Systemic and Tumor-Directed Therapy for Oligometastatic Prostate Cancer

Phase 2

Completed

• Conditions: Newly Diagnosed Oligometastatic Prostate Cancer
• Interventions: Procedure: radical prostatectomy; Radiation: stereotactic body radiotherapy; Drug: Leuprolide; Drug: apalutamide; Drug: abiraterone

• Registration Number: NCT03298087
• Lead Sponsor: VA Office of Research and Development

Brief Summary

This is a trial for patients with newly diagnosed metastatic prostate cancer with 5 or fewer sites of metastases. The trial involves surgery (removal of the prostate) or radiation to the prostate, six months of hormone therapy, and stereotactic body radiotherapy to the sites of metastasis.

Detailed Description

This is a single arm Phase II clinical trial in patients with newly diagnosed M1a,b prostate cancer and 1-5 radiographically visible metastases treated with radical prostatectomy (and post-operative fractionated radiotherapy for pT 3a, pN1, or positive margins) or radiation to the prostate, metastasis directed SBRT, and complete ADT with LHRH analog leuprolide, abiraterone acetate with prednisone, and apalutamide (ARN-509) for a total of six months of systemic therapy. The primary endpoint of our study is the percent of patients achieving a serum PSA of \<0.05 ng/mL six months after recovery of serum testosterone (for patients undergoing radical prostatectomy) or PSA \<nadir+2 (for patients undergoing prostate radiation).

Study Timeline

• Study First Submitted: 2017-09-26
• Study First Submitted QC: 2017-09-26
• Study First Posted: 2017-09-29
• Study Start: 2018-07-01
• Primary Completion: 2024-03-31
• Study Completion: 2024-03-31
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-31
• Last Update Posted: 2024-08-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 28

Inclusion Criteria

1. Biopsy confirmed diagnosis of prostate adenocarcinoma (primary small cell carcinoma of the prostate is not allowed, however adenocarcinoma with neuroendocrine differentiation is allowed)

2. Age 18

3. Presence of 1-5 visible metastases (by NaF PET-CT or PSMA PET-CT including diagnostic CT of the chest, abdomen, and pelvis)

   1. At least one metastasis must be M1a-b
   2. Visceral metastases are not allowed
   3. Patients may have any number of pelvic nodal metastases (but largest must be <2 cm)
   4. Metastases must be amenable to treatment with SBRT
   5. Biopsy of one metastasis must be attempted, unless unsafe to perform. If biopsy is not diagnostic, or unsafe to perform, then a secondary imaging modality (for example, MRI) must also be consistent with metastatic disease (unless PSMA PET-CT was used as initial staging).

4. Patient must be fit to undergo radical prostatectomy, SBRT to all visible sites of metastases, ADT,

5. Total testosterone >200 ng/dL prior to ADT (optimal time to measure total testosterone is between 8 and 9 am)

6. Adequate performance status (ECOG 0-1)

7. Clinical laboratory values at screening:

   1. Hemoglobin 9.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization
   2. Platelet count 100,000 x 109/ L independent of transfusion and/or growth factors within 3 months prior to randomization
   3. Serum albumin 3.0 g/dL
   4. GFR 45 mL/min
   5. Serum potassium 3.5 mmol/L
   6. Serum total bilirubin 1.5 ULN (Note: In subjects with Gilbert's syndrome, if total bilirubin is >1.5 ULN, measure direct and indirect bilirubin and if direct bilirubin is 1.5 ULN, subject may be eligible)
   7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 ULN

8. Medications known to lower the seizure threshold (see list under prohibited medications) must be discontinued or substituted at least 4 weeks prior to study entry.

Exclusion Criteria

1. Any evidence of spinal cord compression (radiological or clinical)

2. Prior pelvic malignancy

3. Prior pelvic radiation

4. Concurrent malignancy aside from superficial skin cancers or superficial bladder tumors

5. Inability to undergo prostatectomy, radiotherapy, or ADT

6. Primary small cell carcinoma of the prostate (prostate adenocarcinoma with neuroendocrine differentiation is allowed)

7. Inflammatory bowel disease or active collagen vascular disease

8. History of any of the following:

   1. Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1year to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)
   2. Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization

