INTERVAL - Intense Exercise Trial for Men With Metastatic Castrate-Resistant Prostate Cancer

Inclusion Criteria:

* Patients must be mCRPC. This is defined as adenocarcinoma of the prostate with systemic metastatic disease despite castrate levels of testosterone (\<50 ng/dL) due to orchiectomy or LHRH agonist.

Patients must have one or more of the following to be considered mCRPC

* Metastatic Disease Progression: \>20% increase in the sum of diameters of measurable lesions from the time of maximal regression or appearance of one or more new lesions.
* Bone Scan Progression: Appearance of one or more new lesions on bone scan attributable to prostate cancer.
* PSA Progression: PSA ≥2 ng/ml that has risen serially on at least two occasions, each at least one week apart (PSA1 \< PSA2 \< PSA3).
* Castrate levels of testosterone must be maintained while on study. Be on androgen deprivation therapy (ADT) with a GnRH agonist/antagonist or prior bilateral orchiectomy. All patients will be required to be on ADT during the study period or have had a prior bilateral orchiectomy. Men with small cell neuroendocrine tumours or features of small cell disease are not eligible.
* At enrolment, patients must fit into one of the following 5 categories:

  1. Treatment naïve for mCRPC (have not yet started approved therapies for CRPC i.e.: Abiraterone/Enzalutamide/Apalutamide/Docetaxel; less than 4 weeks on approved therapies is still considered to be treatment naïve) Or
  2. Receiving Abi/Enza/Apa for mCRPC AND responding or stable (PSA values must be stable or declining after at least 4 weeks since starting Abi/Enza/Apa for mCRPC) Or
  3. Patients with PSA progression while on Abi/Enza/Apa are eligible as long as they are asymptomatic AND there is no intent on starting chemotherapy within 6 months Or
  4. Patients treated with Docetaxel as first line therapy for mCRPC who are asymptomatic without ANY evidence of progression Or
  5. Patients may have progressed following Docetaxel first line and are now receiving treatment with Abi/Enza/Apa. These patients must absolutely be responding or stable (PSA values must be stable or declining after starting Abi/Enza/Apa treatment) and have an expected life expectancy of more than 1 year.

     * 4 weeks since last major surgery and fully recovered.
* No known contraindications to high intensity exercise, including, but not limited to: brain metastases; current congestive heart failure(New York Heart Association Class II, III or IV); serious or non-healing wound, ulcer, or bone fracture; spinal cord compromise or instrumentation due to metastatic disease; peripheral neuropathy INTERVAL Protocol Version 4.0, 19 April 2018 4

  ≥grade 3. No serious cardiovascular events within 12 months including, but not limited to, transient ischemic attack (TIA), cerebrovascular accident (CVA), or myocardial infarction (MI). Patients with a history of hypertension must be well-controlled (\< 160/90) on anti-hypertensive therapy.
* Halabi Nomogram score \<1951 (Risk Category rated as low or intermediate risk)
* Age ≥18 years
* Required Baseline Laboratory Values: ANC ≥ 1500/uL; Platelet count ≥ 100,000/uL; Creatinine ≤ 1.5 x upper limits of normal; Bilirubin ≤ 1.5 x upper limits of normal; AST ≤ 1.5 x upper limits of normal; Serum testosterone ≤ 50 ng/dL
* ECOG performance status 0-1
* Medical clearance by treating physician to undergo a symptom-limited cardiopulmonary exercise test and vigorous aerobic and resistance exercise training, and able to complete an acceptable cardiopulmonary exercise test.
* Exercise Coordination Centre (ECC) review and approval of subject's screening bone scan / areas with bone metastases.
* Men participating in vigorous aerobic exercise for \>60 min/week or structured resistance exercise ≥2 days/week, are not eligible.
* Subject is willing and able to use technological aspects of the trial.
* The subject is fluent in the language

Exclusion Criteria:

* Previous radiographic or clinical progression (PSA progression is permitted) while on treatment with abiraterone, enzalutamide, apalutamide, or a combination.
* Previously identified small cell neuroendocrine tumours or pure small cell carcinoma of the prostate, based on a prior biopsy of the prostate.
* Brain metastases (brain imaging is not required)
* Previous and/or concurrent treatment with other anti-cancer treatments is permitted. Patients are allowed to be treated with chemotherapy during the duration of the trial. Patients who have received chemotherapy as part of initial androgen deprivation therapy for metastatic castration sensitive disease are eligible.
* Currently receiving experimental treatment with non-approved drugs at the time of enrolment. Patients must undergo a 28-day washout between last dose and screening CPET.
* Poorly controlled hypertension. During screening ≥2/3 of readings must be \< 160/90, regardless of whether on a regimen of anti-hypertensive therapy or not.

If patient is currently taking hypertensive medication(s)/therapy, please indicate medication and include in the Treatment and Concomitant Medications Log (SOM: Appendix 11).

* Current congestive heart failure (New York Heart Association Class II, III or IV)
* Recent serious cardiovascular events (within 12 months) including, but not limited to, transient ischemic attack (TIA), cerebrovascular accident (CVA), or myocardial infarction (MI).
* Medical condition such as uncontrolled infection or cardiac disease that, in the opinion of the physician, would make this protocol unreasonably hazardous for the patient.
* Patients with a currently active second malignancy other than non-melanoma skin cancer. Patients are not considered to have a currently active malignancy if they have completed necessary therapy and are considered by their physician to be at \<30% risk of relapse at time of assessment.
* Psychiatric illness, which would prevent the patient from giving informed consent or adhering to the study protocol.
* Serious or non-healing wound, ulcer, or bone fracture.
* Known spinal cord compromise or instrumentation due to metastatic disease in the mCRPC state. Radiation therapy for metastatic disease is allowed.
* Peripheral neuropathy ≥grade 3.
* Men participating in vigorous aerobic exercise for more than 60 minutes per week or structured INTERVAL Protocol Version 4.0, 19 April 2018 15 Resistance exercise two or more days per week (seek ECC approval before exclusion).

Experiences shortness of breath, chest discomfort, or palpitations when performing activities of daily living (patient with these symptoms can participate in the study with cardiologist clearance)

* Ongoing restriction of physical activity with physician documentation
* Has chest pain brought on by physical activity (patient can participate in the study with cardiologist clearance)
* Has developed chest pain in the past month (patient can participate in the study with cardiologist clearance)
* Moderate-to-severe bone pain (i.e., National Cancer Institute's Common Terminology Criteria for Adverse Events grade 2-3 bone pain).
* Men who do not complete the baseline lifestyle and quality-of-life questionnaires and 3-days of diet diaries or country-specific FFQ will not be eligible