Phase II Randomized Trial of Stereotactic Body Radiation Therapy With or Without Durvalumab in Oligometastatic Hormone-Sensitive Prostate Cancer

Trial ID: 2024-513207-13-00
Protocol: POSTCARD - GETUG-P13
Sponsor: Institut De Cancerologie De L Ouest

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Diseases & Conditions

Prostate cancer

Objectives

The primary objective of this study is to evaluate the **two-years progression-free survival** in patients with oligometastatic hormone-sensitive prostate cancer undergoing Stereotactic Body Radiation Therapy (SBRT) with or without the addition of Durvalumab (MEDI4736). This objective is clinically relevant as it aims to determine the efficacy of combining SBRT with an immune checkpoint inhibitor in prolonging the time patients remain free from disease progression, which is crucial for improving long-term outcomes in this patient population.

Secondary objectives include:

Biochemical progression-free survival
Event-free survival (EFS)
Clinical progression-free survival (cPFS)
Distant progression-free survival (dPFS)
Quality of life scoring using the EORTC QLQ-C30 supplemented with QLQ-PR25 and pain with BPI + EVA
Androgen deprivation therapy free survival
Prostate cancer specific survival (PCSS)
Overall survival (OS)
Time to first symptomatic event
Acute and late toxicity due to radiotherapy
Plasma biomarkers measurements
Immune response monitoring
PDL1 expression in circulating tumor cells (CTCs)
Time to castration resistance
Association between PSA levels post-SBRT and survival outcomes
Association between the early binary endpoint "No evidence of disease (NED)" and survival outcomes

Participants

The clinical trial focuses on **oligometastatic hormone-sensitive prostate cancer** and involves a study population exclusively composed of male subjects. The age range of participants is 18 years and older, with no upper age limit specified. Participants are required to have a histologically confirmed diagnosis of prostate cancer and must have experienced a biochemical recurrence, characterized by rising PSA levels, following treatment with curative intent. The trial does not include a vulnerable population. Participants must have a controlled primary tumor and a maximum of five bone or lymph node metastases, as diagnosed by specific imaging techniques. The trial population was selected based on specific inclusion criteria, such as a WHO performance status of 0-1, adequate organ and marrow function, and a life expectancy of more than 24 months. Participants must also have a body weight greater than 30 kg and be willing to comply with the study protocol. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations, such as diet and physical activity, are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **durvalumab** in combination with Stereotactic Body Radiation Therapy (SBRT) in patients with oligometastatic hormone-sensitive prostate cancer. The primary objective is to assess two-year progression-free survival. The trial is expected to run from March 21, 2019, to December 29, 2026, with a maximum treatment period of 12 months for each participant. Participants will be randomly assigned to receive either SBRT with durvalumab or SBRT alone, with durvalumab administered as a **solution for infusion** via **intravenous administration**.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, histologically proven diagnosis of prostate cancer, and controlled primary tumor status. Participants must provide written informed consent and meet specific health criteria, including adequate organ function and a life expectancy of more than 24 months. Follow-up visits will be scheduled to monitor the participants' health status, treatment adherence, and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression or other protocol-defined criteria.

Participant involvement is expected to last up to 12 months, with conditions for early termination including the occurrence of any of the defined progression types: PSA or biochemical progression, local progression, or distant progression. Secondary endpoints include time to progression, quality of life assessments, and overall survival. The study will also monitor acute and late toxicity due to radiotherapy, immune response, and plasma biomarkers. Participants will be closely monitored throughout the trial to ensure safety and adherence to the protocol.

Treatment

The clinical trial involves the administration of **IMFINZI** (durvalumab), a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous administration**. The active substance, durvalumab, is a protein-based therapeutic agent, specifically classified under the ATC code L01XC28. The maximum daily dose is 1.5 grams, with a total maximum dose of 1.5 grams over the treatment period. The treatment duration is set for a maximum of 12 months. The product is manufactured by AstraZeneca AB and is not a pediatric formulation.

In this randomized phase II trial, the experimental treatment with durvalumab is compared against a standard-of-care therapy, which includes Stereotactic Body Radiation Therapy (SBRT). The trial aims to evaluate the two-year progression-free survival in patients with oligometastatic recurrent hormone-sensitive prostate cancer. The study does not utilize a placebo or any other comparator treatment beyond the standard-of-care therapy. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **progression-free survival** over a two-year period. The primary endpoints include three types of progression: PSA or biochemical progression, local progression, and distant progression. These will be registered according to the recommendations of the prostate cancer clinical trials working group. A patient will be considered to have progressive disease if they meet any of the progression criteria or experience death from any cause. The calculation of progression will commence from the point of randomization until progression or death occurs.

