Discussion

Adrenal physiology is critical to the progression of prostate cancer as a contributor of serum androgens, and many prostate cancers take on an adrenal phenotype by upregulation of these adrenal androgenic enzymes and autocrine/paracrine synthesis and usage of androgens to survive the castrate state. There have been many advances in the treatment of mCRPC, with the introduction of new therapies and approaches in the last decade that target the androgen axis, including androgen-targeted agents like abiraterone acetate and AR targeting agents such as enzalutamide, apalutamide and darolutamide, which can prolong mCRPC patients’ survival. However, despite these positive initial responses, resistance remains a barrier to prolonged response in mCRPC. Cytotoxic chemotherapy such as docetaxel and cabazitaxel, immunotherapy such as sipuleucel-T and pembrolizumab, and precision therapies such as the targeted radioligand Lu177-PSMA-617 (Pluvicto) and PARP (poly ADP-ribose polymerase) inhibitors olaparib and rucaparib have been FDA (Food and Drug Administration) approved for prostate cancer.15–19 Even locoregional options such as surgery and radiotherapy are being explored in metastatic disease.19 Specifically, the PARP inhibitors laparib and rucaparib were FDA approved in 2020 for mCRPC patients with a pathogenic mutation in a homologous recombination gene, such as BRCA1 and BRCA2, bringing a survival benefit to this specific subset of the mCRPC patient population.17 18 Our patient has declined genetic testing up until now, but given his continued progression through docetaxel treatment, this will likely be pursued.

Here, we highlight an mCRPC patient progressing on abiraterone who demonstrated a response to adrenalectomy for a functioning adrenal adenoma. Before his adrenalectomy, his PSA and testosterone levels were sharply rising on abiraterone, implying his disease responded to the adrenalectomy rather than abiraterone. This is also supported by his continued relative PSA stability seen after abiraterone was discontinued and the sharp reduction in serum testosterone observed postadrenalectomy. As previously mentioned, bilateral adrenalectomy has been shown to improve symptoms of metastatic prostate cancer as early as the 1940s.9–11 There have been few case reports describing patients with both prostate cancer and adrenal tumours. Alikhan et al reported a case of advanced prostate cancer and a pheochromocytoma, although they did not comment on the effect unilateral adrenalectomy had on the prostate cancer.20 Navani et al described a patient with both mCRPC and metastatic androgen-secreting adrenocortical carcinoma who responded positively to left adrenalectomy,21 and Ashrafi et al reported a patient with CRPC with metastasis involving the adrenal gland that had a durable response to adrenal metastasectomy.22 As far as we know, this is the first reported case of mCRPC on a potent AR inhibitor like abiraterone, who responded positively to the removal of a functional adrenal adenoma.

Biochemical and clinical evidence support that our patient had an adrenal adenoma that secreted aldosterone and perhaps androgenic precursors. Given abiraterone acetate can cause secondary hyperaldosteronism,23 it is important to note that the elevated plasma aldosterone concentration and depressed plasma renin activity were identified before abiraterone therapy was initiated. In the setting of mineralocorticoid excess from abiraterone therapy, mineralocorticoids have been shown to inhibit androgen-induced AR conformational change, AR transcriptional activity and prostate cancer cell growth, suggesting therapies derived from mineralocorticoids may exert positive effects in prostate cancer.24 This is unlikely to be contributing in this patient, as the withdrawal of both excess aldosterone and androgen production after adrenalectomy was associated with prostate cancer remission.

The durable response seen after surgery raises the possibility that aldosterone could have been contributing to disease progression, as has been suggested in preclinical models in both renal and prostate cancer.25 26 A Canadian retrospective cohort study that examined thousands of men with heart failure found that spironolactone exposure significantly reduced the incidence of prostate cancer; this could be due to spironolactone’s known antiandrogen effects, but aldosterone antagonism could play a role in prostate cancer prevention and possibly treatment.27 This needs to be investigated further with more rigorous preclinical and clinical studies, but it offers a possible explanation for the response seen in this patient. The combination of spironolactone and abiraterone could have also been a contributing factor. Spironolactone has well-known antiandrogen activity, but studies have proposed a possible positive androgenic effect of the drug,28 particularly in an androgen-deprived environment, like that created by abiraterone. Several case studies have described the negative effect the combination of spironolactone with abiraterone has on mCRPC.29–32 In this case, it is difficult to determine whether the medication combination withdrawal or the adrenalectomy itself is responsible for this patient’s response, as spironolactone was discontinued at around the same time as his adrenalectomy. Additionally, serum testosterone levels clearly declined postadrenalectomy, which do not explain the spironolactone effect. Either way, this potential drug interaction is important to study further, as spironolactone is a common medication for indications such as heart failure and cirrhosis, conditions with significant patient population overlap with prostate cancer.

Finally, the patient’s adenoma was likely secreting testosterone in addition to aldosterone. Examining the patient’s total testosterone trends while on ADT, there is a rise in testosterone levels leading up his adrenalectomy, followed by a sharp drop after the date of his adrenalectomy. As seen in figure 4, he had almost 2 years of stable testosterone levels after his adrenalectomy, after which these levels started to uptrend. This is likely because of his disease progression. His total testosterone levels are overall decreased given treatment with ADT; however, this trend raises the question of whether this adrenal adenoma was also androgen-secreting, which would have contributed to his durable PSA response after adrenalectomy. Unfortunately, we did not obtain preadrenalectomy functional labs to determine if there were increased circulating adrenal androgens. Nevertheless, cosecreting adrenal tumours producing both aldosterone and androgens, although very rare, have been reported in the literature. Peppa et al described a patient with adrenocortical carcinoma secreting aldosterone, cortisol and androgens, while Schmitt et al described a paediatric patient with a functional adrenal adenoma secreting aldosterone and androgens.33 34 Because this patient was on ADT for his prostate cancer, the symptoms classically associated with androgen-secreting tumours were not observed. However, the trend suggests his adrenalectomy contributed to the decrease in serum testosterone levels, and perhaps a cosecreting adrenal adenoma producing both aldosterone and androgens is the explanation.