Biochemical Recurrence, Oligometastatic Prostate Cancer, Prostatic Neoplasms
Conditions
Keywords
High-risk PSA relapse, Oligometastatic recurrence, Salvage treatment, Metastasis-directed therapy, Pelvic radiotherapy, Androgen Deprivation Therapy, Enzalutamide
Brief summary
The goal of this clinical trial is to learn if adding metastasis-directed radiotherapy with or without pelvic salvage radiotherapy, to intermittent prostate cancer drugs (intensified hormone therapy) can delay the need to restart these drugs in men with oligometastactic prostate cancer recurrence. In practice, this study is open to men whose PSA level (a blood marker of cancer activity) is rising as defined by biochemical recurrence, and who have 1 to 5 areas of cancer spread (1 to 5 metastases defining oligometastatic status) found on a specialized scan (PSMA PET/CT). Since intensified hormone therapy, including androgen deprivation therapy combined with a next-generation hormone therapy, represents the standard treatment strategy for these patients, researchers want to find out if adding radiation therapy can help patients to spend more time off cancer drugs while keeping their cancer under control. The main questions this trial aims to answer are: * Does adding radiation therapy to each metastases with or without pelvic area, lengthen the time before participants need to restart drug treatment? * Does adding radiation therapy increase the number of participants whose PSA drops to a very low level (0.2 ng/mL or lower)? * Does adding radiation therapy affect participants' quality of life? Researchers will randomly assign participants (chosen by chance) to receive either enzalutamide (next-generation hormone therapy) plus androgen-deprivation therapy (first-generation hormone therapy ) alone, or the same association of these drugs combined with radiation therapy aimed at each metastases with or without pelvic area. This comparison will show whether adding radiation therapy helps participants reach a deeper PSA response and go longer without needing cancer drugs. Participants will: * Take enzalutamide and androgen-deprivation therapy for 9 months * Have an equal chance of also receiving radiation therapy to each metastases with or without pelvic area * Stop drug treatment after 9 months if their PSA drops below 0.2 ng/mL, a level showing the cancer is well controlled * Restart drug treatment if their PSA rises again during the treatment-free period * Have regular blood tests and clinic visits to check their PSA, testosterone, and overall health * Complete short quality-of-life questionnaires during the study * Take part in a study conducted at several hospitals in Switzerland, Belgium, and France.
Interventions
RADIATIONRadiotherapy for MDT ± WPRT
Participants receive metastasis-directed therapy (MDT) alone or combined with prostate-bed radiotherapy (PB-RT) and/or whole pelvic radiotherapy (WPRT), as follows (radiotherapy is tailored to each participant's prior curative treatment for prostate cancer, to avoid re-irradiating previously treated volumes) : * Prior radical prostatectomy (RP) alone: MDT plus PB-RT, with or without WPRT. WPRT is mandatory for pelvic nodal involvement (N1) and recommended for node-negative (N0) participants. * Prior RP plus PB-RT: MDT, with or without WPRT. WPRT is mandatory for N1 and recommended for N0 participants. * Prior RP plus PB-RT plus WPRT: MDT alone. * Prior definitive prostate radiotherapy (no prostatectomy): MDT, with or without WPRT. WPRT is mandatory for N1 and recommended for N0 participants.
DRUGAndrogen Deprivation Therapy (ADT)
* All arms should receive ADT for a duration of at least 36 weeks. * The prescription of ADT in both treatment arms will be in accordance with standard practice for the indication, the chosen molecules, and the selected doses. * ADT should be suspended at the end of week 36, if PSA \< 0.2 ng/mL at week 36. In the off-period, ADT will be restarted with a rise of PSA to ≥ 5 ng/mL after primary RT or to ≥ 2 ng/mL after RP ± postoperative RT. For patients in the off-period with rising PSA \< 5 ng/mL after primary RT or \< 2ng/mL after RP * postoperative RT, the decision to restart treatment is led to each investigator. * ADT should be continued until progression at the end of week 36, if PSA ≥ 0.2 ng/mL at week 36.
