nmCRPC (non-metastatic castration-resistant prostate cancer)
What is Castration-Resistant Prostate Cancer?
Castration-resistant prostate cancer, or castrate-resistant prostate cancer (CRPC) is defined as clinical and biochemical progression of prostate cancer despite achieving castrate levels of testosterone (typically <1.7 nmol/L or <50 ng/dL) through androgen deprivation therapy (ADT).
Diagnosis of castration-resistant prostate cancer (CRPC)
Castration-resistant prostate cancer is defined by castrate serum testosterone < 50 ng/dL or 1.7 nmol/L, plus either:
- Biochemical Progression: three consecutive rises in prostate specific antigen (PSA) at least one week apart resulting in two 50% increases over the nadir, and PSA > 2 ng/mL
- Radiological Progression: appearance of new lesions, either two or more new bone lesions on a bone scan or a soft tissue lesion
- Unequivocal clinical progression
This indicates that the cancer is no longer responding to ADT, a foundational treatment for advanced prostate cancer, which aims to reduce circulating levels of androgens, including testosterone and its derivative, dihydrotestosterone.
Types of castration-resistant prostate cancer (CRPC)
Non-metastatic castration-resistant prostate cancer (nmCRPC): No radiologically detectable metastases on conventional imaging.
Metastatic castration-resistant prostate cancer (mCRPC): Evidence of metastatic disease detectable on conventional imaging.
Adapted from: Saad F, et al. 2021.
Non-metastatic castratation-resistant prostate cancer (nmCRPC)
Non-metastatic castration-resistant prostate cancer (nmCRPC), or non-metastatic hormone relapsed prostate cancer, is defined by rising levels of serum PSA and an absence of detectable metastases on conventional imaging in patients receiving ADT.
Patients with nmCRPC are typically asymptomatic, but are at risk of progressing to metastatic disease, which is associated with the development of cancer-related symptoms and higher mortality and morbidity than nmCRPC.
Prevalence of Non-Metastatic Castration-Resistant Prostate Cancer
- In males in the UK, prostate cancer is the most common cancer, with approximately 55,000 new cases and 12,000 deaths every year, on average.
- Approximately 77% of prostate cancer patients develop resistance to ADT and progress to nmCRPC, despite having castrate levels of testosterone.
- Welsh clinical data* indicated 3.9% of prostate cancer cases were categorised as nmCRPC.
Prognosis of Non-Metastatic Castration-Resistant Prostate Cancer
- The majority of patients with mCRPC progress from nmCRPC (approximately 86%), with one-third of patients with nmCRPC progressing to mCRPC within 2 years of diagnosis.
- Median time from PC diagnosis to nmCRPC categorisation is approximately 3.07 years (95% confidence interval [CI] 2.91–3.26) and from nmCRPC categorisation to metastases/death was 2.86 years (95% CI 2.67–3.09).*
* Welsh Retrospective observational cohort study, conducted using routinely collected administrative data in Wales, including prescriptions, diagnostic procedures and hospital admissions 2000-2015 (n= 38,021)
Cause of Non-Metastatic Castration-Resistant Prostate Cancer
- Progression to nmCRPC and failure to maintain suppression of PSA levels despite castrate levels of testosterone is associated with several factors.
- The mechanisms have been attributed to intratumoural androgen synthesis, dysregulated androgen signalling, through splice variants, gain-of-function mutations, and aberrant post-receptor regulation.
- This abnormal signalling contributes to neoplastic cellular proliferation, hormone insensitivity and tumour progression.
Treatment for Non-Metastatic Castration-Resistant Prostate Cancer
Patients with nmCRPC are typically described as asymptomatic, from a tumour burden perspective.
However, it does not reflect the entire clinical picture, as age, underlying comorbidities, associated concomitant medications, and side effects induced by chronic ADT may impact patient symptoms, and decision making when initiating therapy.
Key Therapeutic Goals for nmCRPC:
- Prolong survival
- Delay the onset of cancer-related symptoms
- Minimise treatment-related adverse events
- Preserving quality of life and independence in daily living
Factors Influencing the Management of nmCRPC
Patients with nmCRPC are typically described as generally asymptomatic, from a tumour burden perspective. However, it does not reflect the entire clinical picture, as the patient’s profile and preferences may impact decision making when initiating therapy.
When prostate cancer no longer responds to hormone treatment (ADT), but has not spread beyond the prostate, current options include continuing ADT alone or in combination with an androgen receptor inhibitor (ARI).
Second-generation androgen receptor inhibitors (ARIs) have been developed for the treatment of prostate cancer. These inhibitors, such as enzalutamide, apalutamide, and darolutamide, block the ligand-binding domain of the androgen receptor, inhibiting its activity and preventing its nuclear translocation and interaction with DNA.
In the UK, darolutamide and apalutamide are recommended by NICE and accepted by SMC to patients with nmCRPC and a high risk of developing metastasis (PSA-doubling time< 10 months) to prolong time to metastases and overall survival.
For full information on NUBEQA (darolutamide) in the treatment of nmCRPC, please refer to the Summary of Product Characteristics (SPC)
Abbreviations
ADT, androgen deprivation therapy; ARI, androgen receptor inhibitor; CRPC, castration-resistant prostate cancer, DNA; deoxyribonucleic acid, mCRPC; metastatic castration-resistant prostate cancer, mHSPC; metastatic hormone-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; PC, prostate cancer; PSA, prostate-specific antigen.
PP-NUB-GB-2550 | August 2025