Nonmetastatic Castration-Resistant Prostate Cancer: Current Challenges and Trends

Abstract

Prostate carcinoma is a highly prevalent biologically and clinically diverse disease, generally associated with a consistent elevation of prostate-specific antigen levels. Castration-resistant prostate cancer represents a heterogeneous clinical setting that ranges from patients with an asymptomatic prostate-specific antigen elevation after hormone blockade failure and good performance status to patients with significant debilitating symptoms and rapidly progressive disease, leading to death. Nonmetastatic castration-resistant prostate cancer is a transient disease stage defined over specific criteria established within a sensitive time period. The majority of the patients with nonmetastatic castration-resistant prostate cancer will eventually develop metastatic lesions, associated with prostate cancer-specific morbidity and mortality. However, progression to metastatic disease is a heterogeneous process still not fully understood, with studies suggesting that younger age, high Gleason score (> 7), high prostate-specific antigen levels, reduced prostate-specific antigen doubling time (< 6 months), and a rapid alkaline phosphatase rise as potentially associated factors. Although the nonmetastatic castration-resistant prostate cancer treatment landscape has substantially evolved in recent years, the disease heterogeneity makes treatment decisions for this population challenging in the effort to achieve a balance between the risk of disease progression and the toxicity of new treatments in patients who often have associated comorbidities, yet are generally asymptomatic. The present article addresses the current main challenges in nonmetastatic castration-resistant prostate cancer management, including in diagnosis, owing to the development of new imaging modalities with a direct impact in disease detection, prognostic classification, as a result of the traditionally oversimplified definition of disease aggressiveness (mainly based on prostate-specific antigen doubling time), and patient selection for the most adequate treatment.

Relationship between pyroptosis-mediated inflammation and the pathogenesis of prostate disease

“…Cell death under physiological conditions (e.g., proper autophagy and apoptosis) is necessary to maintain tissue renewal, whereas under pathological conditions (e.g., autophagy, necroptosis, and pyroptosis) predispose to disease development and progression. Prostate diseases include PCa, prostatitis and BPH, all of which are serious threats to men’s health ( 85 – 87 ). A key feature of all three prostate diseases is the fact that they are all affected by inflammation.…”

Androgen deprivation triggers a cytokine signaling switch to induce immune suppression and prostate cancer recurrence

“…The models we employed are anatomically similar to non-metastatic CRPC (nmCRPC) in that the tumor is localized to the prostate, whereas in metastatic CRPC (mCRPC) the TME is derived from the metastatic site, such as bone. Most CRPC is discovered clinically as mCRPC and indeed nmCRPC is likely a transient state that progresses to mCRPC (67). Castration of mice bearing PTEN-deficient or Hi-MYC prostate cancers induces regression and then recurrence – a pattern very similar to that seen in the development of human CRPC.…”

Low-Dose Apalutamide in Nonmetastatic Castration-Resistant Prostate Cancer: A Case Report

“…In 2020, prostate cancer was the third most common newly diagnosed cancer among males in Europe, with approximately 470,000 new cases reported [ 1 ]. Nonmetastatic castration-resistant prostate cancer (nmCRPC) is a transient disease state characterized by the observation of increasing prostate-specific antigen (PSA) levels, despite a patient undergoing androgen deprivation therapy, and the absence of detectable metastases based on conventional imaging, such as computer scans, technetium-99m scintigraphy, and gallium-68 prostate-specific membrane antigen (Ga-68 PSMA) ligand scintigraphy [ 2 ]. A PSA doubling time of less than 10 months in nmCRPC serves as a good prognostic indicator for disease progression, significantly predicting patient survival outcomes [ 3 ].…”