DRUGEnzalutamide
* All arms should receive enzalutamide 160mg daily for a duration of at least 36 weeks. * Enzalutamide should be suspended at the end of week 36, if PSA \< 0.2 ng/mL at week 36. In the off-period, Enzalutamide will be restarted with a rise of PSA to ≥ 5 ng/mL after primary RT or to ≥ 2 ng/mL after RP ± postoperative RT. For patients in the off-period with rising PSA \< 5 ng/mL after primary RT or \< 2ng/mL after RP ± postoperative RT, the decision to restart treatment is led to each investigator. * Enzalutamide should be continued until progression at the end of week 36, if PSA ≥ 0.2 ng/mL at week 36.
Sponsors
Ente Ospedaliero Cantonale, Bellinzona
Clinical Trial Unit Ente Ospedaliero Cantonale
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Superiority design
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven initial diagnosis of adenocarcinoma of the prostate * Rising PSA after local therapy as defined by PSA ≥ 0.2 ng/mL after RP +/- adjuvant/salvage prostate bed RT and at least 2 ng/mL above nadir for primary RT, with a PSADT ≤ 9 months * Serum Testosterone ≥ 150 ng/dl (6.9343 nM/L) * On PSMA PET/CT restaging presence of: 1 to 5 distant metastases that are amenable to MDT ± N1 patients (no limit in the number of nodes) * ECOG performance status 0 - 2 * Age \> or =18 years * Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial * Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations
Exclusion criteria
* More than 5 distant PSMA positive metastases and/or brain or leptomeningeal metastases. * Prostate recurrence (positive PSMA disease) after primary prostate irradiation * Prostate bed recurrence (positive PSMA disease) after salvage/adjuvant irradiation * Pelvic nodal recurrence (positive PSMA disease) after primary WPRT irradiation * Contraindications to pelvic RT and/or MDT * Prior evidence of distant metastatic disease * Contraindications to ADT * Contraindication for treatment with enzalutamide * Prior hormonal therapy (Neoadjuvant/adjuvant therapy to treat PCa ≤ 36 months in duration and ≥ 9 months before randomization is allowed) * Previous treatment with cytotoxic agent for PCa * Any active malignancies (i.e., progressing or requiring any treatment in the previous 36 months) other than prostate cancer (except non-muscle invasive bladder cancer; non-melanomatous skin cancer or a malignancy that is considered cured with minimal risk of recurrence
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to first re-initiation of treatment | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | • Time to first re-initiation of treatment calculated from randomization to the occurrence of one of the following events: * PSA ≥ 0.2 ng/mL at week 36 (treatment is continued until progression), * For patients in the off-period, a rise of PSA to ≥ 5 ng/mL after primary RT or to ≥ 2 ng/mL after RP ± postoperative RT (treatment is restarted as per EMBARK criteria) * For patients in the off-period with rising PSA \< 5 ng/mL after primary RT or \<2ng/mL after RP ± postoperative RT, the investigator decision to start same or new treatment. Death in the absence of progressive disease will be considered as a competing risk for this endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to PSA progression | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | Time to PSA progression: defined by the time from the day of PSA nadir and the day when the PSA increase of ≥ 25% and an absolute increase of ≥ 2 ng/mL above the nadir. |
| PFS (Progression-Free Survival) | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | PFS: defined as the time from randomization to the first progression or death (progression being defined by the appearance of a new recurrence (any N1 or M1) as suggested by PET-CT, or symptoms related to progressive prostate cancer, or death due to any cause). |
| MFS (Metastasis-Free Survival) | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | MFS: defined as time between randomization and the appearance of a new metastatic recurrence (any M1) as suggested by PET-CT, or death due to any cause. |
