Perioperative Propranolol During Prostatectomy to Decrease Cancer Recurrence

PCa is the most commonly diagnosed cancer in Norway (2020) and RALP is the most frequent curative treatment offered to men with non-metastatic PCa. Biochemical recurrence (BCR) is estimated to occur to 40% of patients with EAU IR and HR PCa. Attempts to combat the high recurrence rates after RALP with neoadjuvant treatment, aiming to reduce the local tumor burden and treat possible micrometastasis, has of yet not proven beneficial.

The prostate is highly innervated and recent evidence has shown the importance of nerves in the development and progression of PCa. The action of particularly adrenergic nerves, in sum lead to a pro-cancerous and metastatic state by influencing key hallmarks of cancer like apoptosis resistance, angiogenesis, immune suppression, invasiveness and metastasis.

Perioperative stress caused by the cancer surgery, in this case RALP, has been found to promote cancer progression and recurrence both by enhancing growth of preexisting residual tumor/micrometastasis and facilitating formation of new metastasis. The surgical stress response cause a catecholamine-induced cancer progression where β2-adrenergic receptor (ADRB2) have a key role.

Our newly published pharma co-epidemiologic study indicate perioperative stress can be targeted by a non-selective ß-blocker (nsBB) like propranolol [1]. RCTs have found perioperative administration of propranolol alone, or in conjunction with COX-2 inhibition, to be safe and to reduce biomarkers associated with poor prognosis compared with the control group receiving placebo medication in patients undergoing radical surgery for breast-, ovarian- and colorectal cancer [2-7}.

The result of our register study, together with existing evidence of an effect of propranolol/nsBBs, provides foundation for PeP-RALP, a pilot study to establish the recruitment- and infrastructure feasibility of a double-blinded, placebo controlled RCT. The results of this pilot study will be used to investigate the feasibility of a formal larger RCT aiming to assess efficacy of perioperative propranolol to reduce PCa recurrence and progression after RALP.

Inclusion criteria

• European Association of Urology Intermediate- and High Risk for Biochemical recurrence and planned for curative RALP
• ECOG Performance Status 0-1

Exclusion criteria

Medical Conditions

• Sick sinus syndrome
• Atrioventricular (AV) block grade 2 and 3
• Recent (3 months) myocardial infarction
• Known unstable- or vasospastic- angina
• Heart failure (New York Heart Association [NYHA] > 2)
• Symptomatic peripheral vascular disease (e.g. intermittent claudication)
• Known pulmonary hypertension
• Known carotid artery stenosis or recent (3 months) stroke
• Bronchial asthma or other chronic obstructive pulmonary disease (COPD)
• Kidney failure (estimated Glomerular filtration rate [eGFR]<50)
• Liver failure (cirrhosis, jaundice, signs of hepatic decompression)
• Unregulated diabetes mellitus
• Untreated thyroid disorder
• Depressive episode within last 6 months (within last 12 months if major depressive episode)
• Known drug allergy against propranolol or excipients
• Any medical conditions considered to prohibit Propranolol use as judged by the treating physician (including frailty).
• Participants with known substance- or alcohol-abuse

Prior/Concomitant Therapy

• Recent (<3 month) use of systemic beta-blockers prior to screening.
• Patients receiving non-dihydropyridine calcium channel blocking agents (eg diltiazem, verapamil)
• Patients receiving anti-arrhythmic agents (e.g. amiodarone, sotalol, digoxin, verapamil, flecainide)
• Patients receiving digoxin, rizatriptan, hydralazine, fluvoksamin, or fluoksetin
• Patients using daily anxiolytics (e.g. benzodiazepines), alpha-receptor adrenergic agonists (e.g. clonidine)
• Recommendations in the Summary of Product Characteristics for propranolol regarding concomitant use of other medications will be adhered to.

Diagnostic assessments

• Sinus bradycardia (<60 beats/minute)
• Resting blood pressure <110/60mmHg OR hypertension BP >160/100
• AV-block 2 or 3 on ECG