A FEASIBILITY STUDY OF 177LU-PSMA RADIOLIGAND THERAPY ALTERNATED WITH RADIUM-223 IN PATIENTS WITH BONE-METASTATIC, OLIGO-METASTATIC HORMONE-SENSITIVE PROSTATE CANCER AFTER CURATIVE THERAPY. THE DUET STUDY

Background: Prostate*specific membrane antigen (PSMA) is a type II
transmembrane protein, 100-1000 fold overexpressed in prostate cancer (PCa)
cells that is revolutionizing the way we diagnose and treat men with prostate
cancer. New small molecule peptides with high*binding affinity for the PSMA
active center within the extracellular domain 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.

RLT is based on the delivery of radioactive atoms to tumour- associated
targets. The mechanism of action for RLT is radiation- induced killing of
cells. Radionuclides with different emission properties are used to deliver
radiation. The most commonly used radionuclides are represented by beta-
particles (e.g., 177Lu) or alpha- particles (e.g., 223Ra, 225Ac). 177Lu is
increasingly used because of its optimal imaging range (100-200- keV),
favourable half time (6.6. days) and appropriate β- particle energy for therapy.

Although 177Lu-PSMA RLT is showing exciting 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, treatment with systemic drugs 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.

Radium-223 dichloride (Ra-223) is a targeted alpha emitter that selectively
binds to areas of increased bone turnover in bone metastases and emits
high-energy alpha particles of short range. As a bone-seeking calcium mimetic,
Ra-223 is incorporated into new bone stroma, predominantely within sclerotic
metastatic deposits. The high-energy of the alpha-particle radiation generates
double-stranded DNA breaks, offering a potent and highly localized cytotoxic
effect in the target areas. The short path of the alpha particles minimizes the
toxic effects on adjacent healthy tissue, with a particular benefit for the
bone marrow. In a phase 3, randomized, double-blind, placebo-controlled study,
Ra-223 has proven to significantly improve overall survival (by a treatment
comprising 1 injection per month, at a dose of 50 kBq per kilogram of body
weight intravenously), as compared with placebo. Ra-223 was associated with low
myelosuppression rates and fewer adverse events.

The optimal therapy in patients with oligometastatic bone HSPCa after previous
curative treatment has not yet been defined.

Standard of care: Lifelong androgen deprivation therapy (ADT) is recommended in
cases of bone metastatic, oligometastatic HSPCa. However, ADT is associated
with severe loss in all the domains of health-related quality of life (HRQoL)
and impairment of well-being. In selected cases, stereotactic body radiation
therapy of suspicious lesions is offered, but is only aimed to delay the timing
of initiation of ADT.

Background: Prostate*specific membrane antigen (PSMA) is a type II
transmembrane protein, 100-1000 fold overexpressed in prostate cancer (PCa)
cells that is revolutionizing the way we diagnose and treat men with prostate
cancer. New small molecule peptides with high*binding affinity for the PSMA
active center within the extracellular domain 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.

RLT is based on the delivery of radioactive atoms to tumour- associated
targets. The mechanism of action for RLT is radiation- induced killing of
cells. Radionuclides with different emission properties are used to deliver
radiation. The most commonly used radionuclides are represented by beta-
particles (e.g., 177Lu) or alpha- particles (e.g., 223Ra, 225Ac). 177Lu is
increasingly used because of its optimal imaging range (100-200- keV),
favourable half time (6.6. days) and appropriate β- particle energy for therapy.

Although 177Lu-PSMA RLT is showing exciting 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, treatment with systemic drugs 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.

Radium-223 dichloride (Ra-223) is a targeted alpha emitter that selectively
binds to areas of increased bone turnover in bone metastases and emits
high-energy alpha particles of short range. As a bone-seeking calcium mimetic,
Ra-223 is incorporated into new bone stroma, predominantely within sclerotic
metastatic deposits. The high-energy of the alpha-particle radiation generates
double-stranded DNA breaks, offering a potent and highly localized cytotoxic
effect in the target areas. The short path of the alpha particles minimizes the
toxic effects on adjacent healthy tissue, with a particular benefit for the
bone marrow. In a phase 3, randomized, double-blind, placebo-controlled study,
Ra-223 has proven to significantly improve overall survival (by a treatment
comprising 1 injection per month, at a dose of 50 kBq per kilogram of body
weight intravenously), as compared with placebo. Ra-223 was associated with low
myelosuppression rates and fewer adverse events.

The optimal therapy in patients with oligometastatic bone HSPCa after previous
curative treatment has not yet been defined.