| OS (Overall Survival) | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | OS: defined as the time from randomization to death to any cause. |
| PSA response | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | PSA response: defined by a PSA \< 0.2 ng/ml at 9 months. |
| Pattern of progression | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | Local/regional/distant recurrence will be analyzed: * A local recurrence is defined as the appearance of evidence of a recurrence on imaging inside a PTV\_M volume or the PTV\_PB volume or the PTV\_LNN. * A regional nodal recurrence is defined as the appearance of evidence of a lymphadenopathy in the pelvis but outside the PTV\_LNN volume, in a patient without the diagnosis of hematologic/lymphatic disorder associated with lymphadenopathy or if there is histopathological evidence. * Distant recurrence is defined as the appearance of evidence of a lymphadenopathy outside the PTV\_LNN and outside all the PTV\_M (for lymph nodes previously treated as metastasis), or distant metastases (M1b, M1c) outside all the PTV\_M. |
| Time to castration-resistant disease | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | Time to castration-resistant disease is defined as the time from trial randomization until castration-resistant status, defined as a castrate serum testosterone level below 50 ng/dL (1.7 nmol/L) plus either biochemical progression or radiological progression. Biochemical progression is defined as three consecutive rises in PSA at least 1 week apart, resulting in two 50% increases over the nadir, with a PSA level above 2 ng/mL. Radiological progression is defined as the appearance of two or more new bone lesions on bone scan, or enlargement of a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid Tumours). Symptomatic progression alone is not sufficient to diagnose castration-resistant prostate cancer (CRPC). |
| Adverse events | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | Adverse events: acute (during the first 3 months after the end of MDT ± WPRT and late (3 months after the end of MDT ± WPRT). |
| Quality of life (QoL) - EORTC QLQ-C30 | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | EORTC Quality of Life Questionnaire Core 30 (QLQ-C30), version 3, a 30-item questionnaire. Items are rated on a 4-point scale (1 = "Not at all" to 4 = "Very much"), except the two global health status/QoL items, rated on a 7-point scale (1 = "Very poor" to 7 = "Excellent"). Raw scores are linearly transformed to a 0-100 scale. Higher scores indicate better functioning/quality of life on the functional and global health scales, and greater symptom burden on the symptom scales. |
| Quality of Life - EORTC QLQ-PR25 | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | EORTC Quality of Life Questionnaire Prostate Cancer Module (QLQ-PR25), a 25-item module supplementing the QLQ-C30. Items are rated on a 4-point scale (1 = "Not at all" to 4 = "Very much"). Raw scores are linearly transformed to a 0-100 scale. Higher scores indicate greater symptom burden, except for sexual activity/functioning scales, where higher scores indicate better functioning. |
| Quality of Life - EORTC IL-249 | From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date | A customised 22-item list from the EORTC IL-249, assessing general symptoms, weight-related issues, and sexual quality of life. Items are rated on a 4-point scale (1 = "Not at all" to 4 = "Very much"). Raw scores are linearly transformed to a 0-100 scale; higher scores indicate a greater burden of symptoms or issues. |
Countries
Belgium, France, Switzerland
Contacts
CONTACTThomas Zilli, MD
CONTACTTatiana Terrot
PRINCIPAL_INVESTIGATORThomas Zilli, MD
IOSI-EOC
STUDY_CHAIRBertrand Tombal, MD, PhD
Urology, Cliniques Universitaires Saint Luc, Bruxelles, Belgium
STUDY_CHAIRPiet Ost, MD, PhD
Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Department of Radiation Oncology, Iridium Network, Wilrijk, Belgium
STUDY_CHAIRSilke Gillessen, MD
IOSI-EOC
STUDY_CHAIRPiet Dirix, MD, PhD
Department of Radiation Oncology, Iridium Network, Wilrijk, Belgium
STUDY_CHAIRSalvatore Cozzi, MD
IOSI-EOC
STUDY_CHAIRNicolas Vial, MD
University Hospital of Saint-Etienne
Outcome results
None listed