Management of Oligoprogressive Castration Resistant Prostate Cancer (PCS X)

The Role of Therapeutic Layering of Stereotactic Body Radiotherapy on Darolutamide in the Management of Oligoprogressive Castration Resistant Prostate Cancer: A Pilot Phase II Trial

This is the first pilot phase II trial assessing the response of SBRT layered on Darolutamide (BAY1841788) on RPFS and deferring palliative second line systemic therapy in M0CRPC with oligoprogression.

Study Overview

• Status: Recruiting
• Conditions: Castration-resistant Prostate Cancer; Metastatic Prostate Cancer
• Intervention / Treatment: Drug: Darolutamide (BAY1841788); Radiation: SBRT

Detailed Description

Metastases-directed therapy with stereotactic body radiation therapy (SBRT) is emerging as a new treatment option for solid tumor patients with a limited number of metastases (< 5) at the time of recurrence/progression, so called oligoprogression therapy. As such, oligoprogression is defined as prostate cancer patients with castration resistance and no metastases (M0CRPC) who are receiving ADT and new generation hormonal therapy (enzalutamide, apalutamide or darolutamide) as standard of care, and who are then progressing to oligometastases. The new generation hormonal therapy used in this study will be darolutamide (ODM-201). The rationale behind this approach has been to delay the start of palliative systemic therapies that are most often toxic and associated with a negative impact on patient's quality of life, as well as being more costly. However, to date, there are no prospective published data or ongoing studies that are looking into non metastatic castration resistant prostate cancer (M0CRPC) patients who progress to oligometastases (oligoprogression). To this end, we are proposing this pilot phase II trial to assess the impact of SBRT on radiological progression-free survival (RPFS) of M0CRPC patients who are receiving darolutamide and progress to oligometastatic disease (oligoprogression).

Prostate cancer patients with castration resistance and no metastases (M0CRPC) diagnosed by bone scan and CT scan or MRI will be recruited in this phase II and initiate darolutamide while continuing on ADT (Part 1 of the study), if not receiving darolutamide prior to study entry already. Patients who then progress to wide spread metastases or metastases situated at locations not amenable to ablative therapy will be excluded and treated with second line therapy as per the treating physician. Patients with oligoprogression (< 5 mets) and amenable to ablative therapy will be then treated with SBRT or surgery as an ablative therapy if SBRT is not feasible (Part 2 of the study). All patients will continue to receive non-interrupted LHRH agonist, PSA testing every 6-12 weeks and re-imaging every 6 months. Imaging will also be repeated at the appearance of symptoms or at PSA progression, whichever occurs first and this schedule continues until disease progression.

This is the first pilot phase II trial assessing the response of SBRT layered on darolutamide on RPFS and deferring palliative second line systemic therapy in M0CRPC with oligoprogression. This phase II will consist of 66 M0CRPC patients treated with darolutamide, of which we anticipate 48 will be eligible for SBRT.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Paola Diego; Phone Number: 24404 514-340-8222; Email: paola.diego.ccomtl@ssss.gouv.qc.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2V 1P9
      • Recruiting
      • Prostate Cancer Centre
      • Principal Investigator: Geoffrey Gotto, MD
      • Contact: Lora Mendoza; Email: lora.m@prostatecancercentre.ca
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Recruiting
      • Centre of Applied Urology Research
      • Principal Investigator: Ricardo Rendon, MD
      • Contact: Kelly Macdonald; Email: kellyn.macdonald@nshealth.ca
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Recruiting
      • St. Joseph's Healthcare Hamilton
      • Contact: Marie Therese Balart; Email: mbalart@stjosham.on.ca
      • Principal Investigator: Bobby Shayegan, MD
  • Quebec
    • Longueuil, Quebec, Canada, J4V 2H3
      • Recruiting
      • Service d'urologie et Centre de la prostate
      • Contact: Joanie Valcourt; Email: recherches@servicedurologie.ca
      • Principal Investigator: Elie Antebi, MD
    • Montreal, Quebec, Canada, H2X 3E4
      • Recruiting
      • Centre hospitalier de l'Université de Montréal (CHUM)
      • Principal Investigator: Guila Delouya, MD
      • Contact: Mom Phat; Email: mom.phat.chum@ssss.gouv.qc.ca
    • Montréal, Quebec, Canada, H1T 2M4
      • Recruiting
      • Hôpital Maisonneuve-Rosemont
      • Principal Investigator: Peter Vavassis, MD
      • Contact: Lys Fernet; Email: lys.fernet.cemtl@ssss.gouv.qc.ca
    • Montréal, Quebec, Canada, H3T 1E2
      • Recruiting
      • Sir Mortimer JGH
      • Contact: Paola Diego; Phone Number: 24404 514-340-8222; Email: paola.diego.ccomtl@ssss.gouv.qc.ca
      • Principal Investigator: Tamim Niazi, MD
    • Québec city, Quebec, Canada, G1R 2J6
      • Recruiting
      • L'Hôtel-Dieu de Québec (CHUQ)
      • Contact: Josee Allard; Email: Josee.Allard@chudequebec.ca
      • Principal Investigator: Andrey-Guy Martin, MD
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Recruiting
      • Hôpital Fleurimont (CHUS)
      • Principal Investigator: Myriam Bouchard, MD
      • Contact: Cynthia Ladouceur; Email: cynthia.ladouceur.ciussse-chus@ssss.gouv.qc.ca
    • Trois-Rivières, Quebec, Canada, G8Z 3R9
      • Recruiting
      • Centre hospitalier affilié universitaire régional (CHAUR)
      • Contact: Julie Samson; Email: julie_samson_ciusssmcq@ssss.gouv.qc.ca
      • Principal Investigator: Vincent Trudeau, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria (Part 1):

• Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features;

• M0CRPC at study entry defined as follows:

  1. Ongoing androgen deprivation therapy with a LHRH agonist or bilateral orchiectomy (i.e., surgical or medical castration);
  2. Serum testosterone level ≤ 1.7 nmol/L (50 ng/dL) at the Screening visit;
  3. PSA progression defined by a minimum of two subsequent rising PSA levels with an interval of ≥ 1 week between each determination. Patients who received an anti-androgen must have progression after withdrawal (≥ 4 weeks since last flutamide or ≥ 6 weeks since last bicalutamide or nilutamide). The PSA value at the Screening visit should be ≥ 2 μg/L (2 ng/mL)
  4. PSA doubling time of 10 months or less,
  5. M0 assessed by conventional imaging (CT/MRI + bone scan).

NOTE: If darolutamide started prior to study entry, evidence of inclusion criteria 1-5 listed above prior to start of darolutamide must be submitted to determine study eligibility

• Prior cytotoxic chemotherapy for prostate cancer in adjuvant setting post radical therapy is allowed;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky performance status of > 80% or higher;
• Estimated life expectancy of ≥ 6 months;
• Ability to swallow the study drug whole and comply with study.
• Patients should not have been previously exposed to other ARATs (Abiraterone, Enzalutamide, Apalutamide)

Inclusion Criteria (Part 2):

• ≤ 5 metastatic sites (on conventional imaging);
• ≤ 4 tumors within any given organ system, excluding brain (e.g. up to 4 bone metastases, or 4 lung metastases);
• All sites of disease must be amenable to SBRT with no history of the metastases being irradiated (radiation exposure prior to the development of the metastases is permitted as long as the radiation exposure was not intended for the metastases. For example, if there is prior pelvic radiation to the prostate and a subsequent iliac metastasis develops within the previously irradiated pelvic radiation field, then the iliac metastasis would be eligible per the institution policy and practice);
• In the case of a suspicious lesion in an unusual location such as lung or thoracic lymph nodes (without other abdominal lymph nodes), a confirmatory imaging or biopsy is strongly recommended;

Exclusion Criteria (Part 1):

• Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment;
• Presence of distant metastasis, including previously treated (clinical stage M1) is exclusive, however isolated pelvic nodal disease below the iliac bifurcation (clinical stage N1) is not an exclusion criteria.
• History of another malignancy within the previous 5 years other than curatively treated non-melanoma skin cancer;
• Absolute neutrophil count < 1,500/μL, platelet count < 100,000/μL, or hemoglobin < 5.6 mmol/L (9 g/dL) at the Screening visit (NOTE: patients may not have received any growth factors within 7 days or blood transfusions within 28 days of the hematologic laboratory values obtained at the Screening visit);
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal and total bilirubin > 1.5 times the upper limit of normal at the Screening visit;
• Creatinine > 2 times the upper limit of normal at the Screening visit;

• Clinically significant cardiovascular disease including:

