Circulating Tumour DNA, Metastasis, Prostate Cancer, Toxicity Due to Radiotherapy
Conditions
Brief summary
This multi-center, phase II trial will be conducted in men with castration resistant prostate cancer. The aim of the TRAP trial is to test whether a new precise radiotherapy technique called stereotactic body radiotherapy (SBRT) can slow down the growth of metastatic prostate cancer. If SBRT is effective it will represent a new treatment option in these patients, providing more prolonged control without having to resort to chemotherapy and its potentially unpleasant side effects. In this trial, the investigators will identify men who, despite being on next generation androgen deprivation treatment (Abiraterone or Enzalutamide) have developed one or two new sites of worsening (growing) disease but the rest of their cancer is still responding to hormonal therapy. If it is the case that SBRT can successfully treat the cancer which is resistant to current treatment then the investigators hope they will be able to better control the spread of cancer in these patients for longer. The investigators also hope that they will be able to use the tell-tale products (gene markers) that are released into the bloodstream in these patients, or identify characteristics on novel imaging such as magnetic resonance imaging (MRI) to help identify patients in the future who will benefit the most.
Detailed description
For many men with metastatic prostate cancer, the cancer develops resistance to successive systemic therapies and eventually all treatment options are exhausted and the patient succumbs to their disease. It is therefore vital to find ways of evading prostate cancer resistance. Stereotactic body radiotherapy (SBRT) has the advantage that it destroys cancerous tissue irrespective of the underlying genetic deficit within the progressing metastasis. If the resistant clones are localized to 1-2 metastases and can be destroyed or ablated, the patient can continue to receive the benefit of their systemic (androgen deprivation) treatment (Abiraterone or Enzalutamide) which may continue to control the remainder of their disease for many months, possibly even years. SBRT is a recognised technique for the elimination of isolated metastases in other tumour sites achieving local control of metastasis in 80-90% of cases. This is achieved with very few side effects. In the TRAP trial, the investigators wish to establish whether it is beneficial to target 1 or 2 metastatic sites with SBRT or whether patients will develop polymetastatic progression. Patients enrolled on the trial will receive 30 Gy in 5 fractions on alternate days over 10 days. They will continue their androgen deprivation treatment throughout and following SBRT. Side effects will be closely monitored throughout and patients will be seen at the end of radiotherapy and then 4 weeks after treatment. Thereafter patients will undergo trial follow up three monthly which will includes Prostate Specific Antigen (PSA) monitoring. In addition to the above procedures, the investigators will use a combination of whole body (WB) diffusion weighted (DW) magnetic resonance imaging (WB DW MRI) and circulating tumour (ct) deoxyribonucleic acid (DNA), 'ct DNA' biomarker analysis with the aim of identifying those patients which benefit most from the combination of SBRT and androgen deprivation treatment. WB DW MRI is a novel MRI technique which shows improved sensitivity compared to standard MRI. The marker ctDNA enables the investigators to explore genomic characterisation and variation of metastases and compare findings with previously explored genome mutations in prostate cancer patients.
Interventions
RADIATIONSBRT + ADT
Short course SBRT to 1 or 2 oligo-progressing metastases in addition to continued abiraterone or enzalutamide
Sponsors
Royal Marsden NHS Foundation Trust
Prostate Cancer UK
University College, London
The Christie NHS Foundation Trust
The Leeds Teaching Hospitals NHS Trust
Velindre NHS Trust
University Hospital Birmingham NHS Foundation Trust
Newcastle-upon-Tyne Hospitals NHS Trust
Belfast Health and Social Care Trust
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Interpretation of the two paired WB DW MRI scans (baseline and 6 months) will be conducted by one assessor will be blinded to the identity of the baseline scan to ensure minimisation of any potential bias.
