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Durvalumab

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Radiation (SBRT) + Immunotherapy treatment (Durvalumab)

64 patients will be enrolled in this arm

Durvalumab, will be started one month prior to SBRT and then given for a total of 12 months.

Patient will receive one injection per months (1500 mg/cycle)

SBRT will be started one month after Durvalumab and patients will receive 3 fractions of radiation

Radiation (SBRT)

32 patients will be enrolled in this arm

Patients will receive only 3 fractions of radiation

Durvalumab, MEDI4736, is a immunotherapy,

SBRT (stereotactic body radiotherapy) is a procedure that uses high doses of radiation delivered to a precise target. By using special positioning and implanted markers in the body, radiologists are able to deliver a much higher dose of radiation to a cancer than traditional radiation therapy

SBRT + Durvalumab

SBRT (stereotactic body radiotherapy) is a procedure that uses high doses of radiation delivered to a precise target. By using special positioning and implanted markers in the body, radiologists are able to deliver a much higher dose of radiation to a cancer than traditional radiation therapy

SBRT

STEPHANE SUPIOT

As in other solid tumours, increasing evidence indicates that patients diagnosed with a limited number of prostate cancer metastases, so-called oligometastases, have a better prognosis compared with patients with extensive metastatic disease.

Survival of patients with three or fewer metastases was superior compared with patients with more than three lesions.

The introduction of novel imaging modalities such as Fluorocholine (FCH), Fuciclovine or Ga-PSMA PET CT has increased the detection of oligometastatic prostate cancer (PCa) recurrence, potentially justifying the use of a metastasis-directed therapy with radiotherapy (RT).

Based on several studies, SBRT is now considered as a strongly validated option in oligometastatic prostate cancer.

It is increasingly understood that cancers are recognized by the immune system, and, under some circumstances, the immune system may control or even eliminate tumors.

Programmed death-ligand 1 (PD-L1) is transmembrane protein that has been speculated to play a major role in suppressing the immune system during particular events.

PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody could be used therapeutically to enhance antitumor immune responses in patients with cancer.

Experimental data from multiple cancer models have provided cumulative evidence of an interaction of ionizing radiation with the systemic antitumor immunity and this has created several opportunities in the field.

The oligometastatic setting appears to be the most relevant clinical situation to evaluate the immune response generated by radiotherapy and immune modifiers in patients with an intact immune system. The hypothesize is that Durvalumab will enhance immune response following SBRT targeting oligometastatic lesions. In this randomized 2:1 phase II trial of Stereotactic Body Radiation Therapy with or without durvalumab in oligometastatic hormone sensitive prostate cancer patients, Durvalumab will be started one month prior to SBRT to be able to evaluate PSA and immune response to the drug. It will be combined with SBRT and then given adjuvantly for a total of 12 months.

Prostate Cancer With OligometaSTatic Relapse: Combining Stereotactic Ablative Radiotherapy and Durvalumab (MEDI4736)

A Randomized Phase II Trial of Stereotactic Body Radiation Therapy (SBRT) With or Without Durvalumab (MEDI4736) in Oligometastatic Recurrent Hormone Sensitive Prostate Cancer Patients

The primary outcome will be progression-free survival, defined as the time from randomization until a biochemical-clinical failure

Health-related quality of life will be evaluated using EORTC QLQ-PR25 instruments.Total score is reported

Health-related quality of life will be evaluated using self-administered EORTC QLQ-C30 questionnaire. Total score is reported

ADT will be started in both arms at time of polymetastatic disease, local progression of metastases or symptoms.

AstraZeneca

Institut Cancerologie de l'Ouest

5 radiation treatments (5 Gy per fraction) to the prostate, seminal vesicle and pelvic nodes given every other day over 2 weeks for a total of 25 Gy.

20-25 radiation treatments (range: 1,8 to 2,15 Gy per fraction) to the prostate, seminal vesicle and pelvic nodes given in 20-25 working day treatments over 4-5 weeks for a total of 43 Gy to 46 Gy.

Assess early and late genito-urinary (GU) toxicities induced assessed via the International Prostate Symptom Score (I-PSS) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).

Report and compare changes in a non-inferiority analysis of the International Prostate Symptom Score (I-PSS)

Assess early and late genito-urinary (GU) and gastro-intestinal (GI) toxicities induced and quality of life assessed via expanded prostate cancer index composite (EPIC-26) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).

Report and compare changes in a non-inferiority analysis of the expanded prostate cancer index composite" (EPIC-26):

Assess early and late sexual health in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).

Report and compare changes in a non-inferiority analysis of the Sexual Health Inventory for Men (SHIM)

Assess early and late toxicities reported according to the Common Terminology Criteria for Adverse Events (CTCAE) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).

