Background
Methods/design
Trial design
Objectives
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Primary endpoint
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Percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL
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Secondary endpoints
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Time to biochemical progression
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Time to radiographic progression (PCWG3 criteria)
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Time to initiation of alternative antineoplastic therapy
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Prostate cancer specific survival
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Assessment of health related quality of life using the Functional Assessment of Cancer Therapy - Prostate (FACT-P) scale (http://www.facit.org/FACITOrg/Questionnaires)
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Safety and tolerability (CTCAE v4)
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Inclusion criteria
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Biopsy confirmed diagnosis of prostate adenocarcinoma
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Age ≥ 18
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M1a/b disease with presence of 1–5 visible metastases (by NaF PET/CT or PSMA PET/CT, including CT of the chest, abdomen, and pelvis)
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Biopsy of one metastasis should be attempted, unless deemed not safe or feasible. If biopsy is not performed or is not diagnostic, then a second imaging modality must also be consistent with metastatic disease
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Patients may have any number of pelvic nodal metastases (but largest must be < 2 cm)
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Patient must be fit to undergo radical prostatectomy, to receive SBRT to all visible sites of metastases, and to receive ADT
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Total testosterone > 200 ng/dL prior to ADT
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Adequate performance status (ECOG 0–1)
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Clinical laboratory values at screening:
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Hemoglobin ≥9.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization
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Platelet count ≥100,000 × 109/μL independent of transfusion and/or growth factors within 3 months prior to randomization
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Serum albumin ≥3.0 g/dL
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GFR ≥45 mL/min
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Serum potassium ≥3.5 mmol/L
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Serum total bilirubin ≤1.5 × ULN
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Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 × ULN
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Exclusion criteria
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Primary small cell carcinoma of the prostate
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Presence of visceral metastases
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Patients taking medications known to lower the seizure threshold (unless discontinued or substituted at least 4 weeks prior to study entry)
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Any evidence of spinal cord compression (radiological or clinical)
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Prior pelvic malignancy
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Prior pelvic radiation
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Concurrent malignancy aside from superficial skin cancers or superficial bladder tumors
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Inflammatory bowel disease or active collagen vascular disease
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History of seizure or known condition that may pre-dispose to seizure (e.g., prior stroke within 1 year to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)
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History of severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization
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Current evidence of any of the following:
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Uncontrolled hypertension
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Gastrointestinal disorder affecting absorption
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Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis)
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Baseline severe hepatic impairment (Child-Pugh Class B & C)
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Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily
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Any other condition that in the opinion of the investigator would preclude participation in this study
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If currently receiving treatment with the following drugs:
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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
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Concomitant CYP2C8 inhibitors with narrow therapeutic index. If a concomitant CYP2C8 inhibitor with narrow therapeutic index must be co-administered, patients should be monitored closely for signs of toxicity related to the CYP2C8 inhibitor with a narrow therapeutic index if used concomitantly with abiraterone acetate
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Concomitant strong CYP3A4 inducers. If a strong CYP3A4 inducer must be co-administered, abiraterone acetate dose frequency will be adjusted
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Selection and study enrollment procedures
Interventions
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Primary tumor therapies:
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Radical prostatectomy, open or robot-assisted, with pelvic lymph node dissection. This surgery is performed by an experienced urologic surgeon and is the first treatment intervention, preceding the systemic and radiotherapies.
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Post-operative pelvic RT. This is included if patients are found to have pT3a+, positive margins, or regionally involved nodes (N1). IMRT is delivered to the pelvic nodes (45–50.4 Gy) and prostate bed (66–72 Gy) in conventional fractionation according to RTOG contouring guidelines (modified as needed based on imaging). Gross disease may be boosted while respecting normal tissue dose constraints. This pelvic RT can extend beyond or be completed after ADT.
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Systemic hormonal therapies:
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Patients initiate leuprolide, apalutamide and abiraterone acetate beginning immediately (within 0–3 days) after radical prostatectomy. Patients will receive a single dose of leuprolide, SQ, 45 mg, a six-month depot, and start apalutamide (ARN-509, 240 mg PO daily), and abiraterone acetate co-administered with prednisone (1000 mg PO and 10 mg PO daily, respectively), for a duration of six months.
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Metastasis-directed Stereotactic Body Radiotherapy (SBRT):
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Patients undergo SBRT to all radiographically visible sites of M1a,b metastases within two months of initiation of ADT. A biologically equivalent dose (BED) to tumor of > 100 Gy (for an alpha-beta ratio of 3) is a goal but is not required [2] as constraints must be met [19]. Recommended SBRT dosing is displayed in Table 1.
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Number of Fractions | Recommended Dose per Fraction |
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5 Fractions | 6–8 Gy |
3 Fractions | 9–12 Gy |
1 Fraction | 16–18 Gy |
Follow-up and adherence to interventions
At inclusion | Day 1 | Between day 30–60 | At 6 months | Monthly for first 12 months | Every 3 months thereafter | |
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NaF- or PSMA- PET CT (with CT of chest/abdomen/pelvis) | x | |||||
PSA, total testosterone | x | x | x | |||
Radical prostatectomy | x | |||||
SBRT to all sites of metastases | x | |||||
Prostate bed/nodes RT a | ||||||
Lupron depot (6 month)b | x | |||||
Start apalutamide, abiraterone acetate, prednisone b | x | |||||
Stop apalutamide, abiraterone acetate, taper prednisone | x | |||||
Quality-of-life and toxicity assessments | x | x | x |