Intervention model description
Single arm, prospective interventional cohort study
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Be willing and able to provide written informed consent for the trial and be ≥18 years of age on day of signing informed consent. 2. Have metastatic Castration Resistant Prostate Cancer (CRPC) based on biochemical or pathological diagnosis and be on Enzalutamide or Abiraterone. 3. Have had a minimum of 6 months on Enzalutamide or Abiraterone with evidence of response (PSA, radiological or symptomatic) 4. Have 1 - 2 metastatic lesions progressing on imaging (CT, bone scan, MRI or other local imaging) or a clinical or imaging diagnosis of progression of a non-irradiated primary site with the remainder of their metastases currently controlled by Enzalutamide or Abiraterone. 5. Have had no previous radical radiation to the index area (defined as unable to deliver SBRT doses in this protocol without taking normal tissues beyond tolerance). 6. Have a Performance Status (PS) assessed using the Eastern Co-operative Oncology Group (ECOG) criteria of 0 - 1. 7. Have an oligoprogressing site, including those that have developed on treatment, in bone, lymph node, prostate or lung but not in liver, brain, adrenal or other sites. 8. Patients may be symptomatic in the oligoprogressing area. However, there is no urgent need to start radiotherapy.
Exclusion criteria
1. A clinical need exists to switch therapy immediately (e.g. suspicion of rapid clinical progression, urgent need for palliative radiotherapy). 2. Evidence of previous invasive cancer in the last 5 years, with the exception of non-melanoma skin cancer (non-invasive malignancies such as non-muscle invasive bladder cancer are not excluded). 3. There is a contra-indication to radiotherapy (e.g. inflammatory bowel disease). 4. There is a contra-indication to MRI where required for radiotherapy (e.g. cardiac pacemaker, internal defibrillator, shrapnel injury or claustrophobia).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-Free Survival (PFS) | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | Median progression free survival following SBRT to progression, starting new treatment or death from any cause. Progression is defined as one of the following; (i) PSA progression: PSA rise by at least 25% over post-SBRT baseline (set at 4 weeks), confirmed by a second reading at least 4 weeks later, (ii) Radiological progression: at least 2 new lesions on bone scan or unequivocal progression of soft tissue on CT, or evidence on other local imaging of disease progression (e.g. PET or MRI progression) as per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) (iii) Symptomatic progression: new or progressing symptoms at the site of a metastasis, or (iv) Date at which the clinician decides to stop Abiraterone/Enzalutamide or starts new line of therapy, whichever occurs sooner. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Events | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | Number of patients that had a PFS event following SBRT in the duration of the study. Progression free survival definition is time from SBRT to progression, starting new treatment or death from any cause. Progression is defined as one of the following; (i) PSA progression: PSA rise by at least 25% over post-SBRT baseline (set at 4 weeks), confirmed by a second reading at least 4 weeks later, (ii) Radiological progression: at least 2 new lesions on bone scan or unequivocal progression of soft tissue on CT, or evidence on other local imaging of disease progression (e.g. PET or MRI progression) as per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) (iii) Symptomatic progression: new or progressing symptoms at the site of a metastasis, or (iv) Date at which the clinician decides to stop Abiraterone/Enzalutamide or starts new line of therapy, whichever occurs sooner. |
| Progression-Free Survival (PFS) Estimates | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | Progression free survival estimates following SBRT to progression, starting new treatment or death from any cause. Progression is defined as one of the following; (i) PSA progression: PSA rise by at least 25% over post-SBRT baseline (set at 4 weeks), confirmed by a second reading at least 4 weeks later, (ii) Radiological progression: at least 2 new lesions on bone scan or unequivocal progression of soft tissue on CT, or evidence on other local imaging of disease progression (e.g. PET or MRI progression) as per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) (iii) Symptomatic progression: new or progressing symptoms at the site of a metastasis, or (iv) Date at which the clinician decides to stop Abiraterone/Enzalutamide or starts new line of therapy, whichever occurs sooner. |
| Local Control Rate Following SBRT | At the 6 month timepoint from end of SBRT | Overall control defined as stable disease or partial response of irradiated metastases assessed using the RECIST (v 1.1) criteria on imaging such as computed Tomography (CT), magnetic Resonance Imaging (MRI) or Positron Emission Tomography (PET) scan or control on bone scan |
