The initiation and progression of prostate cancer (PCa) in humans is initially reliant on androgen receptor (AR) signaling [1,2,3]. Directly targeting androgen ligands with androgen-inhibiting drugs (e.g., chemical castration) or decreasing their production via surgical castration has been utilized over the last 80 years in an attempt to suppress AR signaling and PCa-tumor progression [4,5,6]. Unfortunately, androgen-deprivation therapies (ADT) eventually fail for a subset of patients, and despite the presence of castrate levels of androgens, PCa progresses to an incurable form, termed castration-resistant prostate cancer (CRPC) [7,8,9]. This form of prostate cancer often continues AR signaling that is not reliant on androgen ligands (i.e., androgen independent) by way of multiple mechanisms, including mutations in the receptor or copy-number variations, and is typically treated with androgen-receptor inhibitors (ARIs) [10,11,12,13]. Eventually, new driver mutations develop in various genes in CRPC tumors, which leads to the abandonment of AR signaling altogether. Once PCa progresses, irrespective of AR signaling, it is termed androgen-receptor-indifferent PCa, a highly aggressive lethal form of the disease with poor outcomes [14,15]. Recently, the molecular characterization of CPRC and androgen-indifferent prostate cancer (AIPC) have improved our understanding of the drivers of these variants, which is critical for the identification of novel therapeutics. However, animal models for advanced forms of PCa are lacking and are wrought with limitations [16,17], which may make the approval of novel therapeutics challenging and the translation of results between species inconsistent.

The prostate of the dog, unlike that of rodents, is morphologically, histologically, and physiologically similar to that of humans and is under the control of androgens via androgen-receptor signaling [18,19,20]. Dogs also naturally develop other pathologic prostatic conditions with age, such as benign prostatic hyperplasia (BPH), in contrast to rodents, which typically develop prostatic atrophy with age [21,22]. More importantly, dogs are the among the only animals that spontaneously develop PCa, and often present with highly aggressive metastatic disease. The neutering or castration of male dogs is common in developed countries, with the majority of the male dogs in the United States undergoing this procedure [23,24]. It has been shown that castration influences PCa progression as castrated dogs develop PCa at higher rates and experience more metastases than intact dogs [25,26,27,28,29,30].