ONCAlert | Upfront Therapy for mRCC

Considerations When Approaching M0 CRPC

Targeted Oncology
Published Online:12:00 PM, Thu September 19, 2019

Jorge Garcia, MD: The management of castration-resistant prostate cancer [CRPC] has evolved significantly over the past 5 years. Every man who unfortunately develops advanced prostate cancer, over time, will become castration-resistant, with a low level of testosterone. Most men, when they develop advanced disease, eventually progress and develop a rise in PSA [prostate-specific antigen], and/or symptom progression, and/or radiographic progression. Any of those 3 features, in the context of a suppressed testosterone level, which we call a testosterone less than 50, make those men castration-resistant. So unequivocally, every man will progress from castration-naïve to castration-resistant disease.

It’s been thought that the culprit in prostate cancer is the male hormone, DHT [dihydrotestosterone]. But in reality, it is now well documented that the androgen receptor [AR] remains the biggest culprit in the disease. AR basically continues to drive growth. But when you become castration-resistant, what drives that activation of androgen receptor signaling doesn’t appear to be coming from dihydrotestosterone. Rather, it arrives from other growth factors, other androgens; or for that matter, there are many theories as to how one becomes castration-resistant. But androgen receptor remains the most important therapeutic target in that context.

If I step back for a second, when you think of castration-resistant disease, you really have to talk about 2 different groups of patients. We think of those with androgen suppression who, despite a rise in PSA, don’t have symptomatic disease and/or radiographic evidence of disease. That is what we call M0 CRPC, meaning no evidence of objective disease.

The other group are patients who have castration-resistant disease whose objective disease is found by scans, no matter what scans one uses—new emerging technology or the traditional CT [computed tomography] scans or bone scans. It used to be that there was no real standard of care for any man in the context of M0 CRPC. Now, over the last 3 years, we have 3 very powerful oral agents—apalutamide, enzalutamide, and darolutamide, recently—that have really changed and reshaped management for patients with M0 disease.

This is a small group of patients, probably less than 20% to 25% of patients, in the context of what we see in advanced disease and the CRPC space. But clearly, right now those patients have this opportunity to embark on 1 of these 3 agents.

Most men with M0 CRPC are men traditionally like me, who don’t have any symptoms whatsoever. So it’s very important for us to define what the overall goals for these patients are. Traditionally, for FDA registration in the United States, survival used to be the gold standard for registration for drug development, at least in prostate cancer. Nowadays, we have shifted a little bit from that. Now we use something called metastasis-free survival, which basically is your ability to be free of radiographic progression, including symptomatic progression, or dying from any cause in the context of that M0 CRPC space.

It is very important for us to maintain quality of life. It is very important for us to delay time to metastasis, delay time to symptomatic progression, and obviously, to delay the need for patients to embark on cytotoxic agents or more toxic regimens in the context of their natural history. Quality of life and patient reported outcomes have become very important aspects in the management of castration-resistant prostate cancer.

Transcript edited for clarity.

Jorge Garcia, MD: The management of castration-resistant prostate cancer [CRPC] has evolved significantly over the past 5 years. Every man who unfortunately develops advanced prostate cancer, over time, will become castration-resistant, with a low level of testosterone. Most men, when they develop advanced disease, eventually progress and develop a rise in PSA [prostate-specific antigen], and/or symptom progression, and/or radiographic progression. Any of those 3 features, in the context of a suppressed testosterone level, which we call a testosterone less than 50, make those men castration-resistant. So unequivocally, every man will progress from castration-naïve to castration-resistant disease.

It’s been thought that the culprit in prostate cancer is the male hormone, DHT [dihydrotestosterone]. But in reality, it is now well documented that the androgen receptor [AR] remains the biggest culprit in the disease. AR basically continues to drive growth. But when you become castration-resistant, what drives that activation of androgen receptor signaling doesn’t appear to be coming from dihydrotestosterone. Rather, it arrives from other growth factors, other androgens; or for that matter, there are many theories as to how one becomes castration-resistant. But androgen receptor remains the most important therapeutic target in that context.

If I step back for a second, when you think of castration-resistant disease, you really have to talk about 2 different groups of patients. We think of those with androgen suppression who, despite a rise in PSA, don’t have symptomatic disease and/or radiographic evidence of disease. That is what we call M0 CRPC, meaning no evidence of objective disease.

The other group are patients who have castration-resistant disease whose objective disease is found by scans, no matter what scans one uses—new emerging technology or the traditional CT [computed tomography] scans or bone scans. It used to be that there was no real standard of care for any man in the context of M0 CRPC. Now, over the last 3 years, we have 3 very powerful oral agents—apalutamide, enzalutamide, and darolutamide, recently—that have really changed and reshaped management for patients with M0 disease.

This is a small group of patients, probably less than 20% to 25% of patients, in the context of what we see in advanced disease and the CRPC space. But clearly, right now those patients have this opportunity to embark on 1 of these 3 agents.

Most men with M0 CRPC are men traditionally like me, who don’t have any symptoms whatsoever. So it’s very important for us to define what the overall goals for these patients are. Traditionally, for FDA registration in the United States, survival used to be the gold standard for registration for drug development, at least in prostate cancer. Nowadays, we have shifted a little bit from that. Now we use something called metastasis-free survival, which basically is your ability to be free of radiographic progression, including symptomatic progression, or dying from any cause in the context of that M0 CRPC space.

It is very important for us to maintain quality of life. It is very important for us to delay time to metastasis, delay time to symptomatic progression, and obviously, to delay the need for patients to embark on cytotoxic agents or more toxic regimens in the context of their natural history. Quality of life and patient reported outcomes have become very important aspects in the management of castration-resistant prostate cancer.

Transcript edited for clarity.
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