Ali Zahalka, MD, PhD, was one of the recipients of the 2024 Urology Care Foundation™ Research Scholar Awards. These awards provide $40,000 annually for mentored research training for clinical and postdoctoral fellows or early-career faculty. The Society of Urologic Oncology sponsored Dr Zahalka’s award.

The periprostatic autonomic nerves are traditionally associated with erectile function, and great effort is taken to preserve them during prostate cancer treatment. These proerectile nerves are largely parasympathetic and travel along the prostatic capsule. Conversely, sympathetic nerves derived from the hypogastric plexus pierce the capsule at the prostate base near the insertion of the seminal vesicles, richly innervating the prostatic smooth muscle.¹ Emerging evidence has implicated adrenergic nerves in the progression of aggressive prostate cancer and suggests that taking these nerves may be therapeutic.²

It is estimated that 2% to 8% of all men with localized prostate cancer will clinically progress to metastatic disease within 10 years of radical prostatectomy or radiation therapy.³ However, men with high-risk prostate cancer are at the greatest risk for clinical progression, with 22% to 40% developing metastatic disease within 10 years of initial treatment.⁴ Furthermore, the finding of perineural invasion on pathology is associated with higher Gleason grades and an approximate doubling in risk of lethal prostate cancer.⁵ Extracapsular extension, often involving the neurovascular bundle, is also associated with increased risk of biochemical recurrence, metastasis, and death.^6,7 As 90% of prostate cancer metastasis involves the bone marrow, and 97% of bone marrow metastases involve the lumbar vertebrae from which the preganglionic sympathetic nerves that innervate the prostate derive,⁸ targeting this neuroanatomic connection between the prostate and its primary site of metastasis is an active area of investigation. Therefore, development of therapeutic strategies targeting nerves to prevent clinical progression after definitive therapy for prostate cancer is urgently needed.

We have recently demonstrated in preclinical mouse models that adrenergic/sympathetic innervation of the prostate is essential for prostate cancer progression, and that long-acting neuraxial blockade of these nerves inhibits disease progression and metastasis.² Increased prostate nerve density is observed in prostatectomy specimens from patients with prostate cancer,⁹ and increased adrenergic nerve density is associated with more aggressive disease.¹⁰ With support from an AUA/Urology Care Foundation^™ Residency Research Award (Mentor: Dr Ash Tewari, Icahn School of Medicine at Mount Sinai), we have shown in a recent phase 1a clinical trial that neoadjuvant long-acting neuraxial block of the adrenergic periprostatic nerves in patients with high-risk prostate cancer is safe with minimal side effects prior to prostatectomy. To target these nerves we employed transrectal ultrasound-guided injection of ethanol in the dorsomedial aspect of the prostate between the 2 seminal vesicles (Figure). Furthermore, we found that compared with contemporary high-risk controls, patients with neuraxial blockade had a significant reduction in extracapsular extension and seminal vesicle invasion on final pathology (unpublished data). However, the optimal duration of neural inhibition prior to prostatectomy is yet to be determined.

In this current study, we propose to target prostate innervation with a neoadjuvant periprostatic long-acting neuraxial block prior to prostatectomy in a phase 1b dose-range finding trial in patients with high-risk prostate cancer with extracapsular extension. Additionally, we plan to study the role of nerves in regulating the genomic changes that occur in the tumor microenvironment in extraprostatic extension.

This project will enhance our understanding of the role that adrenergic nerves play in extraprostatic extension and how this process influences the biology of locally advanced disease, as well as laying the foundation for a phase 2 trial.