FOcal Radiation for Oligometastatic Castration-rEsistant Prostate Cancer (FORCE)

Study Overview
=================
Brief Summary
-----------------
This clinical trial will determine whether the addition of radiotherapy to standard of care systemic therapy improves objective progression-free survival compared to systemic therapy alone in patients with oligometastatic castration-resistant prostate cancer.

Official Title
-----------------
FOcal Radiation for Oligometastatic Castration-rEsistant Prostate Cancer (FORCE): A Phase II Randomized Trial

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

Intervention / Treatment
-----------------
* Radiation: Ablative Radiation Therapy
* Drug: Hormone therapy or chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects must have biopsy-confirmed adenocarcinoma of the prostate Subjects must discontinue any prior systemic therapies (excluding GnRH agonist/antagonists) without PSA withdrawal effects if using first generation anti-androgens. Luteinizing hormone-releasing hormone (LHRH) analogues must be continued if they have not undergone orchiectomy. (Subjects who recently started systemic therapy for metastatic castration-resistant prostate cancer (mCRPC) are eligible to enroll if new therapy was started ≤ 14 days to consent date.) Subjects must have progressive metastatic castration-resistant prostate cancer based on at least one of the following criteria while having castrate levels (<50 ng/dL) of testosterone: A) PSA progression defined as a 25% increase over baseline value with an increase in the absolute value of at least 2.0 ng/mL that is confirmed by another PSA level with a minimum of a 1-week interval. B) Progression of bidimensionally measurable soft tissue or nodal metastasis by CT scan or MRI based on RECIST criteria C) Progression of bone disease on bone scan as defined by two new lesions arising Subjects must have oligometastatic prostate cancer, defined as between 1 and ≤5 treatment sites that can be treated within a radiotherapy treatment field. Subjects must be medically fit to undergo radiotherapy and systemic therapy as determined by the treating physician. Age ≥ 18 ECOG ≤ 2 (Eastern Cooperative Oncology Group scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 5 where 0 represents perfect health and 5 represents death) No prior invasive malignancy in the past 3-years. Exceptions include non-melanomatous skin cancer and in situ cancers of the bladder or head and neck are permissible. Subjects must freely sign informed consent to enroll in the study. Subjects must use contraception up to 90 days after last drug dose. Exclusion Criteria: Planned systemic therapy with Radium-223 dichloride or sipuleucel-T Tumor requiring emergent radiation in view of provider Life expectancy estimate of <3 months Presence of known parenchymal brain metastasis Uncontrolled intercurrent illness Inability to undergo radiotherapy, systemic treatment, CTs or bone scans Biopsy proven pure small cell or neuroendocrine prostate cancer

