, particularly those with advanced dis- tolerated treatment, and patients usually discuss any QoL
ease, are typically older and as such are at higher risk of falls issues or adverse effects of treatment at their regular clinic

13
2650 Irish Journal of Medical Science (1971 -) (2023) 192:2643–2651

visit (either monthly initially or every 3 months during ports being an advisor and or investigator for Amgen, Astellas, Astra-
long-term treatment). Although not formally reported, the Zeneca, Bayer, Ferring, MSD, Novartis, Janssen, and Pfizer.
clinical experiences of the authors show that QoL with Open Access This article is licensed under a Creative Commons Attri-
apalutamide in the real-world setting seems to be compa- bution 4.0 International License, which permits use, sharing, adapta-
rable to that reported in the TITAN and SPARTAN clinical tion, distribution and reproduction in any medium or format, as long
trials [27]. as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
Conclusions the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
Apalutamide, used in combination with ADT, is an impor- copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
tant addition to the rapidly evolving treatment landscape in
prostate cancer and can improve survival for patients with
mHSPC and those with high-risk nmCRPC. Real-world References
experience with apalutamide supports the efficacy and safety
findings reported by the TITAN and SPARTAN clinical tri- 1. Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statis-
als; in clinical practice, apalutamide in combination with tics 2020: GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries. CA Cancer J Clin
ADT can be used in a broad patient population including 71:209–249
patients with high- and low-volume/risk mHSPC, patients 2. Rebello RJ, Oing C, Knudsen KE et al (2021) Prostate cancer
with de novo metastatic disease or metastases following Nat Rev Dis Primers 7:9
treatment for localised disease, as well as older patients. 3. Sandhu S, Moore CM, Chiong E et al (2021) Prostate cancer.
Lancet 398:1075–1090
Importantly, intensification of ADT with apalutamide can 4. GBD 2017 Disease and Injury Incidence and Prevalence Col-
significantly delay the development of metastases, as well laborators (2018) Global, regional, and national incidence,
as prolonging OS in patients with high-risk nmCRPC who, prevalence and years lived with disability for 354 diseases and
until recently, have had limited treatment options. Physicians injuries for 195 countries and territories, 1990–2017: a sys-
tematic analysis for the Global Burden of Disease study 2017.
prescribing apalutamide should conduct a thorough assess- Lancet 392:1789–1858
ment of the patient’s history and current medications and 5. Sweeney CJ, Chen Y-H, Carducci M et al (2015) Chemohormo-
monitor patients regularly during treatment to assess effec- nal therapy in metastatic hormone sensitive prostate cancer. N
tiveness and manage any side effects, particularly skin rash Engl J Med 373:737–746
6. Fizazi K, Tran NP, Fein L et al (2017) Abiraterone plus pred-
during the first 6 months of treatment. Apalutamide in com- nisone in metastatic, castration-sensitive prostate cancer. N Engl
bination with ADT is a generally well-tolerated regimen, J Med 377:352–360
with manageable side effects that do not usually increase the 7. Fizazi K, Tran NP, Fein L et al (2019) Abiraterone acetate plus
overall treatment burden for patients or further impact their prednisone in patients with newly diagnosed high-risk meta-
static castration-sensitive prostate cancer (LATITUDE): final
disease-related QoL. overall survival analysis of a randomized, double-blind, phase
3 trial. Lancet Oncol 20:686–700
8. Francini E, Gray KP, Xie W et al (2018) Time of metastatic
Funding Open Access funding enabled and organized by Projekt disease presentation and volume of disease are prognostic for
DEAL. Medical writing and editorial support were provided by Joshua metastatic hormone sensitive prostate cancer (mHSPC). Prostate
Branter, PhD, and Tom Rouwette, PhD, of Excerpta Medica, with 78:889–895
financial support from Janssen. 9. James ND, Sydes MR, Clarke NW et al (2016) Addition of
docetaxel, zoledronic acid, or both to first-line long-term hor-
Declarations mone therapy in prostate cancer (STAMPEDE): survival results
from an adaptive, multiarm, multistage, platform randomised
Conflict of interest M. Bögemann is an employee of Janssen; reports controlled trial. Lancet 387(10024):1163–1177
receiving grants from Astellas, Ipsen, and Janssen; reports consul- 10. James ND, de Bono JS, Spears MR et al (2017) Abiraterone for
tancies/honoraria from AAA, Amgen, Astellas, AstraZeneca, Bayer, prostate cancer not previously treated with hormone therapy. N
BMS, Exelixis, Janssen, Lilly, MSD, Novartis, Roche, and Sanofi. G. Engl J Med 377:338–351
Facchini reports consultancies/honoraria from Amgen, Astellas, As- 11. James ND, Clarke NW, Cook A et al (2022) Abiraterone acetate
traZeneca, Bayer, BMS, Ipsen, and Janssen. T. Bauernhofer reports plus prednisolone for metastatic patients starting hormone ther-
consultancies and honoraria for lectures from Astellas, AstraZeneca, apy: 5-year follow-up results from the STAMPEDE randomised
BMS, Janssen, Merck, and MSD; and a grant from AstraZeneca. R. trial (NCT00268476). Int J Cancer 151(3):422–434
Cathomas reports being on an advisory board for Astellas, AstraZene- 12. Armstrong AJ, Szmulewitz RZ, Petrylak DP et al (2019) ARCHES:
ca, Bayer, BMS, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche, a randomized, phase III study of androgen deprivation therapy with
and Sanofi. E. Xylinas reports consultancies/honoraria for Astellas, enzalutamide or placebo in men with metastatic hormone-sensitive
AstraZeneca, Bayer, BMS, Janssen, MSD, and Pfizer. B. Tombal re- prostate cancer. J Clin Oncol 37:2974–2986

