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Early Treatment Approaches in Prostate Cancer

Panelists:Raoul S. Concepcion, MD, FACS, Urology Associates; Michael D. Fabrizio, MD, FACS, Eastern Virginia Medical School; Jorge A. Garcia, MD, FACP, Taussig Cancer Institute; Judd W. Moul, MD, FACS, Duke University Medical Center; Charles J. Ryan, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Sunday, Jan 24, 2016



Transcript:

Raoul S. Concepcion, MD, FACS:
As medical oncologists, we’re the ones following patients. We’ve ushered them through therapy. We started, as you appropriately mentioned, Judd, LHRH therapy very, very early. And I think what gets lost on urologists is many of these patients are ECOG 0s and 1s, they’re asymptomatic, especially those who are pre-chemotherapy. The median survival in the control arm for COUGAR 302 is approximately 31 months?

Charles J. Ryan, MD: Yeah, yeah.

Raoul S. Concepcion, MD, FACS: I think the audience needs to understand that there’s a limited survival benefit.

Charles J. Ryan, MD: I also look at it this way, and, in fact, we’ve presented this idea of a prognostic index model from 302. And it’s fairly intuitive. There’s a wide range of people going on to 302, ranging from patients with PSAs in the 200 range with elevations of their alkaline phosphatase and 12-bone metastasis, to people with PSAs of 10 with 3-bone metastasis. And it’s fairly intuitive.

But if you look at the more advanced patients, the survival was shorter, but the response proportion was lower, the hazard ratio was lower, and they were more likely to go on and develop symptoms earlier. And there’s this broad window of chemotherapy-naive castration-resistant prostate cancer (CRPC). And the data seemed to continue to come back to say that the earlier the intervention, the better. And if you’re waiting for a patient to suffer and have pain or complications, you’re waiting too long. So the idea is start them before they get to that risk.

Jorge A. Garcia, MD, FACP: What is unique about that is the fact that if you look at the entry criteria for both PREVAIL and COUGAR 302, for patients without symptoms or with minimal symptomatic disease, the NCCN Guidelines broadened that to include treating symptomatic patients, for which I would argue that we don’t have to.

I think most of us clinically think it is appropriate to actually use an oral agent in that symptomatic patient. But we don’t have true data as to how those patients do over time. If you look at your nomogram, it’s the same features that we have seen with MD Anderson’s nomograms looking at LDH and so forth.

The only difference with these nomograms is the Brief Pain Inventory (BPI) score, which is hard to do in the clinic sometimes because we just simply gauge how much pain are you having and we decide whether or not it’s actually enough for us to treat with an oral agent or move into chemotherapy.

Charles J. Ryan, MD: The BPI score for the 302 patients, they had to have a 0 or 1. And even those with minimal pain had a worse outcome than those with zero pain.

Jorge A. Garcia, MD, FACP: Correct.

Judd W. Moul, MD, FACS: Quick question. Both of you talked about the challenge, the three-month or the eight-week challenge with the oral therapies, assess at 12 weeks and then discontinue at 12 weeks. Why not throw in six cycles of docetaxel right at that point, a la CHAARTED or STAMPEDE? Is that being tested?

Jorge A. Garcia, MD, FACP: If you go back in history, when docetaxel was approved in the United States, the SWOG 9916 and the TAX 327 trials specifically stated that you can receive chemotherapy if you have metastatic hormone-refractory disease with or without symptoms. And one of the caveats of that data is that when you look at the long-term follow-up, 80% of patients who actually had no symptoms whatsoever went on to get docetaxel, 30% of those patients were alive seven years later.

So there was a concern that maybe we were waiting too long to treat patients with chemotherapy and perhaps then asymptomatic patients should actually also get chemotherapy. And, the question that we have at the time is how can I change your quality of life so drastically, there is no data as to what is the best time for chemotherapy. However, I changed over the last two to three years because of the data with early chemotherapy.

It is possible that if indeed chemotherapy can be given earlier to a very selective group of patients, your outcome is likely to do better than if you wait until someone has a lot of symptoms. Time to progression will be shorter when you start someone at that time. So I think that in the context of castration-resistant disease, I don’t think you need to wait for having someone with a lot of symptoms to start chemotherapy.

But I would argue that clinically speaking, if you compare an oral agent with chemotherapy, most men in America will get to an oral agent before chemotherapy.

Charles J. Ryan, MD: I would say that given the number of available therapies we have, it’s never appropriate to wait for symptoms any more.

Jorge A. Garcia, MD, FACP: Correct, exactly.

Charles J. Ryan, MD: And I want to make another point about the TAX 327, which was if you look at the hazard ratio for survival in the symptomatic group versus the asymptomatic group, the hazard ratio for survival was not significant in the symptomatic group.

Jorge A. Garcia, MD, FACP: Correct.

Charles J. Ryan, MD: Over mitoxantrone. That again points to that being a later event.