Standard of care: Lifelong androgen deprivation therapy (ADT) is recommended in
cases of bone metastatic, oligometastatic HSPCa. However, ADT is associated
with severe loss in all the domains of health-related quality of life (HRQoL)
and impairment of well-being. In selected cases, stereotactic body radiation
therapy of suspicious lesions is offered, but is only aimed to delay the timing
of initiation of ADT.

Rational: As of today, none of the currently available treatment options in
patients with bone oligometastatic HSPCa has proven to result in an improved
long-term PSA-free survival or *cure*. RLT is a promising new therapeutic
approach to treat metastatic PCa. This tumor-specific treatment is directed
against PSMA, which is overexpressed in PCa cells. In the last few years,
several 177Lutetium (Lu)-labeled PSMA ligands have been developed and are
currently applied in nuclear medicine departments worldwide to treat mCRPC
patients. Moreover, Radium-223 RLT has proven efficacy in patients with bone
metastatic mCRPC. Based on the mode of action, RLT could be more effective in
low volume disease because of the high tumor uptake of radioligands in
small-size limited lesions.

Hypothesis: Treatment regimens with agents that have different modes of action
have repeatedly shown to improve recurrence-free and overall survival in
patients with advanced stages of PCa. So, hypothetically, treatment regimens in
which different cytotoxic ag

This study has been transitioned to CTIS with ID 2024-518985-29-02 check the CTIS register for the current data.

To prospectively investigate if a treatment strategy in which two types of
cytotoxic RLT, i.e., an alpha-emitter and a beta-emitter, are alternatively
offered to patients with oligometastatic HSPCa, is feasible and safe

This is a single center, interventional, one-arm phase I-II study.

After screening and baseline imaging with 18F-PSMA PET/ diagnostic CT without
intravenous contrast, patients will be enrolled. Signed informed consent will
be obtained. A baseline bone scintigraphy will be performed for the assessment
of bone metastatic disease.

Patients enrolled in the trial will receive three intravenous applications of
Radium-223, in a dosis of 5.5 kBq/kg body weight at t = 0 weeks, t = 4 weeks
and t = 8 weeks (±1), and two intravenous applications of 7.4 GBq 177Lu-PSMA
RLT at t = 6 weeks and t = 12 weeks (±1). (Figure 1 and 2)

Two, four, six, eight, ten, twelve and fourteen weeks (i.e. every two weeks)
after the first treatment injection, patients will be monitored for toxicity
(assessment of (SAE), laboratory testing (Figure 3), and assessment of HRQoL).
Patients are monitored for adverse events by phone or physical consultation.
Laboratory testing consists of hematology, chemistry and PSA at the outpatient
clinic. Quality of life will be assessed using standardized questionnaires
(EORTC QLQ-C30, EORTC QLQ-PR25 and xerostomia inventory before each injection.

1. Hematological. If grade >= 2 is observed, then blood levels are monitored
each week until toxicity is regressed to grade 1or lower. If clinically
indicated, blood transfusions or transfusions with platelets
2. Chemical. If grade >= 2 is observed, blood levels are monitored each week
until toxicity is regressed to grade 1 or lower.
3. Other toxicity, i.e. dry mouth. If grade >= 2 is observed, toxicity is
monitored each week until toxicity is regressed to grade 1 or lower.

If grade >= 2 occurs (either hematological, chemical or other), treatment may be
postponed for one or two weeks.

The end of study is planned at t = week 14 after the first injection. Here
patients are evaluated for adverse events, including laboratory testing. Also,
response evaluation is done by PSMA PET/CT.

All adverse events will be monitored, as defined by NCI Common Terminology
Criteria for Adverse Events (CTCAE v5.0).

After completion of the study protocol patients will be followed-up according
to the standard of care. At three months after the last RLT, a CT scan of
abdomen/thorax, a bone scan and a PSMA PET scan is performed as clinical
response evaluation along laboratory testing. Patients will be followed towards
the timing that ADT is initiated.

The study will require time and effort from participating patients. All
patients will undergo an extra bone scan, an extra blood draweI, and a
questionnaire on health-related quality of life (HRQoL) prior to inclusion.

For monitoring of treatment safety and for registration of side effects,
participants need to undergo several blood drawels. They are required to
complete questionnaires that deal with HRQoL and general well-being. The
extensive monitoring is also beneficial for the patients (see study protocol
below).

A potential risk is the therapeutic injection with 177Lu-PSMA or Radium-223
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.