13
Irish Journal of Medical Science (1971 -) (2023) 192:2643–2651 2651

13. Davis ID, Martin AJ, Stockler MR et al (2019) Enzalutamide of the TITAN study of apalutamide vs placebo in patients with
with standard first-line therapy in metastatic prostate cancer. N metastatic castration-sensitive prostate cancer receiving androgen
Engl J Med 381:121–131 deprivation therapy. J Clin Oncol 39(15 suppl):5068
14. Chi KN, Agarwal N, Bjartell A et al (2019) Apalutamide for 28. Chi KN, Saad F, Chowdbury S et al (2020) Prostate-specific anti-
metastatic castration-sensitive prostate cancer. N Engl J Med gen kinetics in patients with advanced prostate cancer treated with
381:13–24 apalutamide: results from the TITAN and SPARTAN studies. J
15. Chi KN, Chowdhury S, Bjartell A et al (2021) Apalutamide Clin Oncol 38(15 suppl):5541
in patients with metastatic castration-sensitive prostate cancer: 29. Small EJ, Chi KN, Chowdhury S et al (2022) Association between
final survival analysis of the randomized, double-blind, phase patient-reported outcomes and changes in prostate-specific anti-
III TITAN study. J Clin Oncol 39:2294–2303 gen in patients with advanced prostate cancer treated with apalu-
16. European Association of Urology. EAU Guidelines 2022 on Pros- tamide in the SPARTAN and TITAN studies. J Clin Oncol 40(6
tate Cancer. https://​uroweb.​org/​guide​line/​prost​ate-​cance​r/#1. suppl):073
Accessed 8 Mar 2022 30. Parker C, Castro E, Fizazi K et al (2020) Prostate cancer: ESMO
17. Fizazi K, Foulon S, Carles J et al (2022) Abiraterone plus pred- clinical practice guidelines for diagnosis, treatment, and follow-
nisone added to androgen deprivation therapy and docetaxel in up. Ann Oncol 31:1119–1134
de novo metastatic castration-sensitive prostate cancer (PEACE- 31. Bjartell A, Ye D, Agarwal N et al (2020) Apalutamide plus andro-
1): a multicentre, open-label, randomised, phase 3 study with a gen deprivation therapy for metastatic castration-sensitive prostate
2 × 2 factorial design. Lancet 399(10336):1695–1707 cancer in TITAN: outcomes in patients with de novo mCSPC vs
18. Smith MR, Hussain M, Saad F et al (2022) Darolutamide and progression to mCSPC after localised disease at diagnosis. Eur
survival in metastatic, hormone-sensitive prostate cancer. N Engl Urol Open Sci 19(Suppl 2):e863
J Med 24:1132–1142 32. Shen J, Chowdbury S, Agarwal N et al (2021) Apalutamide for
19. Fizazi K, Maldonado X, Foulon S et al (2021) A phase 3 trial with advanced prostate cancer in older patients: combined analysis of
a 2x2 factorial design of abiraterone acetate plus prednisone and/ TITAN and SPARTAN. Ann Oncol 32(suppl 5):S626–S677
