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The Future of Treatment for Nonmetastatic CRPC

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: Thursday, Jan 25, 2018



Transcript: 

Charles J. Ryan, MD: Nonmetastatic castration-resistant prostate cancer has been a problem for physicians because we wanted to intervene with the newer therapies that we have, but in some cases, we haven’t had the regulatory approval to do so. Payers have, in some cases, said it’s not appropriate to treat that. But once we have data that show that we can improve metastasis-free survival in nonmetastatic patients, and once we can show that there’s a clinical benefit associated with treating it in that clinical state, I think we will all be very gratified that we have an option to give to our patients.

Judd W. Moul, MD: One of the things that may affect M0 CRPC is better imaging. The trials that we talked about were all done with classic traditional imaging, meaning if a patient did not have metastases seen on a bone scan or the patient didn’t have metastases seen on a CAT scan, they were deemed to be nonmetastatic. At the same time, for these new drugs are potentially coming online for M0 CRPC, we have novel PET scans that are now coming online that supposedly do a better job of picking up early metastasis.

One of the things that we have to watch out for is, will the M0 category of patients shrink as these more effective imaging agents come online? How will that affect the use of enzalutamide and apalutamide, and potentially darolutamide, in the future?

Beyond these oral antiandrogens, the other exciting thing is molecular signatures and recognizing that prostate cancer, advanced prostate cancer, is probably a multitude of diseases and is eventually going to be defined by its molecular genetics. As an example, a couple of really hot papers have come out in the last couple of years. One showing that about 12% of men presenting with metastatic prostate cancer actually had hereditary mutations in key driver genes. In plain English, for up to almost 1 out of 7 patients who presents at our doorstep with metastatic prostate cancer, their prostate cancer may be caused by a hereditary mutation.

Some of those genes include the BRCA genes that are widely known and used in breast cancer and ovarian cancer. And to follow up on that further, in some patients, they have these BRCA mutations. Interestingly, the PARP inhibitors, which are now used in ovarian and breast cancer, and also effective in prostate cancer. So, that’s the first proof of principle that molecular genetics in prostate cancer can actually make a difference in therapeutics. If it wasn’t for those molecular discoveries, who would have ever even imagined that a drug used in breast cancer and ovarian cancer to treat a BRCA-positive woman would have any bearing on prostate cancer?

And so, it’s the first example of really exciting times, and I would imagine that 10, 15, or 20 years from now we’ll probably still be using hormonal therapy and androgen deprivation therapy as our backbone therapy for advanced prostate cancer. But at that point, we’ll probably be layering in many more novel pharmacologic agents based on the molecular signature of that cancer.

Julie Graff, MD: There are other drugs in development for metastatic castration-resistant prostate cancer. One of the hot areas is PARP inhibitors. For those patients with prostate cancer who have metastatic castration-resistant prostate cancer where their tumor expresses DNA repair defects, they may be getting PARP inhibitors, which are drugs already approved in the ovarian cancer setting. So, if a cancer cell is missing BRCABRCA1 or BRCA2—or ATM, it can’t repair double-strand breaks very efficiently. And then you throw in a PARP inhibitor, which blocks another pathway of repairing double-strand DNA breaks, and the cancer cell dies.

That’s an area that’s being actively explored at this point, and it’s possible that it, too, will move up earlier in the disease. I myself am doing studies of checkpoint inhibition with pembrolizumab, which is a PD-1 inhibitor. We’re learning more about the genetic instability of these tumors. Not all prostate cancer patients have a multi-mutated tumor, but for those who do, PD-1 inhibition might be effective.

There are also other studies of alpha particles. Radium-223 is currently approved for people with symptomatic skeletal tumors, but it only goes to the bone. And there are many agents in development, like actinium-225 or lutetium-177, that can attack tumors outside of the bone. So, we’ll see more movement in intravenous radiopharmaceuticals.

I am most looking forward to curing some of my patients. I think that’s on the horizon, either with new treatments, combinations of current treatments, better understanding the patient’s biology, or setting the bar even higher for our clinical trials. Not just helping people live 3 months longer, but actually wiping out this disease: that’s what I’m most hopeful for.

