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Cancer Therapy AdvisorSystemic Therapy for Nonmetastatic Castration-Resistant Prostate Cancer

Three ARPIs — darolutamide, enzalutamide, and apalutamide — show level 1 evidence to improve overall survival and delay metastasis in nmCRPC patients. This early use of potent second-generation AR antagonists is a shift from older treatment options such as ketoconazole and dexamethasone.

Two leading genitourinary medical oncologists, Jingsong Zhang and Evan Y. Yu, engage in a comprehensive discussion about the current state of nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment. They explore the effects of second-generation androgen receptor pathway inhibitors (ARPIs), patient selection considerations, balancing treatment benefits and risks, and future research needs in the field.

Key Points:

  • Patient selection for ARPI treatment typically hinges on prostate-specific antigen (PSA) doubling time. Those with a doubling time of less than 10 months are at high risk for metastasis and are thus suitable candidates for treatment.
  • The key criteria for patient selection also include comorbidities, anticipated survival, and the risk-benefit ratio of treatment. Severe comorbidities can limit treatment options. Although FDA approval is relatively loose, physicians usually stick to a 10-month PSA doubling time or less for treatment initiation.
  • The discussion of adverse events (AEs) should occur upfront, with most side effects being similar to those experienced with standard androgen deprivation therapy (ADT). It’s vital to ensure the risk-benefit ratio remains in favor of treatment while managing potential side effects.
  • Both the National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) endorse using ADT plus enzalutamide, apalutamide, or darolutamide to delay metastasis in high-risk nmCRPC patients.
  • All oncology treatments require a risk-and-benefit discussion. Shared decision-making with patients, their families, and healthcare teams is essential. Safety concerns associated with long-term use, financial toxicity, and potential side effects should be thoroughly discussed.
  • Future research needs include investigating how early ARPIs can be introduced to still see benefit. Studies are needed to determine whether ARPIs can be moved to localized disease states.

Additional Points:

  • Darolutamide, enzalutamide, and apalutamide treatments show very few contraindications. Exceptions include significant arrhythmia, heart failure with less than 30% life expectancy, or renal failure requiring hemodialysis.
  • The use of next-generation imaging techniques, like positron emission tomography (PET) scans, is not common in nmCRPC as it doesn’t significantly impact practice. The focus remains on treating aggressive cancer with minimal disease burden.
  • Current ARPI research might shift focus from M0CRPC to other disease states as PSMA PET becomes more common. The M0CRPC disease state may be perceived as having less unmet need, given the presence of effective treatments.


  • ARPIs have ushered in a new era in the treatment of nmCRPC, offering improved survival rates and delayed metastasis. Although patient selection requires careful assessment of PSA levels and comorbidities, the majority of patients can benefit from these therapies. And while research continues to seek novel treatment approaches, the availability of ARPIs has fundamentally altered the management of nmCRPC.

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“The whole idea is to turn this into a chronic disease, which it really is; I wouldn’t even say it’s becoming — it really is, for the vast majority of patients, a chronic disease.”

Evan Y. Yu, MD
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