SAVE: Radiotherapy Combined With a LHRH (Ant)Agonist Versus Apalutamide in Patients With Biochemical Recurrence After RP
Study Details
Study Description
Brief Summary
This is a phase II randomized, open-label study comparing salvage radiotherapy in combination with 6 months of androgen-deprivation therapy (ADT) with LHRH agonist or antagonist (arm A) versus anti-androgen therapy (AAT) with apalutamide 240mg daily (arm B) in hormone-naïve patients with biochemical progression after radical prostatectomy. All subjects will receive salvage radiotherapy as standard of care and will be randomly assigned in a 1:1 ratio to receive either 6 months of androgen-deprivation therapy (ADT) with LHRH agonist or antagonist through 6 monthly, two 3-monthly or one 6-monthly injections (control arm) or 6 28-day cycles of apalutamide 240mg daily (interventional arm). The study will include a screening phase, treatment phase, and a post-treatment phase. The primary objective of the trial is to compare sexual function between the 2 groups based on the Expanded Prostate cancer Index Composite (EPIC)-26 sexual domain scores at 9 months after start of hormonal treatment.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 2 |
Detailed Description
After radical prostatectomy, around one third of patients will have biochemical progression. Salvage radiotherapy (SRT) is still potentially curative, but about 40-50% of patients will progress further. Recently, success rates of SRT were significantly improved through the use of concomitant anti-androgen (AAT) or androgen-deprivation (ADT) therapy. In RTOG 96-01, 2 years of bicalutamide 150 mg resulted in a 5% overall survival benefit at 12-years. In GETUG-AFU 16, 5-year progression-free survival was significantly improved when SRT was combined with 6 months of an LHRH agonist. Based on GETUG-AFU 16, most radiation oncologists now combine SRT with at least 6 months of ADT. However, ADT comes with several serious side-effects, both physical (cardiovascular, metabolic, musculoskeletal) and psychological (sexual, emotional and cognitive). It appears worthwile to look for alternatives in the form of AAT. In that respect, apalutamide, a potent competitive and purely antagonistic second-generation anti-androgen, is the ideal candidate.
This trial is a phase II randomized, open-label study comparing salvage radiotherapy in combination with 6 months of ADT (arm A) versus AAT with apalutamide 240mg daily (arm B) in hormone-naïve patients with biochemical progression after radical prostatectomy. All subjects will receive salvage radiotherapy as standard of care and will be randomly assigned in a 1:1 ratio to receive either 6 months of ADT with LHRH agonist or antagonist through 6 monthly, two 3-monthly or one 6-monthly injections (control arm A) or 6 28-day cycles of apalutamide 240mg daily (interventional arm B).
The study will include a screening phase, treatment phase, and a post-treatment phase.
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Screening phase: allows for assessment of subject eligibility up to 35 days prior to randomization.
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Treatment phase: includes the hormonal treatment for 6 months, to be started at the most 2 weeks after randomization and standard salvage radiotherapy. During the treatment phase, patients will have 3 study visits:
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treatment initiation visit: first injection of LHRH (ant)agonist (arm A) or cycle 1, day 1 (C1D1) of apalutamide (arm B).
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Concurrent with RT visit: if necessary (depending on product prescribed) injection of LHRH (ant)agonist (arm A) or cycle 4, day 1 (C4D1) of apalutamide (arm B).
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End of treatment visit: at the end of the 6 months of hormonal therapy.
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Post-treatment phase: will begin after a subject completes the treatment phase and the end of treatment visit and will continue until the primary endpoint is reached, i.e. the 9-months (3 months after end of treatment visit) EPIC-26 sexual domain score.
The primary objective of the trial is to compare sexual function between the 2 groups based on the EPIC-26 sexual domain (0 - 100 scale, with higher scores representing better sexual function) at 9 months after start of hormonal treatment (primary endpoint). The following secondary endpoints will be explored:
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Quality of life: assessed using EPIC-26 as well as the EORTC quality of life questionnaires C30 and PR25 as well as FACT-P.
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Toxicity: will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
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Efficacy: prostate-specific antigen (PSA) response rates, defined as a decline from baseline in PSA level of 80% or greater, as well as PSA complete response rates, defined as a decline from baseline in PSA level of 90% or greater, will be prospectively collected at the 4 treatment visits.