Transcript Edited for Clarity 
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Transcript: 

Charles J. Ryan, MD: Nonmetastatic castration-resistant prostate cancer has been a problem for physicians because we wanted to intervene with the newer therapies that we have, but in some cases, we haven’t had the regulatory approval to do so. Payers have, in some cases, said it’s not appropriate to treat that. But once we have data that show that we can improve metastasis-free survival in nonmetastatic patients, and once we can show that there’s a clinical benefit associated with treating it in that clinical state, I think we will all be very gratified that we have an option to give to our patients.

Judd W. Moul, MD: One of the things that may affect M0 CRPC is better imaging. The trials that we talked about were all done with classic traditional imaging, meaning if a patient did not have metastases seen on a bone scan or the patient didn’t have metastases seen on a CAT scan, they were deemed to be nonmetastatic. At the same time, for these new drugs are potentially coming online for M0 CRPC, we have novel PET scans that are now coming online that supposedly do a better job of picking up early metastasis.

One of the things that we have to watch out for is, will the M0 category of patients shrink as these more effective imaging agents come online? How will that affect the use of enzalutamide and apalutamide, and potentially darolutamide, in the future?

Beyond these oral antiandrogens, the other exciting thing is molecular signatures and recognizing that prostate cancer, advanced prostate cancer, is probably a multitude of diseases and is eventually going to be defined by its molecular genetics. As an example, a couple of really hot papers have come out in the last couple of years. One showing that about 12% of men presenting with metastatic prostate cancer actually had hereditary mutations in key driver genes. In plain English, for up to almost 1 out of 7 patients who presents at our doorstep with metastatic prostate cancer, their prostate cancer may be caused by a hereditary mutation.

Some of those genes include the BRCA genes that are widely known and used in breast cancer and ovarian cancer. And to follow up on that further, in some patients, they have these BRCA mutations. Interestingly, the PARP inhibitors, which are now used in ovarian and breast cancer, and also effective in prostate cancer. So, that’s the first proof of principle that molecular genetics in prostate cancer can actually make a difference in therapeutics. If it wasn’t for those molecular discoveries, who would have ever even imagined that a drug used in breast cancer and ovarian cancer to treat a BRCA-positive woman would have any bearing on prostate cancer?

And so, it’s the first example of really exciting times, and I would imagine that 10, 15, or 20 years from now we’ll probably still be using hormonal therapy and androgen deprivation therapy as our backbone therapy for advanced prostate cancer. But at that point, we’ll probably be layering in many more novel pharmacologic agents based on the molecular signature of that cancer.

Julie Graff, MD: There are other drugs in development for metastatic castration-resistant prostate cancer. One of the hot areas is PARP inhibitors. For those patients with prostate cancer who have metastatic castration-resistant prostate cancer where their tumor expresses DNA repair defects, they may be getting PARP inhibitors, which are drugs already approved in the ovarian cancer setting. So, if a cancer cell is missing BRCABRCA1 or BRCA2—or ATM, it can’t repair double-strand breaks very efficiently. And then you throw in a PARP inhibitor, which blocks another pathway of repairing double-strand DNA breaks, and the cancer cell dies.

That’s an area that’s being actively explored at this point, and it’s possible that it, too, will move up earlier in the disease. I myself am doing studies of checkpoint inhibition with pembrolizumab, which is a PD-1 inhibitor. We’re learning more about the genetic instability of these tumors. Not all prostate cancer patients have a multi-mutated tumor, but for those who do, PD-1 inhibition might be effective.

There are also other studies of alpha particles. Radium-223 is currently approved for people with symptomatic skeletal tumors, but it only goes to the bone. And there are many agents in development, like actinium-225 or lutetium-177, that can attack tumors outside of the bone. So, we’ll see more movement in intravenous radiopharmaceuticals.

I am most looking forward to curing some of my patients. I think that’s on the horizon, either with new treatments, combinations of current treatments, better understanding the patient’s biology, or setting the bar even higher for our clinical trials. Not just helping people live 3 months longer, but actually wiping out this disease: that’s what I’m most hopeful for.

Transcript Edited for Clarity 
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