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Nonmetastatic CRPC: Considerations for Apalutamide

Insights From: Julie Graff, MD, Oregon Health and Science University; Judd W. Moul, MD, Duke University Medical Center; Charles J. Ryan, MD, UCSF Helen Diller Comprehensive Cancer Center
Published: Wednesday, Jan 10, 2018



Transcript: 

Judd W. Moul, MD: The safety profile for apalutamide is good. It’s at least comparable to the other agents in this space. In the phase II trial, less than 20% of patients had to be discontinued from the drug due to side effects. One of the concerns that we have with this class of drugs, be it apalutamide or enzalutamide, or bicalutamide for that matter, is the issue with crossing the blood brain barrier. That leads to potential falls and even, in the severe case, seizures.

Fortunately, in the apalutamide trials, to my knowledge, there have been no seizures related to use of apalutamide and the fall risk has been very manageable, less than 15% or 20%. And most of those have been very minor falls. There were very, very few grade 4 or 5 significant falls with the use of apalutamide in the SPARTAN Trial. And that’s significant, because we definitely need drugs in this space to treat our patients with M0 CRPC, but yet these patients are still, for the most part, in excellent health with good performance status. We need a drug that’s safe.

Fortunately, these patients will likely be alive and well for quite a number of years. We certainly don’t want to give them a drug that’s going to have a lot of toxicity. Other side effects that were sometimes seen included diarrhea. I think that occurred in about 20% to 30% of the patients. Again, that was relatively mild and not a major problem.

Apalutamide is given at a dose of 240 mg orally once a day. That is the dose that was used in the phase III trials, and I’m assuming that would be the commercially available dose once the drug is cleared by the FDA. The clinical significance is great because this is the first drug to get to this point with the FDA as far as asking for official regulatory approval for M0 CRPC in the setting of these novel oral anti-androgens. Prior to this, there had been a number of bone-targeted agents that were a different class of drugs, and we were trying to see if that class of drugs would delay metastases in M0 CRPC. Those drugs did not reach significance to achieve FDA approval.

So apalutamide, by getting to the point where it delayed clinical metastases, is the first drug to get to this point with the FDA. As a clinician in the trenches who takes care of a lot of men with advanced prostate cancer, this would be a significant advance because it would be first time that I’ve had a new agent in my toolbox to use for M0 CRPC.

Speaking as a urologist, many of these patients are still in the urology practice. They are patients who we treated for a localized disease, they’ve been patients who we have placed on traditional androgen deprivation therapy, and they’re still being followed by us. And so, to have a novel oral agent, such as apalutamide, be approved for M0 CRPC where I would be able to use that as a urologist, that would be a great thing.

Julie Graff, MD: I think the approval of apalutamide will lead us to move the second-generation androgen receptor antagonists earlier in the treatment of prostate cancer. At this time, in the United States at least, we have to wait until there’s a lesion that we can see on a radiograph. I do know that other countries are able to use these drugs sooner, but I believe that most countries cannot. So, we’ll start using our androgen receptor antagonists earlier, and then we’ll reserve our chemotherapy and other drugs for later on in the disease course.  

Transcript Edited for Clarity 
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Transcript: 

Judd W. Moul, MD: The safety profile for apalutamide is good. It’s at least comparable to the other agents in this space. In the phase II trial, less than 20% of patients had to be discontinued from the drug due to side effects. One of the concerns that we have with this class of drugs, be it apalutamide or enzalutamide, or bicalutamide for that matter, is the issue with crossing the blood brain barrier. That leads to potential falls and even, in the severe case, seizures.

Fortunately, in the apalutamide trials, to my knowledge, there have been no seizures related to use of apalutamide and the fall risk has been very manageable, less than 15% or 20%. And most of those have been very minor falls. There were very, very few grade 4 or 5 significant falls with the use of apalutamide in the SPARTAN Trial. And that’s significant, because we definitely need drugs in this space to treat our patients with M0 CRPC, but yet these patients are still, for the most part, in excellent health with good performance status. We need a drug that’s safe.

Fortunately, these patients will likely be alive and well for quite a number of years. We certainly don’t want to give them a drug that’s going to have a lot of toxicity. Other side effects that were sometimes seen included diarrhea. I think that occurred in about 20% to 30% of the patients. Again, that was relatively mild and not a major problem.

Apalutamide is given at a dose of 240 mg orally once a day. That is the dose that was used in the phase III trials, and I’m assuming that would be the commercially available dose once the drug is cleared by the FDA. The clinical significance is great because this is the first drug to get to this point with the FDA as far as asking for official regulatory approval for M0 CRPC in the setting of these novel oral anti-androgens. Prior to this, there had been a number of bone-targeted agents that were a different class of drugs, and we were trying to see if that class of drugs would delay metastases in M0 CRPC. Those drugs did not reach significance to achieve FDA approval.

So apalutamide, by getting to the point where it delayed clinical metastases, is the first drug to get to this point with the FDA. As a clinician in the trenches who takes care of a lot of men with advanced prostate cancer, this would be a significant advance because it would be first time that I’ve had a new agent in my toolbox to use for M0 CRPC.

Speaking as a urologist, many of these patients are still in the urology practice. They are patients who we treated for a localized disease, they’ve been patients who we have placed on traditional androgen deprivation therapy, and they’re still being followed by us. And so, to have a novel oral agent, such as apalutamide, be approved for M0 CRPC where I would be able to use that as a urologist, that would be a great thing.

Julie Graff, MD: I think the approval of apalutamide will lead us to move the second-generation androgen receptor antagonists earlier in the treatment of prostate cancer. At this time, in the United States at least, we have to wait until there’s a lesion that we can see on a radiograph. I do know that other countries are able to use these drugs sooner, but I believe that most countries cannot. So, we’ll start using our androgen receptor antagonists earlier, and then we’ll reserve our chemotherapy and other drugs for later on in the disease course.  

Transcript Edited for Clarity 
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