Raoul S. Concepcion, MD, FACS: Mike, have you found it difficult to get your partners, to get off that mindset of, oh, they have to have symptoms before I even start looking, let alone treating?

Michael Fabrizio, MD, FACS: Yes. I think the last six months have made it a lot easier, with the CHAARTED and STAMPEDE trials, to get these patients chemotherapy earlier. And now we are absolutely treating these patients earlier, but all of these drugs need to be used earlier in the spectrum of the disease.

Raoul S. Concepcion, MD, FACS: Right, and I think in the following segments we’re going to stress the point that you were exactly making, Chuck, is the concept of treating early, vis-a-vis lower PSAs, lower volume of disease. Hopefully those patients should do better clinically with an increased survival.

Michael Fabrizio, MD, FACS: Staying with chemo for just a second though, one of the problems is we don’t really have a great definition of when to start. Do you start it with four mets or with the entire pelvis being eaten up? Is that actually a single met or is that an entire system that’s affected? I think we need to define those a little bit better because I think it’s very confusing not just for the medical oncologists but certainly for the urologist to know when to get these patients to chemotherapy earlier.

Raoul S. Concepcion, MD, FACS: Exactly, exactly.

Jorge A. Garcia, MD, FACP: Just to interject for a second, if you actually look at the impact of having one bone met with regards to mortality and subsequent skeletal-related events, it’s huge. So, if you have metastatic disease, you’re destined to have prostate cancer. So I don’t think that the concept of waiting until you have more disease is really reasonable today.

If you look at the European data prior to all the oral agents that we have, 5% of patients who have bone metastasis independent of volume were actually alive at five years. So 95% of patients died within those five years. If you now look at the data in America, it goes up around 28% or so. But just imagine telling that 55-year-old guy, I’m going to put you on an oral agent whose median survival is 35 months. So, as much as we love the oral agents, the median survival of those agents also incorporates subsequent therapy.

I think there’s a misconception out there with patients that say, oh, the next miracle agent is going to drive my PSA to zero and I’m almost cured and the reality of it is no. Even those patients still have a median survival that is limited, and even though it is a great therapy, you have to incorporate the subsequent therapy into that equation.

So I actually have changed how I speak to my patients about that because I had a patient of mine who was very excited about therapy and then he asked me for the publication and I gave it to him. And he almost fell. You’re telling me that with this agent, even though my PSA is zero now, my median survival is 35 months? And I say yes.

Charles J. Ryan, MD: Well, half of patients lived over 35 months.

Jorge A. Garcia, MD, FACP: Exactly.

Raoul S. Concepcion, MD, FACS: Right.

Charles J. Ryan, MD: There’s a wide range of outcomes that patients need to be aware of.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity

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Transcript:

Raoul S. Concepcion, MD, FACS:
As medical oncologists, we’re the ones following patients. We’ve ushered them through therapy. We started, as you appropriately mentioned, Judd, LHRH therapy very, very early. And I think what gets lost on urologists is many of these patients are ECOG 0s and 1s, they’re asymptomatic, especially those who are pre-chemotherapy. The median survival in the control arm for COUGAR 302 is approximately 31 months?

Charles J. Ryan, MD: Yeah, yeah.

Raoul S. Concepcion, MD, FACS: I think the audience needs to understand that there’s a limited survival benefit.

Charles J. Ryan, MD: I also look at it this way, and, in fact, we’ve presented this idea of a prognostic index model from 302. And it’s fairly intuitive. There’s a wide range of people going on to 302, ranging from patients with PSAs in the 200 range with elevations of their alkaline phosphatase and 12-bone metastasis, to people with PSAs of 10 with 3-bone metastasis. And it’s fairly intuitive.

But if you look at the more advanced patients, the survival was shorter, but the response proportion was lower, the hazard ratio was lower, and they were more likely to go on and develop symptoms earlier. And there’s this broad window of chemotherapy-naive castration-resistant prostate cancer (CRPC). And the data seemed to continue to come back to say that the earlier the intervention, the better. And if you’re waiting for a patient to suffer and have pain or complications, you’re waiting too long. So the idea is start them before they get to that risk.

Jorge A. Garcia, MD, FACP: What is unique about that is the fact that if you look at the entry criteria for both PREVAIL and COUGAR 302, for patients without symptoms or with minimal symptomatic disease, the NCCN Guidelines broadened that to include treating symptomatic patients, for which I would argue that we don’t have to.

I think most of us clinically think it is appropriate to actually use an oral agent in that symptomatic patient. But we don’t have true data as to how those patients do over time. If you look at your nomogram, it’s the same features that we have seen with MD Anderson’s nomograms looking at LDH and so forth.

The only difference with these nomograms is the Brief Pain Inventory (BPI) score, which is hard to do in the clinic sometimes because we just simply gauge how much pain are you having and we decide whether or not it’s actually enough for us to treat with an oral agent or move into chemotherapy.