Report and compare changes in a non-inferiority analysis of the toxicities reported according to the Common Terminology Criteria for Adverse Events (CTCAE)

Assess the 5 and 10 years biochemical disease-free survival (bDFS) in the UHF group and compare them for non-inferiority to those of the control group.

Report and compare the biochemical disease free survival (bDFS)

Assess the 5 and 10 years disease-free survival (DFS) in the UHF group and compare them for non-inferiority to those of the control group.

Report and compare the disease free survival (DFS)

Assess the 5 and 10 years metastasis-free survival (MFS) in the UHF group and compare them for non-inferiority to those of the control group.

Report and compare the metastase free survival (MFS)

Assess the 5 and 10 years overall survival (OS) in the UHF group and compare them for non-inferiority to those of the control group.

Report and compare the overall survival (OS)

Andre-Guy Martin, MD MSc FRCPC

Josee Allard

Juanita M Crook, MD, FRCPC

Sarah Rauth, MD,FRCPC

Wayne Koll, MD, FRCPC

Steven Tisseverasinghe, MD, FRCPC

Danny Duplan, MD, FRCPC

Marjory Jolicoeur, MD, FRCPC

Peter Vavassis, MD, FRCPC

Tamim Niazi, MDCM

Marie Duclos, MD

Annie Ebacher, MD

Andre-Guy Martin, MD,MSc,FRCPC

Josée Allard, MSc

Randomized Phase III study, comparing pelvic ultra-hypo fractionated radiotherapy (UHF: 5Gy/fraction) to a standard or moderate hypo-fractionation (1.8-2.15Gy/fraction), both associated to an HDR prostate +/- adjacent seminal vesicles brachytherapy boost (HDR-BT)+ ADT according to NCCN guidelines. Considering that the calculated bio-equivalent doses to the tumor are similar for all treatment options, the UHF technique is deemed to be non-inferior to the standard approach. Treatment acceptability, tolerance and adverse events will be reported and compared for non-inferiority as the primary objective. Secondary objectives are biochemical control, metastasis-free, disease specific and overall survival.

Prostate cancer is the most common non-skin cancer in North American men. In 2020, an estimated 23 300 Canadian men will be diagnosed with prostate cancer of which, 4200 will die. Fortunately, with an early screening, most will have a localized disease at diagnosis. Despite this, high risk disease affects a growing portion of the population and this according to age (29.3%, 39.1%, 60.4%, et 90.6% respectively at 55-59, 65-69, 75-79, \& 85-89 years of age). Gleason score 8 to 10 tumors follow the same pattern (16.5%, 23.4%, 37.2%, and 59.9% at respective ages). Those patients are at risk for harboring lymph nodes metastasis.

Multiple therapeutic options, with similar biochemical disease-free survival (bDFS) are available: surgery +/- salvage radiotherapy +/- androgen deprivation therapy (ADT) or radiotherapy (RT) +/- HDR-BT +/- ADT. For men with high-risk disease, the combined approach of RT + HDR-BT + ADT might even offer higher cancer specific survival (CSS) rates when compared to surgery.

HDR-BT allows for the delivery of a very high (ablative) dose of radiation while giving a lower dose to the nearby organs at risk (OARs). Recently published literature showed that pelvic RT plus HDR-BT significantly increased bDFS (84 vs 77%).

Pelvic RT is generally given on a daily basis (5 days/week) over a period of 4-5 weeks, with 1,8-2,15Gy per fraction. This requires a substantial time investment from patients undergoing treatment. Many studies have shown that prostate cancer offers a radiation cell kill ratio (α/β) of 0.9-1.5 Gy. Furthermore, the most commonly used α/β value for prostate cancer is 1,5 Gy (range 0,8 - 2,2). This low α/β ratio offers a more efficient cell kill with hypo-fractionated doses, offering a better tumor control with a lower cumulative dose, given in a shorter time span. Recently, a multicentric randomized phase III study has shown similar late toxicity and oncologic control outcomes between UHF (\>/= 5 Gy/fraction) and conventionally fractionated RT. However, until now, no phase III study has compared combined UHF pelvic RT to standard fractionation combined with an HDR-BT in this population.

The proposed experimental fractionation scheme for whole pelvic RT in this study will be 5Gy administered every other day over 2 weeks (UHF). It will be compared to standard pelvic RT (1.8-2.15Gy/working day) given over 4 to 5 weeks. Both will be combined with a single 15 Gy fraction of HDR-BT and ADT (goserelin). The UHF treatment modality significantly reduces the overall treatment time, freeing machine-time and allowing more patients to be treated. Given its low α/β ratio, prostate cancer is readily amenable to UHF fractionation. The bio-equivalent dose calculations were done based on published litterature. Neo-adjuvant and adjuvant ADT (goserelin) will be administered for a duration according to NCCN guidelines.

