Determining the clinical relevance of the interaction between enzalutamide and the opioid morphine and the DOAC edoxaban to improve rational pharmacological care of patients with prostate cancer

Globally, prostate cancer is the most commonly diagnosed cancer among men, with
1.4 million patients in 2016 of whom 381,000 died. The majority of death from
prostate cancer are due to metastatic disease, identified either at diagnosis
or after relapse following local therapies. Over the past decade multiple
oncolytic drugs have been approved for the treatment of different stages of
prostate cancer. Enzalutamide is one of the oncolytic drugs that showed
efficacy and safety in most of the features of prostate cancer. Approximately
17% of the patients treated with enzalutamide need pain control and 18% are
using cardiovascular drugs. Nearly all opioids are metabolized through one of
the CYP enzymes induced by enzalutamide, making optimal pain management
difficult. For pain control, while using enzalutamide, morphine is being
advised since morphine is mainly glucuronidated by UGT2B7 and to a lesser
extent UGT1A1. Enzalutamide is in vitro an inducer of UGT1A1 and may inhibit
UGT2B7 which could alter morphine concentrations, though the clinical relevance
of this interaction is unknown. In patients with cancer, Direct Oral
Anticoagulants (DOACs) are frequently used since vitamin-K antagonists were
reported less effective than DOACs in preventing thromboembolic events.
However, DOACs are all metabolized through CYP3A4 or P-gp. Due to interaction
potential with DOACs, patients treated with enzalutamide are switched to Low
Molecular Weight Heparin (LMWHs) administered subcutaneously which is
considered safe but less patient friendly. For patients comfort DOACs are
preferred over the use of LMWHs. Since rivaroxaban and apixaban are both major
substrates for CYP3A4, combination with enzalutamide is prohibited. Dabigatran
is a DOAC which is only metabolized by P-gp and edoxaban is a minor substrate
for CYP3A4. Therefore, both might be safe to combine with enzalutamide.
However, in patients with an active malignancy edoxaban is preferred according
to national guidelines. Though theoretically an interaction may occur, this has
not been objectivated between edoxaban and enzalutamide. For patients comfort
this combination is preferred over the use of LMWHs. Edoxaban is a substrate
for the efflux transporter P-glycoprotein (p-gp) and metabolized via
carboxylesterase-1 (CES-1) and CYP3A4/5. Metabolism by CES-1 leads to the
formation of the predominant metabolite M4, while CYP3A4/5 medicates the
formation of M6. Both are active metabolites with equipotent anticoagulant
activity compared to the parent drug. Due to the low abundance of the
metabolites (<10% for M4 and <5% for M6), they do not contribute significantly
to the anticoagulant activity of the parent drug15. Therefore, interaction via
CYP3A4/5 is considered not clinically relevant for edoxaban. Enzalutamide is a
potent inducer of CYP3A4 and is in vitro an inhibitor of P-gp. Though, P-gp
could also be induced by enzalutamide through PXR. However, recently Poondru et
al. showed that enzalutamide is a mild inhibitor of P-gp16. Still, it is
unknown if enzalutamide has a significant effect on the edoxaban exposure. The
purpose of this study is to evaluate the effect of enzalutamide on morphine and
edoxaban pharmacokinetics. This information is urgently needed to optimize the
treatment of patients with prostate cancer using enzalutamide and facilitate
the evidence-based decision between different oncolytic drugs used in patients
with prostate cancer.

This study has been transitioned to CTIS with ID 2024-517646-34-00 check the CTIS register for the current data.

The objective of this study is to evaluate the effect of enzalutamide on
morphine and edoxaban pharmacokinetics. This information is urgently needed to
optimize the treatment of patients with prostate cancer using enzalutamide and
facilitate the evidence-based decision between different oncolytic drugs used
in patients with prostate cancer.

multicentre, prospective, parallel pharmacology study in 16 patients who are on
treatment with edoxaban and who are on treatment with enzalutamide (arm 1) or
who are not on treatment with enzalutamide (control arm 2).
multicentre, prospective, parallel pharmacology study in 24 patients rwho are
on treatment with morphine and who are on treatment with enzalutamide (arm 3)
or who are not on treatment with enzalutamide (control arm 4).

In the edoxaban group: patients participating in this study will have one
pharmacokinetic assessments after 4 weeks of enzalutamide treatment (arm 1), or
5 days of edoxaban treatment (arm 2). In both arms 9 x 3 mL EDTA blood will be
drawn at the visit. For patients using edoxaban and enzalutamide concomitantly,
an extra 3 mL blood will be drawn.

In the morphine group: patients participating in this study will have one
pharmacokinetic assessments after 4 weeks of enzalutamide treatment (arm 3), or
a single-dose of morphine (arm 4). In both arms 8 x 3 mL EDTA blood will be
drawn at the visit, and 1 x 3 mL EDTA blood for the enzalutamide patients.

For patients using edoxaban and morphine concomitantly, who are participating
in both treatment-arms at the same time, 9 x 6 mL EDTA blood will be drawn at
both visits (with and without enzalutamide)

Patients will not benefit from participating in this study. The results of this
study might contribute to optimisation of handling drug-drug interactions with
enzalutamide in prostate cancer patients in the future.
Patients who participate in the study will receive enzalutamide according to
the label. The interaction between enzalutamide and morphine nor edoxaban has
been studied and combination of treatments is not prohibited according to the
drug labels. In a review of Shatzel et al. it is suggested that combining
enzalutamide with edoxaban can be done safely without dose reductions.
For morphine, the single-dose will be low and is also considered safe.
Therefore the risk for participation in this study is regarded negligible.
Collection of blood through a once placed indwell cannula will only introduce a
minimal risk for patients nor will the collection of blood interfere with
standard treatment.