Immediate Curative vs Conservative Treatment in Older Men With M0, High-risk Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
It is currently unclear if immediate curative treatment (radiotherapy or surgery) of high-risk prostate cancer without metastasis in older men (>=75 years) generates the same survival benefits as in younger patients or if the harms/ side-effects of immediate curative treatment outweigh the benefits. In this study the investigators randomize older patients with high-risk, non-metastatic high-risk prostate cancer to either immediate curative therapy or to conservative, more problem-oriented therapy to investigate if immediate curative treatment prolongs life, improves quality of life and is cost-effective.

Detailed Description
-----------------
There is a lack of both level 1 evidence and consensus regarding the optimal treatment strategy for older men (>=75 years) with non-metastatic, high-risk prostate cancer. Currently, in Scandinavia, the majority of older patients are treated conservatively, i.e. with hormone therapy or watchful waiting while some centers recommend immediate curative therapy regardless of patient age. Older patients thus risk both undertreatment and overtreatment of their cancer. This randomized clinical trial investigates if immediate curative therapy of high-risk, non-metastatic prostate cancer prolongs life (as it does in younger patients) and improves health-related quality of life. Furthermore, this trial investigates if the early side effects of immediate curative therapy are compensated by better long-term tumor control, better quality of life, functional status and improved survival.

Official Title
-----------------
A Randomized, Open-label, Multicenter, Parallel Group Treatment, Phase 3, Two-arm Study to Measure the Effect on Overall Survival and Quality of Life of Immediate Curative Therapy Compared With Standard Conservative Treatment in Older Male Participants Aged ≥ 75 Years With Non-metastatic, High-risk Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Radiation: Radiotherapy or surgery
* Other: initial observation
* Drug: Hormone therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must be 75 years of age or older, at the time of signing the informed consent. Participants who are healthy as determined by medical evaluation and geriatric G8/ miniCOGTM evaluation (G8: Fit, score >14, or reversibly frail; miniCOGTM: score >2) And who have PCa (diagnosed ≤6 months) with one or both of the following features: Gleason grade 8-10 (ISUP group 4 and 5) other than microscopic, low-volume disease (tumor must be either palpable or visible on MRI, i.e., PIRADS 4 or 5) Locally advanced PCa (T3 or T4) (unequivocal findings of clinical/ radiological T3 or clinical/ radiological T4 on DRE or MRI; broad capsular contact of tumor on MRI is treated as localized disease, T2, in the context of this study) Able to read, understand and fill in HRQoL questionnaires (PROMS) Male Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: Medical Conditions Dementia (unable to consent) Prior/Concomitant Therapy Prior radiation to the pelvis Hormone therapy >3 months prior to randomization Diagnostic assessments Lymph node metastasis (N0) on MRI, CT or PSMA-PET CT (equivocal N-findings =N0; borderline cases will be discussed and called by a study tumor board). Distant metastasis (M0) on MRI, CT, bone scan or PSMA-PET CT (equivocal bone scan findings need to be confirmed with MRI or CT; borderline cases will be discussed by a study tumor board). Other Exclusions Disabled or severe comorbidity (identified by G8 screening) Unable to read, understand or fill out HRQoL questionnaires (PROMS)

Ages Eligible for Study
-----------------
Minimum Age: 75 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, parallel, open-label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: immediate curative therapy<br>Patients randomized to the intervention arm will receive immediate curative therapy in the form of either radiotherapy to the prostate in combination with hormone therapy (ADT or monotherapy) or surgery (radical prostatectomy). Standard treatment in this arm is radiotherapy + hormone therapy. Surgery is reserved for patients with strong preferences against radiotherapy. | Radiation: Radiotherapy or surgery<br>* see arm/ group description<br>|
| Active Comparator: initial observation/ hormone therapy<br>Patients in this arm will either be observed (with localized high-risk prostate cancer) or receive hormone therapy (locally advanced prostate cancer; ADT or monotherapy). Further local or systemic therapy is given at doctor's discretion triggered by local or/ and systemic progression. | Other: initial observation<br>* see arm/ group description<br>Drug: Hormone therapy<br>* androgen depression therapy (ADT) by either LHRH agonist or antagonist or androgen monotherapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | overall survival | 10 years following end of recruitment | 
| Burden of disease | European Organisation for Research and Treatment of Cancer questionnaire for assessment of health-related quality of life elderly patients with cancer (EORTC ELD 14), burden of disease scale (2 questions, score 0-100, high scores indicate high burden of disease) | 0-10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Role functioning | European Organisation for Research and Treatment of Cancer questionnaire for quality of life of cancer patients (EORTC-QLQ-C30), RF2 scale (2 questions, score 0-100, high scores indicate a high / healthy level of functioning) | 0-10 years | 
| Urinary irritative/ obstructive symptoms | Expanded Prostate Cancer Index Composite Short Form questionnaire (EPIC-26),urinary scales (score 0-100, higher scores indicating better outcomes) | 0-10 years | 
| bowel symptoms | Expanded Prostate Cancer Index Composite Short Form questionnaire (EPIC-26), bowel scales (score 0-100, higher scores indicating better outcomes) | 0-10 years | 
| Prostate cancer morbidity | hospitalizations, interventions, complications due to local progression/ systemic progression) | 0-10 years | 
| Prostate-cancer-specific survival | Prostate cancer deaths in intervention and control group | 0-10 years | 
| Metastasis-free survival | time to metastasis detected radiographically due to symptoms or biochemical progression | 0-10 years | 
| Symptom-/ intervention-free survival | time to symptoms/ need for interventions due to prostate cancer progression | 0-10 years | 
| Quality of life-adjusted years | Euro QoL group questionaire (EQ-5D-5L) (1 =full health; 0= dead) | 0-10 years | 
| need for secondary and tertiary therapy | use of second- and third-line therapies | 0-10 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
prostate cancer, older patients, immediate curative treatment, conservative treatment