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care<br>Standard of care therapy will be up to the treating medical oncologist and is not the study intervention. Current systemic therapy is most commonly a second generation androgen pathway inhibitor, including enzalutamide or abiraterone, although other standard agents (e.g. docetaxel, cabazitaxel) are allowed. Patients should begin systemic treatment within 3 weeks of randomization. Standard of care systemic therapy may continue in the absence of toxicities or other specific criteria per protocol. | Drug: Hormone therapy or chemotherapy<br>* Current standard of care dosing with standard agents; hormone therapy or chemotherapy.<br>* Other names: cabazitaxel;|
| Experimental: Standard of Care + Ablative Radiation<br>Standard of care systemic therapy plus radiation. Radiation will start within 8 weeks of randomization and complete by day 84. Standard of care systemic therapy may continue in the absence of toxicities or other specific criteria per protocol. | Radiation: Ablative Radiation Therapy<br>* Radiotherapy will typically be delivered to a total EQD2 (Equivalent dose in 2Gy fractions) that ranges between conventional 30 Gy in 10 fractions, to SBRT (Stereotactic Body Radiation Therapy) with 50 Gy in 5 fractions.<br>Drug: Hormone therapy or chemotherapy<br>* Current standard of care dosing with standard agents; hormone therapy or chemotherapy.<br>* Other names: cabazitaxel;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median duration of response | Duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. A patient's designated response at any one time is a combination of the assessment of target lesions, non-target lesions, bone lesions and disease symptoms. Progression in this measure is defined as worsened pain or new sites of disease on imaging. Progression by pain due to prostate cancer requires evidence of disease at the site of pain and one or more palliative intervention (opioid therapy for 10 out of 14 consecutive days, radionuclide therapy or radiation therapy). Response and progression definitions used will be a combination of the criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee v1.1 and the Prostate Cancer Working Group 3. | At 12 and at 18 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median objective progression free survival (PFS) time | PFS is defined as the duration of time from start of treatment to date of progression or death (whichever is first). Initiation of other prostate directed therapies (excluding bisphosphonates or RANKL inhibitors) is considered to be progression. Reported as Kaplan-Meier estimates, including median at 12 months and 24 month. | At 12 and at 24 months | 
| Median prostate specific antigen (PSA) PFS | The Median PSA PFS is defined as the median duration of time from start of treatment to date that PSA progression is documented or death occurs (whichever is first). PSA progression is defined as a 25% increase over baseline or nadir whichever is lower and an increase in the absolute value of PSA level by 2 ng/ml. Reported as Kaplan-Meier estimates, including median at 12 months and 24 month. | At 12 and at 24 months | 
| Median radiographic PFS | Radiographic PFS is defined as the duration of time from start of treatment to date that progression is radio-graphically documented or death occurs (whichever is first). Reported as Kaplan-Meier estimates, including median at 12 months and 24 month. | At 12 and at 24 months | 
| Overall survival time | Overall survival (OS) is defined as the duration of time from start of treatment to death. Reported as Kaplan-Meier estimates, including median at 12 months and 24 month. | At 12 and at 24 months | 
| Prostate cancer specific survival time | Prostate Cancer Specific Survival (PCSS) is defined as the duration of time from start of treatment to death from prostate cancer. Reported as Kaplan-Meier estimates, including median at 12 months and 24 month. | At 12 and at 24 months | 
| Non-irradiated metastases free survival time | Non-irradiated metastases free survival is defined as the duration of time from start of treatment to the date of progressive disease of a new target lesion, a new non-measurable/non-target lesion or emergence of 2 or more new skeletal lesions on a bone scan. Reported as Kaplan-Meier estimates, including median at 12 months and 24 month. | At 12 and at 24 months | 
| The proportion of patients with complete PSA response | The number of patients whose PSA becomes undetectable (≤0.2 ng/ml) will be counted in each treatment arm and divided by the number of patients who received any protocol treatment to provide the proportion of patients with complete PSA response. Complete PSA response is defined as an undetectable PSA (≤0.2 ng/ml). | 24 months | 
| The proportion of patients with a PSA Partial Response 50 (PR50) | The number of patients whose PSA declines by 50% decline (PSA partial response 50 (PR50)) will be counted in each treatment arm and divided by the number of patients who received any protocol treatment to provide the proportion of patients with PR50. PR50 response is defined as a decrease in PSA value by ≥ 50%. | 24 months | 
| The proportion of patients with a PSA Partial Response 90 (PR90) | The number of patients whose PSA declines by 90% decline (PSA partial response 90 (PR90)) will be counted in each treatment arm and divided by the number of patients who received any protocol treatment to provide the proportion of patients with PR90. PR90 response is defined as a decrease in PSA value by ≥ 90%. | 24 months | 
| The proportion of patients that respond to treatment | The measurable disease response rate (CR + PR) will be calculated for patients evaluable for measurable disease response. Complete response (CR) is defined as a disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduced in short axis to <10 mm. There can be no appearance of new lesions. Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions. | 24 months | 
| Patient-reported outcome based on NCCN-FACT FPSI-17 (version 2) | The National Comprehensive Cancer Network Functional Assessment of Cancer Therapy - Prostate Symptom Index (NFPSI-17), version 2 is used to assess high priority symptoms/QOL concerns in patients with advanced prostate cancer (PC). It is a 17-item survey with a recall period of the past 7 days; scored using a 5 point Likert-type scale. Items are scored from 1-4 with some items reverse scored. Described using means or medians. | 24 months |