In these COVID-19 pandemic times, a reduction in the number of patients' visits to the clinic is highly desirable in order to limit the risk of virus transmission. UHF would also lower the socio-economic burden incurred by the patients and their families. It also increases the therapeutic efficiency reducing costs for both, patients and health services. The proposed study aims to demonstrate the non-inferiority of UHF treatment compared to standard of care. If this hypothesis is confirmed, all future patients could benefit from it.

In order to improve the quality of life of men diagnosed with prostate cancer this study aim to demonstrate that combined UHF pelvic RT plus HDR-BT (+ ADT according to NCCN guidelines) is safe and non-inferior to standard fractionation regimens in regard to toxicities and tumor control for prostate cancer patients with risk of nodal involvement. Therefore, 500 men will be recruited, in order to confirm the hypothesis.

Pelvic Nodes Ultra-Hypo vs Conventionally Fractionated IMRT With HDR Boost in Prostate Cancer.

Pelvic Nodes Ultra-Hypo Fractionated Versus Conventionally Fractionated IMRT With HDR Brachytherapy Boost in Prostate Cancer: A Collaborative Multi-institutional Non-inferiority Phase 3 Trial. (PCS-XI)

Testosterone blood level, every 3 months for 3 years, every 6 months for 2 years, then annually.

Serum creatinine to evaluate renal function.

List of added medications (name and dosage) needed to alleviate symptoms of potential side effects of therapy and evolution of disease.

Evaluate loss of outcomes (dollars) due to treatment

Tumor extension description if presence of bony metastasis or not (for staging purposes)

Abdominal + Pelvis (thorax not compulsory) for tumor extension description =determination if presence of distant metastasis or not (for staging purposes)

Bone density evaluation to prevent osteoporosis

Recommended but not compulsory - Prostate MRI (tumor description of dominant involved lesion) for determination if presence extension extra capsulary or not.

Optional (tumor extension description if presence of metastasis or not)

Assess early genito-urinary (GU) toxicities induced opposed to baseline assessed via the International Prostate Symptom Score (I-PSS) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).

Assess early health-related quality of life opposed to baseline assessed via the Expanded Prostate Cancer Index Composite (EPIC-26) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 3 months for 1 year.

Assess late genito-urinary (GU) toxicities induced opposed to baseline evaluated by the International Prostate Symptom Score (I-PSS) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).

Assess late health-related quality of life opposed to baseline assessed via the Expanded Prostate Cancer Index Composite (EPIC-26) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 6 months up to 36 months, then annually.

Assess early quality of life opposed to baseline assessed via the Sexual Health Inventory for Men (SHIM) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 3 months for 1 year.

Assess early sexual health status opposed to baseline assessed via the Sexual Health Inventory for Men (SHIM) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 6 months up to 36 months, then annually.

Assess early reported toxicities opposed to baseline assessed via the Common Terminology Criteria for Adverse Events (CTCAE) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 3 months for 1 year, every 6 months up to 36 months, then annually.

Assess the 5 years the biochemical disease-free survival (bDFS) in the UH group and compare them for non-inferiority to those of the control group.

Assess the 5 years the disease-free survival (DFS) in the UH group and compare them for non-inferiority to those of the control group.

Assess the 5 years the Metastasis Free Survival (MFS) in the UH group and compare them for non-inferiority to those of the control group.

Assess the 5 years the Overall Survival (OS) in the UH group and compare them for non-inferiority to those of the control group.

Assess the 10 years the biochemical disease-free survival (bDFS) in the UH group and compare them for non-inferiority to those of the control group.

Assess the 10 years the disease-free survival (DFS) in the UH group and compare them for non-inferiority to those of the control group.

Assess the 10 years the Metastasis Free Survival (MFS) in the UH group and compare them for non-inferiority to those of the control group.

Assess the 10 years the Overall Survival (OS) in the UH group and compare them for non-inferiority to those of the control group.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Prostate Cancer With OligometaSTatic Relapse: Combining Stereotactic Ablative Radiotherapy and Durvalumab (MEDI4736)	NCT03795207	Node; Prostate Bone Metastases Prostate Cancer...	SBRT + Durvalum... SBRT	18 Years -	Institut Cancerologie de l'Ouest
Pelvic Nodes Ultra-Hypo vs Conventionally Fractionated IMRT With HDR Boost in Prostate Cancer.	NCT05820633	Prostate Cancer Node; Prostate Radiotherapy Si...	Report and comp... Report and comp... Report and comp... Report and comp... Report and comp... Report and comp... Report and comp... Report and comp...	18 Years - 95 Years	CHU de Quebec-Universite Laval

Spots Global Cancer Trial Database for node; prostate