Secondary endpoints will include various time-to-event analyses, such as the time from randomization to PSA progression, local progression, distant progression, or death. Quality of life will be evaluated using the EORTC QLQ-C30 supplemented with QLQ-PR25, and pain will be assessed with BPI + EVA. Additional secondary endpoints include prostate cancer-specific survival, overall survival, time to first symptomatic event, and acute and late toxicity due to radiotherapy, which will be scored using the Common Toxicity Criteria version 5.0. Biomarker assessments will involve plasma biomarker measurements, immune response monitoring, and PDL1 expression in circulating tumor cells (CTCs). The association between PSA levels at 3, 5, and 7 months post-SBRT and survival outcomes will also be explored.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
Age > or = 18 years at time of study entry
Histologically proven diagnosis of prostate cancer (PCa)
PCa patients with a biochemical recurrence “Rising PSA” following treatment with curative intent (radical prostatectomy, primary radiotherapy or a combination of both) as defined by the EAU guidelines.
Amended A maximum of 5 bone or lymph node metastases diagnosed on Ga-PSMA PET CT, OR a maximum of 3 bone or lymph node metastases diagnosed on FCH-PET CT o ≤ 4 cm for bone metastases o ≤ 2 cm for lymph node metastases
WHO performance state 0-1
Controlled primary tumor. In case the PSA > 0,2 ng/ml in the postoperative setting patients are eligible if a multiparametric MRI or PET scan of the prostate bed rules out a local relapse. Patients after primary radiotherapy should undergo MRI of the prostate according to the European Society of Urogenital Radiology (ESUR) guidelines to rule out local relapse. In case of a suspicious lesion, a biopsy should confirm local recurrence and patients should be referred for local salvage prostatectomy when distant metastases are ruled out. If MRI rules out local relapse, patients are eligible.
If ADT has been previously administered to the patient, a minimum of 12 months must have elapsed between the predicted duration of the last injection and inclusion of the patient in the study. For this category of patients, serum testosterone has to be higher than 8.5 nmol/l prior to inclusion.
Adequate normal organ and marrow function as defined below: o Haemoglobin ≥9.0 g/dL o Absolute neutrophil count (ANC) ≥ 1.5 x 103 /L (≥ 1500 per mm3) o Platelet count ≥ 75 x 109/L (≥75,000 per mm3) o Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician. o AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN o Measured creatinine clearance (CL) ≥ 40 ml/min or Calculated creatinine CL ≥ 40 ml/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Creatinine CL (ml/min) = Weight (kg) x (140 – Age) 72 x serum creatinine (mg/dL)
Body weight > 30kg
Life expectancy of > 24 months
Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
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Exclusion Criteria

Serum testosterone level < 8.5 nmol/l
Vertebral metastases with a minimum distance inferior to 5 mm between GTV and spinal cord
Suppressed
Lymph nodes greater than 20 mm
Modified Patient with PSA doubling time less than 3 months and with two metastases or more
Spinal cord compression
Any unresolved toxicity NCI CTCAE (5.0) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria - Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
PSA rise while on active treatment (LHRH-agonist, LHRH-antagonist, anti-androgen, maximal androgen blockade, oestrogen)
Lung, Brain, Liver or other visceral metastases
Relapsed primary tumor
Perihilar lymphnode metastases
Previous irradiation of the oligometastatic site using a dose > 20 Gy less than 5 years ago
Previous treatment with a cytotoxic agent for PCa
Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids...)
Participation in another clinical study with an investigational product during the last 4 weeks
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
Any prior immune therapy (CTLA-4, PD1 or PD-L1 inhibitor, including durvalumab)
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab,. The following are exceptions to this criterion:  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent  Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of Durvalumab.
History of allogenic organ transplantation
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:  Patients with vitiligo or alopecia  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement  Any chronic skin condition that does not require systemic therapy  Patients without active disease in the last 5 years may be included but only after consultation with the study physician  Patients with celiac disease controlled by diet alone
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement
History of another primary malignancy except for  Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease  Adequately treated carcinoma in situ without evidence of disease
History of leptomeningeal carcinomatosis
History of active primary immunodeficiency
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment
Male patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period