Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative neoadjuvant trial in high‐risk localized prostate cancer

Abstract

Background Localized prostate cancers (PCs) may resist neoadjuvant androgen receptor (AR)‐targeted therapies as a result of persistent intraprostatic androgens arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of neoadjuvant indomethacin (Indo), which inhibits the steroidogenic enzyme AKR1C3, in addition to combinatorial anti‐androgen blockade, in men with high‐risk PC undergoing radical prostatectomy (RP). Methods This was an open label, single‐site, Phase II neoadjuvant trial in men with high to very‐high‐risk PC, as defined by NCCN criteria. Patients received 12 weeks of apalutamide (Apa), abiraterone acetate plus prednisone (AAP), degarelix, and Indo followed by RP. Primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included minimal residual disease (MRD) rate, defined as residual cancer burden (RCB) ≤ 0.25cm3 (tumor volume multiplied by tumor cellularity) and elucidation of molecular features of resistance. Results Twenty patients were evaluable for the primary endpoint. Baseline median prostate‐specific antigen (PSA) was 10.1 ng/ml, 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had pCR and 6 (30%) had MRD. Therapy was well tolerated. Over a median follow‐up of 23.8 months, 1 of 7 (14%) men with pathologic response and 6 of 13 (46%) men without pathologic response had a PSA relapse. There was no association between prostate hormone levels or HSD3B1 genotype with pathologic response. Conclusions In men with high‐risk PC, pCR rates remained low even with combinatorial AR‐directed therapy, although rates of MRD were higher. Ongoing follow‐up is needed to validate clinical outcomes of men who achieve MRD.

Neoadjuvant Androgen Receptor Signaling Inhibitors before Radical Prostatectomy for Non-Metastatic Advanced Prostate Cancer: A Systematic Review

“…After the screening, a full-text review of 30 articles was performed. According to our inclusion criteria, we finally identified 20 studies eligible for systematic review [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. Of the twenty studies, we identified eight phase II RCTs comparing the efficacy and/or safety of ARSI-based combination therapy versus other combinations or ADT/ARSI alone (Table 1) [13][14][15][16][17][18][19][20].…”

“…Several studies assessing the efficacy of neoadjuvant ARSIs used a pathological endpoint as a surrogate for long-term oncological outcomes (Table 2 and Supplementary Tables S3 and S4) [13][14][15][17][18][19]21,22]. However, no consensus yet exists regarding the ideal definition of a pathological response following neoadjuvant hormonal therapy.…”

“…The definition of MRD differed across studies. Four studies defined the MRD as residual cancer <5 mm as the longest length in the crossing section dimension [13,15,17,18], and one study used the <3 mm cut-off [14], and two studies defined it as RCB < 0.25 cm 3 [18,21]. Following the definition of combined pathologic response (pCR + MDR) reported by McKay et al in 2021 [17], we calculated the combined pathologic response of each study.…”

“…Three phase II RCTs and one single-arm study have assessed the efficacy of double AR-SIs + ADT as a neoadjuvant therapy for advanced clinically non-metastatic PCa [15,17,19,21]. The rationale for this intensified regimen is to investigate whether blocking all sources of androgen production (i.e., testes, adrenal gland, and intratumoral) and maximally blocking the androgen receptor could improve the pathologic response compared to incomplete androgen blockade.…”

Neoadjuvant Systemic Therapy Prior to Radical Prostatectomy for Clinically Localized High-Risk Prostate Cancer

“…Results of two phase II trials suggested no improvement in rates of complete pathologic response or reduction in residual tumor in patients treated with apalutamide in addition to abiraterone and LHRH agonist (39,51). A single-arm Phase II trial reported pathologic features after 3-months of neoadjuvant apalutamide, abiraterone, degarelix and indomethacin prior to prostatectomy (53). The addition of indomethacin may further decrease production of testosterone by inhibiting AKR1C3.…”