  1. Stroke or myocardial infarction within 6 months;
  2. Uncontrolled angina within 6 months;
  3. Coronary/peripheral artery bypass graft within 6 months;
  4. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within three months results in a left ventricular ejection fraction that is ≥ 45%;
  5. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
  6. Uncontrolled hypertension as indicated by a resting systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg at screening. Patients may be re-screened after adjustments of antihypertensive medications;
  7. Bradycardia as indicated by a heart rate of < 50 beats per minute on the Screening ECG;
• Gastrointestinal disorder or procedure which expects to interfere significantly with absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months);
• Major surgery within 4 weeks of enrollment (Day 1 Visit);
• Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease
• Use of opiate analgesics (eg. morphine, fentanyl, etc.) for pain from prostate cancer within 4 weeks of enrollment (Day 1 visit). This does not apply to non-morphine drugs like codeine;
• Radiation therapy for treatment of the primary tumor within 3 weeks of enrollment (Day 1 visit);
• Radiation or radionuclide therapy for treatment of metastasis;
• Primary disease not treated;
• Hormone naïve prostate cancer patients;
• Treatment with estrogens or AR inhibitors (bicalutamide, flutamide, nilutamide, cyproterone acetate) within 4 weeks of enrollment (Day 1 visit);
• Treatment with systemic biologic therapy for prostate cancer (other than approved bone targeted agents and GnRH-analogue therapy) or other agents with anti-tumour activity within 4 weeks of enrollment (Day 1 visit);
• Prior use of an investigational agent that blocks androgen synthesis (e.g., abiraterone acetate, enzalutamide, Apalutamide, TAK-700, TAK-683, TAK-448) or targets the androgen receptor (e.g., BMS 641988) on clinical trials;
• Known or suspected contraindications or hypersensitivity to darolutamide or GnRH agonists or any of the components of the formulations;
• Use of an investigational agent within 4 weeks of enrollment (Day 1 visit);
• Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within four weeks of enrollment (Day 1 visit);
• Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data;
• Unable to swallow study medications and comply with study requirements

Exclusion criteria (Part 2):

• Known or suspected brain metastasis or active leptomeningeal disease;
• > 5 metastasis;
• More than 4 metastasis in the same organ;
• Patients considered for SBRT in previous history of radiation therapy to the same area.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Darolutamide (BAY1841788)+ SBRT; CRPC subjects will receive LHRH agonist in combination with the new generation of hormonal therapy Darolutamide (300mg). Subjects who progress on LHRH + Darolutamide and develop oligometastases will receive SBRT	Drug: Darolutamide (BAY1841788); Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg.; Other Names: ODM-201; Radiation: SBRT; SBRT will consist of 2-5 fractions of highly targeted radiation therapy delivered every other day. The radiation component will be completed in 4-10 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiographic Progression-free Survival	Time from first day of SBRT until confirmed second radiological progression or start of new antineoplastic therapy	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Assessment of Cancer Therapy-Prostate	Evaluate the impact of the treatment on the patient's quality of life using the FACT-P questionnaire	5 years
Quality of Life - Fatigue	Evaluate the impact of the treatment on the patient's quality of life using the Brief Fatigue Inventory (BFI) questionnaire	5 years
Quality of Life - Pain	Evaluate the impact of the treatment on the patient's quality of life using the Brief Pain Inventory (BPI) questionnaire	5 years
Toxicity of ODM-201	To determine acute and late toxicity due to ODM-201, scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	5 years
Time to Subsequent Systemic Antineoplastic Therapy	Time to the administration of subsequent antineoplastic systemic therapy	5 years
PSA response	PSA value and onset of biochemical failure will be recorded	5 years
Overall Survival	Time from randomization until death from any cause	5 years
Disease Specific Survival	Time from randomization until death due to prostate cancer	5 years
Time to Skeletal-related Event (SRE)	Date of first SRE will be recorded	5 years
Local Control	To evaluate the impact of SBRT on oligometastases progression by radiographic imaging or the start of new antineoplastic therapy.	5 years

Collaborators and Investigators

• Sponsor: Sir Mortimer B. Davis - Jewish General Hospital
• Investigators: Principal Investigator: Tamim Niazi, MD, Jewish General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2020
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: August 24, 2019
• First Submitted That Met QC Criteria: August 26, 2019
• First Posted (Actual): August 28, 2019

Study Record Updates

• Last Update Posted (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: PCS X

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No