Clinical considerations for the management of androgen indifferent prostate cancer

Abstract

Background: Many systemic therapies for advanced prostate cancer work by disrupting androgen receptor signaling. Androgen indifferent prostate cancer (AIPC) variants, including aggressive variant prostate cancer (AVPC), neuroendocrine prostate cancer (NEPC), and double negative prostate cancer (DNPC), are increasingly common and often overlapping resistance phenotypes following treatment with androgen receptor signaling inhibitors in men with metastatic castration-resistant prostate cancer and are associated with poor outcomes. Understanding the underlying biology and identifying effective therapies for AIPC is paramount for improving survival for men with prostate cancer. Methods: In this review, we summarize the current knowledge on AIPC variants, including our current understanding of the clinical, morphologic, and molecular features as well as current therapeutic approaches. We also explore emerging therapies and biomarkers aimed at improving outcomes for men with AIPC. Results and Conclusions: Establishing consensus definitions, developing novel biomarkers for early and accurate detection, further characterization of molecular drivers of each phenotype, and developing effective therapies will be critical to improving outcomes for men with AIPC. Significant progress has been made towards defining the clinical and molecular characteristics of AVPC, NEPC, and DNPC. Novel diagnostic approaches, including cell-free DNA, circulating tumor cells, and molecular imaging are promising tools for detecting AIPC in clinical practice. Building on previous treatment advances, several clinical trials are underway evaluating novel therapeutic approaches in patients with AIPC informed by an understanding of variant-specific biology. In this review, we discuss how these recent and ongoing studies will help to improve diagnosis, prognosis, and therapy for men with AIPC.

BET inhibition sensitizes immunologically-cold Rb-deficient prostate cancer to immune checkpoint blockade

“…To further potentiate the anti-tumor immune responses mediated by JQ-1, Rb-deficient tumor bearing mice were treated also with androgen deprivation therapy (ADT) using degarelix (chemical castration), a standard-of-care treatment for advanced prostate cancer that we and others have demonstrated elicits increased immune infiltration in wild-type Myc-CaP tumor-bearing mice (35). Consistent with prior clinical data (36), while degarelix alone did not induce signficant anti-tumor responses in Rb-deficient tumor-bearing animals, the addition of degarelix to JQ-1 and anti-PD-L1 significantly enhanced the anti-tumor response elicited by corresponding singlet and doublet therapies (Fig. 5B).…”

Systemic ablation of Camkk2 impairs metastatic colonization and improves insulin sensitivity in TRAMP mice: Evidence for cancer cell-extrinsic CAMKK2 functions in prostate cancer

“…As such, these genetically defined prostate cancers have been classified as aggressive variant prostate cancers (AVPCs), of which NEPCs are typically included [31]. Curiously, while disease relapse was observed at 30 weeks in TRAMP mice at the primary site (prostate) regardless of diet, systemic Camkk2 loss dramatically impaired the metastatic colonization of the lungs at the same timepoint in HFD-fed TRAMP mice (Figure 4).…”

Therapy considerations in neuroendocrine prostate cancer: what next?

“…Patients with histologically confirmed small cell NEPC or CRPC with aggressive variant clinical features (AVPC) are often treated with systemic therapy regimens used for SCLC, based on clinical, pathologic, and molecular similarities between NEPC and SCLC (Berchuck et al 2021). Similar to SCLC, they tend to be initially responsive to platinum-based chemotherapy with objective response rates of 50-60% (Sella et al 2000, Papandreou et al 2002.…”