At this point in time, no study has directly compared apalutamide to LHRH agonists or antagonists in combination with SRT. This trial may be a preamble to the design of a registration trial in such patients or indeed patients with a intermediate and high-risk localized disease that are scheduled for EBRT or brachytherapy as radical treatment and also benefit from 6 months of hormonal treatment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Arm A The standard hormonal treatment in combination with salvage radiotherapy is ADT by a LHRH agonist or antagonist for 24 weeks. LHRH agonists and antagonists include leuprolide, goserelin, triptorelin, and degarelix. |
Drug: Leuprorelin Acetate 45Mg Powder for Injection Suspension Vial
Leuprorelin acetate 45mg for 6 months; subcutaneous use
Drug: Goserelin Acetate 10.8 MG Subcutaneous Implant
Goserelin acetate 10.8mg for 6 months; subcutaneous use
Drug: Triptorelin Pamoate
Triptorelin pamoate 22.5mg for 6 months; intramuscular use
Drug: Degarelix acetate
Degarelix acetate 80mg for 6 months; subcutaneous use
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| Experimental: Arm B Patients will receive 6 cycles (each cycle is 30 days) of the study drug (4x 60mg tablets daily in a single intake). |
Drug: Apalutamide
Apalutamide 240mg daily for 6 months (i.e. 6 28-day cycles); oral use
|
Outcome Measures
Primary Outcome Measures
- EPIC-26 sexual domain score [9 months after start of hormonal treatment]
EPIC-26 sexual domain score (0 - 100 scale, with higher scores representing better sexual function)
Secondary Outcome Measures
- FACT-P quality of life global score [9 months after start of hormonal treatment]
Health related quality of life (QoL) will be assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire designed for patients with prostate cancer. It consists of 27 core items which assess 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. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, as well as a global QoL score. Higher scores represent better QoL.
- EORTC QLQ C30 quality of life score [9 months after start of hormonal treatment]
Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C30. The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single- item measures. These include five functional scales (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale.
- EORTC QLQ PR25 quality of life score [9 months after start of hormonal treatment]
Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) PR25. scale. The EORTC QLQ-PR25 is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 25 items specifically related to prostate cancer.
- Grade of acute toxicity [After obtaining informed consent and up to 30 days after last dose]
Acute as well as late toxicity will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (published November 27, 2017)
- PSA response rates [0, 3, 6, and 9 months]
Prostate-specific antigen (PSA) response rates, defined as a decline from baseline in PSA level of 80% or greater, as well as PSA complete response rates, defined as a decline from baseline in PSA level of 90% or greater, will be prospectively collected at 0, 3, 6, and 9 months.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male, > 18 years old.
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ECOG 0-1.
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Histologically confirmed adenocarcinoma of the prostate.
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Previous radical prostatectomy (RP), pT2-3, pN0 or pNx.
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PSA detectable with confirmed rise (at least 2 weeks apart) at least 8 weeks after RP.
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Hormone-naive disease.
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Patients amendable to take oral medication.
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Patients must have 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 x 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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Serum creatinine <2.0 × upper limit of normal (ULN)
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Serum potassium ≥3.5 mmol/L
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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)
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Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 × ULN
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Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry.
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Patient agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. Must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug.
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Patients who have received the information sheet and signed the informed consent form.
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Patients must be willing to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Exclusion Criteria:
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Patients with severe erectile dysfunction according to international index of erectile function (IIEF-5) questionnaire (score 1-7).
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Allergies, hypersensitivity or known intolerance to the study drugs or excipients.
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History of any of the following:
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Seizure or known condition that may pre-dispose to seizure (including but not limited to prior stroke, transient ischemic attack, loss of consciousness within 1 year prior to randomization, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect).
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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.
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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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Patients already included in another clinical trial involving an experimental drug.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | OLVZ Aalst | Aalst | Belgium | 9300 | |
| 2 | AZ Sint-Jan | Brugge | Belgium | 8000 | |
| 3 | Hopital Erasme | Bruxelles | Belgium | 1070 | |
| 4 | UZ Gent | Gent | Belgium | 9000 | |
| 5 | CH Jolimont | Haine-Saint-Paul | Belgium | 7100 | |
| 6 | UZ Brussel | Jette | Belgium | 1090 | |
| 7 | AZ Groeninge | Kortrijk | Belgium | 8500 | |
| 8 | CHU UCL Namur | Namur | Belgium | 5000 | |
| 9 | GZA | Wilrijk | Belgium |
Sponsors and Collaborators
- Cancer Research Antwerp
- Janssen Pharmaceutica
Investigators
- Principal Investigator: Piet Dirix, Gasthuis Zusters Antwerpen
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CTOR18001GZA