Prostate Cancer Treatments

Non-metastatic Castration Resistant Prostate Cancer (nmCRPC)

• In the U.S., there are about 50,000–60,000 cases of non-metastatic castration resistant prostate cancer (nmCRPC) annually.
• "Prostate Cancer Working Group 3 defines nmCRPC as rising PSA level with 25% increase above the nadir level (considering a starting value of ≥1ng/mL) with minimum rise of 2 ng/mL, no evidence of local recurrence or distant metastases on conventional imaging including radionuclide bone imaging, CT scan or MRI, and serum testosterone level <50 ng/mL (castrate level)."
• The typical metastasis-free survival (MFS) of those with this type of prostate cancer is around 25–30 months.  
• Around one-third of them develop bone metastasis in 2 years.
• The approximate time needed for the prostate-specific antigen (PSA) to increase 2X or the doubling time (PSA-DT) is around 10 months. This poses a huge risk of proceeding to metastasis for those with nmCRPC.
• The insufficiency of radiologic evidence of metastatic illnesses and the lack of clinical symptoms made it difficult to develop treatment strategies for nmCRPC.
• Prior to some recent advancements in nmCRPC treatment, treating the disease entail proceeding with the GnRH agonist, combining first-generation AR antagonist (nilutamide, flutamide or bicalutamide) with a GnRH agonist, raising the amount of bicalutamide, using other androgen receptor (AR) antagonist, withdrawal of AR antagonist, or alternative hormonal treatments with negligible effect on the overall survival (OS).
• A known constraint of studying localized prostate cancer is the long-term monitoring needed to determine the effect of the treatment on OS. This can last for more than ten years in certain cases.
• There are no novel AR-targeted agent yet that positively impacted OS in the nmCRPC setting.
•  Androgen deprivation can help in slowing down the cancer but for most of the patients who received this treatment, castration-resistant conditions can still occur.

Metastatic Castration Sensitive Prostate Cancer

• Focusing on the androgen receptor (AR) pathway is a major part of treating those with castration-sensitive prostate cancer.
• This type of prostate cancer is usually the onset stage of advanced prostate cancer. It cannot anymore be managed with local therapy only.
• This cancer is the original one for which there is already a targeted treatment which involves focusing on the AR and castration. Testosterone can also be reduced as part of the treatment.
• This treatment is considered to be highly successful in many patients and is generally tolerated versus other types of therapies.
• Patients with the advanced form of this disease could have been harboring this disease for a long time. This then leaves the opportunity to receive several treatments but also allow for comorbid diseases to develop.
• Combining docetaxel and androgen ablation is known to increase the chances of surviving the disease as evidenced by the phase III STAMPEDE trial. During the trial, docetaxel greatly increased the OS in men who just got a "hormone-naïve advanced prostate cancer" diagnosis.
• Based on the outcome of the trial, the OS was 77 months and 67 months respectively for those being treated with docetaxel with ADT compared to those who are just receiving ADT only.
• However, even if castration is a well-accepted treatment, it has accompanying toxicities especially for the elderly.

Summary of Findings

• Our one hour of research provided some of the challenges encountered by doctors when treating non-metastatic castration resistant prostate cancer (nmCRPC) versus treating metastatic castration sensitive prostate cancer.
• As there was no geographic focus provided, we are assuming a global focus. If a more targeted approach is desired, for example, the United States, this would have to be clearly communicated to us in any reply.
• Given that there are available studies and reports on this topic, we are proposing the next steps below.