Metastasis-directed therapy in oligoprogressive castration-refractory prostate cancer: a randomized phase 3 trial

The primary objective of this randomized phase 3 trial is to evaluate whether the addition of **metastasis-directed therapy** enhances overall survival compared to standard care in patients with oligoprogressive metastatic castration-refractory prostate cancer. This is clinically relevant as improving overall survival is a critical endpoint in the management of this aggressive form of prostate cancer, which is resistant to conventional hormone therapy.

Secondary objectives include:

• Assessing **quality of life** using the EORTC QLQ-C30 and QLQ-PR25, with evaluations at baseline and follow-up at months 1, 3, 6, 12, and 24.
• Calculating **cancer-specific survival** from randomization to prostate cancer-related death.
• Determining **radiographic progression-free survival** from randomization to the first progression on imaging, with assessments every 6 months or as needed.
• Evaluating **acute and late toxicity** from metastasis-directed therapy using the Common Toxicity Criteria Version 5.0 at each follow-up visit.
• Analyzing the **cost-effectiveness** of metastasis-directed therapy in this patient population.

The clinical trial focuses on **oligoprogressive metastatic castration-refractory prostate cancer** and involves a study population exclusively composed of male participants aged 18 years or older. The sponsor has not provided the total number of participants. The trial population was selected based on specific criteria, including the presence of castration-refractory disease, defined by a testosterone level of less than 50 ng/dL or 1.7 nmol/L, and biochemical or radiologic progression. Participants must have a WHO performance status of 0-2 and should not have any psychological, sociological, or geographical conditions that could impede compliance with the study protocol. Prior treatment of the primary tumor by radiotherapy or surgery is required, and if untreated, local therapy should be added to the treatment. The trial excludes female subjects and does not involve a vulnerable population. Participants are required to have a maximum of five extracranial progressive lesions, and the inclusion in the trial must be approved by a multidisciplinary board meeting. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.

The clinical trial is designed to evaluate the impact of **metastasis-directed therapy** in patients with oligoprogressive metastatic castration-refractory prostate cancer. This is a randomized, phase III trial with a double-blind, controlled design. The trial aims to assess whether the addition of metastasis-directed therapy can increase overall survival compared to standard care. The trial is expected to run until July 2029, with recruitment starting in July 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a diagnosis of acinar adenocarcinoma and castration-refractory disease. Following randomization, participants will attend follow-up visits at months 1, 3, 6, 12, and 24 to monitor quality of life, cancer-specific survival, and radiographic progression-free survival. Imaging will be performed every six months or as needed based on clinical symptoms or PSA progression. The end-of-study visit will occur at the conclusion of the trial or upon early termination.

The expected length of participant involvement is up to 24 months, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or adverse events that compromise participant safety. The trial will utilize various pharmaceutical interventions, including **lutetium (177Lu) zadavotide guraxetan**, **radium ra 223 dichloride**, and **talazoparib**, among others, administered through oral or injection routes. The primary endpoint is overall survival, while secondary endpoints include quality of life, cancer-specific survival, and cost-effectiveness of the therapy.

The clinical trial involves the administration of **177Lu PSMA I&T solution for injection**, which is a **solution for injection** containing the active substance **lutetium (177Lu) zadavotide guraxetan**. This radiopharmaceutical is administered via **injection** with a maximum daily dose of 55 kilobecquerel(s) per kilogram (kBq/kg) and a total maximum dose of 330 kBq/kg over a treatment period of up to 24 weeks.

Another treatment used in the trial is **Xofigo 1100 kBq/mL solution for injection**, containing **radium Ra 223 dichloride**. This is also a **solution for injection** administered via **injection**. The dosing schedule is similar to the 177Lu PSMA I&T, with a maximum daily dose of 55 kBq/kg and a total maximum dose of 330 kBq/kg over 24 weeks.

**Talzenna 0.25 mg hard capsules** are included in the study, containing the active substance **talazoparib**. These are administered **orally** with a maximum daily dose of 0.5 mg and a total maximum dose of 2000 mg over a treatment period of up to 300 days.

**NUBEQA 300 mg film-coated tablets** contain **darolutamide** and are administered **orally**. The maximum daily dose is 1200 mg, with a total maximum dose of 20000 mg over a 300-day treatment period.

**ZYTIGA 500 mg film-coated tablets** contain **abiraterone acetate** and are administered **orally**. The maximum daily dose is 1000 mg, with a total maximum dose of 31 kg over a treatment period of up to 1000 days.

**Xtandi - 40 mg film-coated tablets** contain **enzalutamide** and are administered **orally**. The maximum daily dose is 160 mg, with a total maximum dose of 4.96 kg over a treatment period of up to 1000 days.

**JEVTANA 60 mg concentrate and solvent for solution for infusion** contains **cabazitaxel**. This is a **solution for infusion** administered via **intravenous infusion**. The maximum daily dose is 25 mg/m², with a total maximum dose of 750 mg/m² over a 30-day treatment period.

**Lynparza 150 mg film-coated tablets** contain **olaparib** and are administered **orally**. The maximum daily dose is 600 mg, with a total maximum dose of 18.6 kg over a treatment period of up to 1000 days.

**Erleada 60 mg film-coated tablets** contain **apalutamide** and are administered **orally**. The maximum daily dose is 240 mg, with a total maximum dose of 7.44 kg over a treatment period of up to 1000 days.

**TAXOTERE 20 mg/1 ml concentrate for solution for infusion** contains **docetaxel**. This is a **concentrate for solution for infusion** administered via **IV infusion**. The maximum daily dose is 75 mg/m², with a total maximum dose of 450 mg/m² over an 18-day treatment period.

**Akeega 100 mg/500 mg film-coated tablets** contain **niraparib** and **abiraterone acetate**. These are administered **orally** with a maximum daily dose of 200 mg and a total maximum dose of 20000 mg over a treatment period of up to 500 days.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be calculated from the day of randomization until death from any cause. This endpoint provides a direct measure of the treatment's impact on patient longevity.

Secondary endpoints include Quality of Life (QOL), Cancer Specific Survival (CSS), Radiographic Progression-Free Survival (rPFS), and Metastasis-Directed Therapy induced acute and late toxicity scoring. Quality of life will be evaluated using the EORTC QLQ-C30 supplemented with QLQ-PR25, and quality-of-life-years will be assessed with the EuroQOL classification system (EQ-5D-5L). These assessments are scheduled at baseline and during follow-up consultations at months 1, 3, 6, 12, and 24. CSS will be calculated from the day of randomization until death specifically from prostate cancer. rPFS will be determined from the day of randomization until the first day of progression on conventional imaging or PSMA PET-CT, with imaging performed every 6 months or as needed based on PSA progression or symptoms. Toxicity will be scored using the Common Toxicity Criteria Version 5.0 at every follow-up visit.

Additional assessments include the cost-effectiveness of metastasis-directed therapy and the predictive value of 18F PSMA PET-CT in patients with oligoprogressive metastatic castration-refractory prostate cancer. These comprehensive efficacy assessments will provide a robust evaluation of the treatment's impact on both survival and quality of life, as well as its economic and predictive value in this patient population.