177Lu-PSMA RADIOLIGAND THERAPY IN PATIENTS WITH LYMPH NODE METASTATIC HORMONE-SENSITIVE PROSTATE CANCER UNDERGOING ROBOT-ASSISTED LAPAROSCOPIC RADICAL PROSTATECTOMY AND EXTENDED PELVIC LYMPH NODE DISSECTION

Rationale: Prostate*specific membrane antigen (PSMA) is a receptor on the
surface of prostate cancer (PCa) cells that is revolutionizing the way we image
and treat men with prostate cancer [1,2]. New small molecule peptides with high*
binding affinity for the PSMA receptor allows high quality, highly specific
positron emission tomography (PET) imaging [3,4], in addition to the
development of targeted radionuclide therapy for men with PCa. This targeted
therapy for PCa has, to date, predominately used 177Lutetium (Lu)-labeled PSMA
peptides [5,6]. Early clinical studies evaluating the safety and efficacy of
177Lu-PSMA radioligand therapy (RLT) have demonstrated promising results with a
significant proportion of men with metastatic castration resistant prostate
cancer (mCRPC), who have already failed other therapies, responding clinically
to 177Lu-PSMA RLT [7-9].

Although 177Lu-PSMA RLT is showing promising treatment responses in men with
mCRPC and suggests a low toxicity profile, it has not been widely investigated
in patients with metastatic hormone-sensitive prostate cancer (HSPCa). As of
today, neo-adjuvant treatment with systemic drugs prior to curative treatment
is proof of concept in advanced or metastatic HSPCa as well as in other cancer
types and leads to improved oncological outcome, potentially by eradicating
micro-metastatic disease [10-12]. It is well worth investigating whether
systemic 177Lu-PSMA RLT could be used as neo-adjuvant treatment prior to
robot-assisted laparoscopic radical prostatectomy (RARP) and extended pelvic
lymph node dissection (ePLND) in patients with oligometastatic HSPCa. Before a
systemic treatment can be implemented into clinical practice, and as a
neo-adjuvant treatment before curative surgery, it first needs to be assessed
whether the surgery itself is not impeded by the neo-adjuvant therapy such as
by drug-induced toxicity. Drug-induced toxicity might result in a delay in the
timing of surgery and/or may lead to drug-related surgical difficulties.
Secondly, the current study protocol gives a unique opportunity to assess the
effect of systemic 177Lu-PSMA RLT on histological parameters, both within the
prostate tumor and in the resected lymph-nodes, thus offering the gold standard
verification of treatment to the surgically resected specimens.

Besides, the study will focus on the quality of life (QoL) and well-being of
men undergoing 177Lu-PSMA RLT and will investigate the 12-month
prostate-specific antigen (PSA) free survival in those patients who undergo
177Lu-PSMA RLT and subsequently undergo RALP and ePLND.

This is the first study to be performed in patients with suspicion of lymph
node-positive PCa metastases on PSMA PET/CT imaging (miN1 disease) undergoing
RARP and ePLND, (pre)treated with 177Lu-PSMA RLT.

To investigate if surgery is feasible and safe in patients with newly diagnosed
lymph node metastatic HSPCa who have received two cycles of (neo-adjuvant)
systemic 177Lutetium (Lu)-labeled prostate-specific membrane antigen (PSMA)
radioligand therapy (RLT). Secondly, to study the therapeutic effect of
177Lu-PSMA RLT on histopathological variables in the resected prostate gland
and the resected pelvic lymph nodes. Thirdly, to assess the toxicity of
177Lu-PSMA RLT, fourthly, to study the quality of life (QoL) and well-being of
patients receiving 177Lu-PSMA RLT. Fifthly, to study the PSA progression-free
survival at 12 months after 177Lu-PSMA RLT and radical surgery.

This is a single center, single arm, prospective, non-randomized, phase I-II
pilot study on the feasibility, safety, tolerability and efficacy of systemic
177Lu-PSMA RLT.

After screening and baseline imaging with either [68Ga] or [18F] PSMA PET/CT
and mpMRI, patients with lymph node metastatic HSPCa will be planned for two
cycles of neo-adjuvant systemic 177Lu-PSMA RLT.

The study will require time and effort from participating patients. All
patients will undergo a PSMA PET/CT and a mpMRI prior to inclusion. Also, for
monitoring, they will receive several blood draws for safety evaluation and
patients will be required to complete questionnaires that deal with
quality-of-life. The extensive monitoring is also beneficial for the patients
(see study protocol below).

A potential risk is the therapeutic injection with 177Lu-PSMA RLT itself, as it
is not completely clear yet what the long-term toxicity of this new treatment
is. However, it is important to note that the administered radiation doses are
in the lower range of the previously published data in mCRPC patients [7,8].