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 cells that is revolutionizing the way we image and treat men with prostate cancer (PCa). New small molecule peptides with high‐binding affinity for the PSMA receptor have allowed high quality, highly specific positron emission tomography (PET) imaging, 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. 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.

Although 177Lu-PSMA RLT is showing exciting treatment responses in men with mCRPC and suggests a low toxicity profile, it has not been investigated in patients with hormone-sensitive prostate cancer (HSPCa). Before a systemic treatment can be implemented into clinical practice, treatment verification by the histologically evaluation of obtained tissue is mandatory. The current study protocol gives a unique opportunity to assess the effect of 177Lu-PSMA RLT on histological parameters, both within the prostate tumor and in 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 who undergo 177Lu-PSMA RLT and subsequently undergo robot-assisted laparoscopic radical prostatectomy (RARP) and extended pelvic lymph node dissection (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.

Hypothesis:
As for now, 177Lu-PSMA has not been widely studied in patients within earlier phases of disease such as lymph node metastatic HSPCa. In theory, RLT could be more effective in low volume disease because of the very high tumor uptake of radioligands in small lesions.

Objective:
To investigate the therapeutic effect of two cycles of 177Lutetium (Lu)-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) on histopathological variables in the resected prostate gland and lymph-nodes, in patients with newly diagnosed lymph node metastatic HSPCa (1-3 metastases; miN1). Secondly, to study the quality of life (QoL) and well-being of patients receiving 177Lu-PSMA RLT. And thirdly, to study the PSA progression-free survival at 12 months after 177Lu-PSMA RLT and surgery.

Study design:
This is a prospective, non-randomized, phase I-II cohort trial on the tolerability and efficacy of systemic 177Lu-PSMA RLT.

Study population:
Ten patients with locally advanced, i.e. lymph node metastatic HSPCa (1-3 metastases), who are planned to undergo RARP and ePLND, and who are deemed clinically fit for 177Lu-PSMA RLT, will be recruited.

Methods:
After screening and baseline imaging with either [68Ga] or [18F] PSMA PET/CT and mpMRI, patients with locally advanced HSPCa will be planned for two cycles of pre-operative 177Lu-PSMA RLT.

Locally advanced disease is defined as a pre-operative [68Ga] or [18F] PSMA PET/CT scan showing increased PSMA expression in the lymph nodes within the surgical template suspicious for lymph node metastatic disease (1-3 metastases; miN1).

Patients will receive two intravenous applications of 7.4GBq 177Lu-PSMA RLT 12 and 6 weeks respectively before surgery. Four weeks after each treatment injection, patients will be monitored for toxicity and adverse events. Furthermore, QoL will be assessed using standardized questionnaires (EORTC-QLQC30 and EORTC-QLQ-BM22) prior and four weeks after each treatment injection. After surgery, the follow-up regime will be standard of care.

Main study parameters/endpoints:
It is hypothesized that systematic treatment with 177Lu-PSMA RLT and concurrent local radical treatment leads to a histological response in the resected prostate specimen and in the resected lymph nodes. Furthermore, it is hypothesized that 177Lu-PSMA RLT leads to a sustained disease-free survival in a substantial subset of patients in newly diagnosed, locally advanced, HSPCa with an acceptable toxicity and a minimal effect on QoL after 12 months.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
The study will require time and effort from participating patients. All patients will undergo a PSMA PET/CT and an mpMRI prior to inclusion. Also, for monitoring, they will receive several blood draws for safety evaluation and need 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.

As for now, 177Lu-PSMA has not been widely studied in patients within earlier phases of disease such as lymph node metastatic HSPCa. In theory, RLT could be more effective in low volume disease because of the very high tumor uptake of radioligands in small lesions.

6 timepoints:
t = -6 / 0 Screening
t = 0 Injection first Cycle 177Lu-PSMA RLT
t = 2 Adverse event evaluation
t = 6 QoL questionnaires, Injection second Cycle 177Lu-PSMA RLT
t = 8 Adverse event evaluation
t = 12 QoL questionnaires, RARP + ePLND

Regular follow-up

Two cycles of 177Lu-PSMA RLT in patients, prior to RARP + ePLND