9. Current evidence of any of the following:

   1. Uncontrolled hypertension
   2. Gastrointestinal disorder affecting absorption
   3. Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis)
   4. Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily
   5. Any condition that in the opinion of the investigator would preclude participation in this study
   6. Concomitant strong CYP3A4 inducers. (If a strong CYP3A4 inducer must be co-administered, abiraterone acetate dose frequency will be adjusted).
   7. Treatment with CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment cannot be used, a dose reduction of the CYP2D6 substrate may be considered.
   8. Baseline severe hepatic impairment (ChildPugh Class B & C)

10. Presence of visceral metastases (i.e., stage M1c)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental Arm	apalutamide	Radical prostatectomy (and post-operative fractionated radiotherapy for pT=3a, pN1, or positive margins), metastasis directed SBRT, and complete ADT with LHRH analog leuprolide, abiraterone acetate with prednisone, and apalutamide (ARN-509) for a total of six months of systemic therapy.
Experimental Arm	abiraterone	Radical prostatectomy (and post-operative fractionated radiotherapy for pT=3a, pN1, or positive margins), metastasis directed SBRT, and complete ADT with LHRH analog leuprolide, abiraterone acetate with prednisone, and apalutamide (ARN-509) for a total of six months of systemic therapy.
Experimental Arm	radical prostatectomy	Radical prostatectomy (and post-operative fractionated radiotherapy for pT=3a, pN1, or positive margins), metastasis directed SBRT, and complete ADT with LHRH analog leuprolide, abiraterone acetate with prednisone, and apalutamide (ARN-509) for a total of six months of systemic therapy.
Experimental Arm	stereotactic body radiotherapy	Radical prostatectomy (and post-operative fractionated radiotherapy for pT=3a, pN1, or positive margins), metastasis directed SBRT, and complete ADT with LHRH analog leuprolide, abiraterone acetate with prednisone, and apalutamide (ARN-509) for a total of six months of systemic therapy.
Experimental Arm	Leuprolide	Radical prostatectomy (and post-operative fractionated radiotherapy for pT=3a, pN1, or positive margins), metastasis directed SBRT, and complete ADT with LHRH analog leuprolide, abiraterone acetate with prednisone, and apalutamide (ARN-509) for a total of six months of systemic therapy.

Primary Outcome Measures

Name	Time	Method
PSA<0.05ng/mL (radical prostatectomy) or PSA <nadir+2ng/mL (prostate radiation)	6 months after recovery of testosterone	PSA is a biomarker for disease burden in prostate adenocarcinoma and offers a non-invasive and sensitive assessment of disease control after treatment in the vast majority of patients.

Secondary Outcome Measures

Name	Time	Method
time to biochemical progression	up to 5 years	biochemical, radiographic, or clinical
Time to radiographic progression	up to 5 years	per PCWG3 criteria
Time to initiation of additional antineoplastic therapy	up to 5 years	antineoplastic therapy includes any systemic or focal anti-prostate cancer therapy
Prostate cancer specific survival	up to 5 years	Prostate cancer specific survival
Patient reported outcomes as assedded by Functional Assessment of Cancer Therapy - Prostate (FACT-P) scale - patient questionnaire	up to 5 years	This uses the Functional Assessment of Cancer Therapy - Prostate (FACT-P) questionnaire. It assesses patient function in four domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 12 site specific items to assess for prostate related symptoms. Items are rated on a 0 to 4 Likert type scale and combined to produce subscale scores for each domain and a global score, the higher the score, the better the quality of life. Range from 0-150 . Data will be aggregated per patient and over time.
Number of participants with treatment-related adverse events as assessed by physician using CTCAE v4.0 criteria	up to 5 years	CTCAE v4 criteria are a set of criteria for the standardized classification of adverse effects cancer therapy. The CTCAE system is a product of the US National Cancer Institute. The criteria are assessed by physician. The grades range from 0 to 5 (higher is worse). Data will be aggregated per patient and over time and classified by organ system (e.g., genitourinary, gastrointestinal, etc).

Trial Locations

Locations (3)

VA Long Beach Healthcare System, Long Beach, CA; 🇺🇸 Long Beach, California, United States

VA Greater Los Angeles Healthcare System, West Los Angeles, CA; 🇺🇸 West Los Angeles, California, United States

Hunter Holmes McGuire VA Medical Center, Richmond, VA; 🇺🇸 Richmond, Virginia, United States