| Median Overall Survival (OS) | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | Median OS following SBRT until death from any cause. |
| Overall Survival (OS) Events | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | Number of patients who had an OS event following SBRT in the duration of the study. Overall survival definition is time from SBRT to death from any cause. |
| Overall Survival (OS) Estimates | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | OS estimates following SBRT to death from any cause. |
| Median Time to Administration of Next Line of Therapy or Death | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | Median time following SBRT to alternative therapy administration or death. |
| Administration of Next Line of Therapy or Death Events | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | Number of patients that started new treatment or died following SBRT in the duration of the study. |
| Time to Administration of Next Line of Therapy or Death | Time on study (up to 24 months from the end of SBRT, with further follow-up after 24 months if patient data were available). | Time estimates from SBRT to alternative therapy administration or death. |
| Health Related Quality of Life | Up to 12 months from the end of SBRT | Patient Reported Quality of Life assessed using the EuroQol (EQ) EQ-5D-5L questionnaire. VAS scale is from 0-100. A higher VAS score indicates better quality-of-life. Outcome data has been reported for (i) all completed assessments and for (ii) assessments conducted up to the point of disease progression, in order to exclude the potential influence of progression on quality-of-life outcomes. |
| Number of Participants With Incidence and Severity of Treatment Induced Symptoms (RTOG) | Up to 24 months from the end of SBRT | Severity of acute and late side-effects resulting from SBRT assessed using the RTOG (Radiation Therapy Oncology Group) scoring criteria. A higher RTOG grade suggests higher severity of symptoms. Overall maximum grade for each patient at each timepoint is reported. |
| Number of Participants With Incidence and Severity of Treatment Induced Symptoms (CTCAE) | Up to 24 months from the end of SBRT | Severity of acute and late side-effects resulting from SBRT assessed using the Common Terminology Criteria for Adverse Events (CTCAE). A higher CTCAE grade suggests higher severity of symptoms. Overall maximum grade for each patient at each timepoint is reported. |
| Prostate Specific Antigen (PSA) Values | Up to 12 months from the end of SBRT | Prostate Specific Antigen (PSA) values recorded post-SBRT |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORAlison Tree, FRCR
Royal Marsden NHS Foundation Trust
Participant flow
Pre-assignment details
Of the 86 patients registered for screening, 85 patients met eligibility criteria and passed screening. Of the 85 patients that passed screening, 81 patients were eligible to receive trial treatment. The trial aimed to treat 84 patients but only 81 patients received trial treatment - once 85 patients has been registered and passed screening, patient drop out exceeded the number expected, and patients were not replaced.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 74 years |
| Androgen Deprivation Therapy Abiraterone | 47 Participants |
| Androgen Deprivation Therapy Enzalutamide | 34 Participants |
| Disease Burden High (≥4 Lesions) | 37 Participants |
| Disease Burden Low (<4 Lesions) | 43 Participants |
| Disease Burden Not available | 1 Participants |
| Disease Burden sites Adrenal | 1 Participants |
| Disease Burden sites Bone | 56 Participants |
| Disease Burden sites Lung | 3 Participants |
| Disease Burden sites Lymph nodes | 37 Participants |
| Disease Burden sites Other (Right ureteric lesion, Uretic lesions, Peritoneal, Right testicle) | 4 Participants |
| Disease Burden sites Prostate | 47 Participants |
| ECOG Performance Status 0 | 29 Participants |
| ECOG Performance Status 1 | 52 Participants |
| Gleason sum score at diagnosis 10 | 4 Participants |
| Gleason sum score at diagnosis 5 | 1 Participants |
| Gleason sum score at diagnosis 6 | 5 Participants |
| Gleason sum score at diagnosis 7 | 36 Participants |
| Gleason sum score at diagnosis 8 | 6 Participants |
| Gleason sum score at diagnosis 9 | 22 Participants |
| Gleason sum score at diagnosis Not available | 7 Participants |
| Number of oligo-progressing lesions 1 | 52 Participants |
| Number of oligo-progressing lesions 2 | 29 Participants |
| PSA value at diagnosis | 41.5 ug/l |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 81 Participants |
| Treatment History Previous chemotherapy | 26 Participants |
| Treatment History Previous prostatectomy/pelvic surgery | 14 Participants |
| Treatment History Previous radiotherapy | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 33 / 81 |
| other Total, other adverse events | 43 / 81 |
| serious Total, serious adverse events | 1 / 81 |
Outcome results
None listed