or local radiotherapy in men with de novo metastatic castration- 33. Erleada (apalutamide) tablets. Summary of product characteristics
sensitive prostate cancer (mCSPC): first results of PEACE-1. J (SmPC). https://​www.​janss​enmed​icalc​loud.​me/​en-​us/​erlea​da-​smpc-​
Clin Oncol 39(15 suppl):5000 AE-​QA. Accessed 8 Mar 2022
20. Smith MR, Kabbinavar F, Saad F et al (2005) Natural history of 34. Fendler WP, Weber M, Iravani A et al (2019) Prostate-specific
rising serum prostate-specific antigen in men with castrate non- membrane antigen ligand positron emission tomography in men
metastatic prostate cancer. J Clin Oncol 23:2918–2925 with nonmetastatic castration-resistant prostate cancer. Clin Can-
21. Smith MR, Saad F, Chowdhury S et al (2018) Apalutamide treat- cer Res 25:7448–7454
ment and metastasis-free survival in prostate cancer. N Engl J Med 35. Lowentritt B, Pilon D, Khilfeh I et al (2022) Attainment of early,
378:1408–1418 deep prostate-specific antigen response in metastatic castration-
22. Smith MR, Mehra M, Nair S et al (2020) Relationship between sensitive prostate cancer: a comparison of patients initiated on
metastasis-free survival and overall survival in patients with non- apalutamide or enzalutamide. J Clin Oncol 40(6 suppl):43
metastatic castration-resistant prostate cancer. Clin Genitourin 36. Rathkopf DE, Scher HI (2018) Apalutamide for the treatment of
Cancer 18(2):e180–e189 prostate cancer. Exp Rev Anticancer Ther 18:823–836
23. Hussain M, Fizazi K, Saad F et al (2018) Enzalutamide in men 37. Tohi Y, Kataoka K, Miyai Y et al (2021) Apalutamide-associated
with nonmetastatic, castration-resistant prostate cancer. N Engl J skin rash in patients with prostate cancer: histological evaluation
Med 378:2465–2474 by skin biopsy. IJU Case Rep 4:299–302
24. Sternberg CN, Fizazi K, Saad F et al (2020) Enzalutamide and 38. Sagawa N, Watanabe Y, Mizuno Y et al (2020) A case of toxic
survival in nonmetastatic, castration-resistant prostate cancer. N epidermal necrolysis associated with apalutamide administration.
Engl J Med 382:2197–2206 J Cutan Immunol Allergy 3:134–135
25. Fizazi K, Shore N, Tammela TL et al (2019) Darolutamide in
nonmetastatic castration-resistant prostate cancer. N Engl J Med Publisher's Note Springer Nature remains neutral with regard to
380:1235–1246 jurisdictional claims in published maps and institutional affiliations.
26. Smith MR, Saad F, Chowdhury S et al (2021) Apalutamide and
overall survival in prostate cancer. Eur Urol 79:150–158
27. Agrawal N, Chowdbury S, Bjartell A et al (2021) Health-related
quality of life and patient reported outcomes at final analysis

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