Charles J. Ryan, MD: The BPI score for the 302 patients, they had to have a 0 or 1. And even those with minimal pain had a worse outcome than those with zero pain.

Jorge A. Garcia, MD, FACP: Correct.

Judd W. Moul, MD, FACS: Quick question. Both of you talked about the challenge, the three-month or the eight-week challenge with the oral therapies, assess at 12 weeks and then discontinue at 12 weeks. Why not throw in six cycles of docetaxel right at that point, a la CHAARTED or STAMPEDE? Is that being tested?

Jorge A. Garcia, MD, FACP: If you go back in history, when docetaxel was approved in the United States, the SWOG 9916 and the TAX 327 trials specifically stated that you can receive chemotherapy if you have metastatic hormone-refractory disease with or without symptoms. And one of the caveats of that data is that when you look at the long-term follow-up, 80% of patients who actually had no symptoms whatsoever went on to get docetaxel, 30% of those patients were alive seven years later.

So there was a concern that maybe we were waiting too long to treat patients with chemotherapy and perhaps then asymptomatic patients should actually also get chemotherapy. And, the question that we have at the time is how can I change your quality of life so drastically, there is no data as to what is the best time for chemotherapy. However, I changed over the last two to three years because of the data with early chemotherapy.

It is possible that if indeed chemotherapy can be given earlier to a very selective group of patients, your outcome is likely to do better than if you wait until someone has a lot of symptoms. Time to progression will be shorter when you start someone at that time. So I think that in the context of castration-resistant disease, I don’t think you need to wait for having someone with a lot of symptoms to start chemotherapy.

But I would argue that clinically speaking, if you compare an oral agent with chemotherapy, most men in America will get to an oral agent before chemotherapy.

Charles J. Ryan, MD: I would say that given the number of available therapies we have, it’s never appropriate to wait for symptoms any more.

Jorge A. Garcia, MD, FACP: Correct, exactly.

Charles J. Ryan, MD: And I want to make another point about the TAX 327, which was if you look at the hazard ratio for survival in the symptomatic group versus the asymptomatic group, the hazard ratio for survival was not significant in the symptomatic group.

Jorge A. Garcia, MD, FACP: Correct.

Charles J. Ryan, MD: Over mitoxantrone. That again points to that being a later event.

Raoul S. Concepcion, MD, FACS: Mike, have you found it difficult to get your partners, to get off that mindset of, oh, they have to have symptoms before I even start looking, let alone treating?

Michael Fabrizio, MD, FACS: Yes. I think the last six months have made it a lot easier, with the CHAARTED and STAMPEDE trials, to get these patients chemotherapy earlier. And now we are absolutely treating these patients earlier, but all of these drugs need to be used earlier in the spectrum of the disease.

Raoul S. Concepcion, MD, FACS: Right, and I think in the following segments we’re going to stress the point that you were exactly making, Chuck, is the concept of treating early, vis-a-vis lower PSAs, lower volume of disease. Hopefully those patients should do better clinically with an increased survival.

Michael Fabrizio, MD, FACS: Staying with chemo for just a second though, one of the problems is we don’t really have a great definition of when to start. Do you start it with four mets or with the entire pelvis being eaten up? Is that actually a single met or is that an entire system that’s affected? I think we need to define those a little bit better because I think it’s very confusing not just for the medical oncologists but certainly for the urologist to know when to get these patients to chemotherapy earlier.

Raoul S. Concepcion, MD, FACS: Exactly, exactly.

Jorge A. Garcia, MD, FACP: Just to interject for a second, if you actually look at the impact of having one bone met with regards to mortality and subsequent skeletal-related events, it’s huge. So, if you have metastatic disease, you’re destined to have prostate cancer. So I don’t think that the concept of waiting until you have more disease is really reasonable today.

If you look at the European data prior to all the oral agents that we have, 5% of patients who have bone metastasis independent of volume were actually alive at five years. So 95% of patients died within those five years. If you now look at the data in America, it goes up around 28% or so. But just imagine telling that 55-year-old guy, I’m going to put you on an oral agent whose median survival is 35 months. So, as much as we love the oral agents, the median survival of those agents also incorporates subsequent therapy.

I think there’s a misconception out there with patients that say, oh, the next miracle agent is going to drive my PSA to zero and I’m almost cured and the reality of it is no. Even those patients still have a median survival that is limited, and even though it is a great therapy, you have to incorporate the subsequent therapy into that equation.

So I actually have changed how I speak to my patients about that because I had a patient of mine who was very excited about therapy and then he asked me for the publication and I gave it to him. And he almost fell. You’re telling me that with this agent, even though my PSA is zero now, my median survival is 35 months? And I say yes.

Charles J. Ryan, MD: Well, half of patients lived over 35 months.

Jorge A. Garcia, MD, FACP: Exactly.

Raoul S. Concepcion, MD, FACS: Right.

Charles J. Ryan, MD: There’s a wide range of outcomes that patients need to be aware of.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
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