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Optimal Treatment Approaches for mCRPC

Insights From: Evan Yu, MD, University of Washington; Ulka Vaishampayan, MD, Barbara Ann Karmanos Cancer Institute ; Neeraj Agarwal, MD, Huntsman Cancer Institute
Published: Thursday, Dec 06, 2018



Transcript: 

Ulka Vaishampayan, MD: The definition of castrate resistant disease is when the testosterone is suppressed but the disease is progressing. Conventionally, we use serum testosterone of 50 ng/dL or less as to be considered castrate levels of testosterone. If you have the patient continued on androgen deprivation therapy—typically what we use is the LHRH [luteinizing hormone-releasing hormone] analogs for this—and their disease is progressing either by PSA [prostate-specific antigen] progression or new areas of disease symptoms, etcetera, that is considered castrate resistant disease.

A number of treatments in metastatic prostate cancer have at least been evaluated in parallel. We don’t have very good comparison trials. Most of the studies have compared the novel agents to placebo and shown efficacy that way. We don’t have direct head-to-head comparison trials, in general because the mechanisms of action of each of these agents are different. It does make sense to think about the patient’s circumstances, the sites of metastases, the type of progression, and the symptoms, and then arrive at a decision point as to which treatment to pick for the patient at the right time. Chances are you will be able to sequence from one treatment to another, but ideally you want to try and minimize toxicity and still get that survival benefit in when you are picking or choosing a therapy in CRPC.

In terms of layering treatment, there is very minimal evidence for combination treatments in metastatic CRPC. What evidence we do have so far suggests that layering treatments is not a good idea, except along with LHRH analogue therapies. All our treatments in metastatic CRPC have been evaluated by adding them on to androgen deprivation therapy, or LHRH analogue therapy. I think at a minimum, that will continue as a baseline treatment, and any other treatment is added or layered on top. But with 2 different treatment approaches in metastatic CRPC, regarding whether or not to combine them and add them on top of one another, the small evidence that we do have of combining abiraterone and radium-223 shows that there is a higher risk of fractures and no improved efficacy. At this point, layering 2 different treatments in metastatic CRPC cannot be recommended.

Neeraj Agarwal, MD: The mechanism of resistance to AR [androgen receptor]–targeted therapy, based on current knowledge, is androgen receptor amplification or androgen receptor mutation, or both. Those remain the most common mechanisms behind resistance to AR-targeted therapy, although we know there are other factors that may come into play, such as upregulation of c-MET or many other signaling pathways like PI3-kinase. There can be aberrations in the PI3-kinase pathway. It can get upregulated. But I think the primary mode of mechanism of resistance remains aberration in AR pathway, either AR amplification or mutation.

Transcript Edited for Clarity
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Transcript: 

Ulka Vaishampayan, MD: The definition of castrate resistant disease is when the testosterone is suppressed but the disease is progressing. Conventionally, we use serum testosterone of 50 ng/dL or less as to be considered castrate levels of testosterone. If you have the patient continued on androgen deprivation therapy—typically what we use is the LHRH [luteinizing hormone-releasing hormone] analogs for this—and their disease is progressing either by PSA [prostate-specific antigen] progression or new areas of disease symptoms, etcetera, that is considered castrate resistant disease.

A number of treatments in metastatic prostate cancer have at least been evaluated in parallel. We don’t have very good comparison trials. Most of the studies have compared the novel agents to placebo and shown efficacy that way. We don’t have direct head-to-head comparison trials, in general because the mechanisms of action of each of these agents are different. It does make sense to think about the patient’s circumstances, the sites of metastases, the type of progression, and the symptoms, and then arrive at a decision point as to which treatment to pick for the patient at the right time. Chances are you will be able to sequence from one treatment to another, but ideally you want to try and minimize toxicity and still get that survival benefit in when you are picking or choosing a therapy in CRPC.

In terms of layering treatment, there is very minimal evidence for combination treatments in metastatic CRPC. What evidence we do have so far suggests that layering treatments is not a good idea, except along with LHRH analogue therapies. All our treatments in metastatic CRPC have been evaluated by adding them on to androgen deprivation therapy, or LHRH analogue therapy. I think at a minimum, that will continue as a baseline treatment, and any other treatment is added or layered on top. But with 2 different treatment approaches in metastatic CRPC, regarding whether or not to combine them and add them on top of one another, the small evidence that we do have of combining abiraterone and radium-223 shows that there is a higher risk of fractures and no improved efficacy. At this point, layering 2 different treatments in metastatic CRPC cannot be recommended.

Neeraj Agarwal, MD: The mechanism of resistance to AR [androgen receptor]–targeted therapy, based on current knowledge, is androgen receptor amplification or androgen receptor mutation, or both. Those remain the most common mechanisms behind resistance to AR-targeted therapy, although we know there are other factors that may come into play, such as upregulation of c-MET or many other signaling pathways like PI3-kinase. There can be aberrations in the PI3-kinase pathway. It can get upregulated. But I think the primary mode of mechanism of resistance remains aberration in AR pathway, either AR amplification or mutation.

Transcript Edited for Clarity
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