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How Is the Prostate Cancer Treatment Landscape Evolving?

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Published on November 11, 2019

Prostate cancer expert Dr. Christopher Sweeney, from the Dana-Farber Cancer Institute, shares the latest advances in treatment research for prostate cancer. Watch as Dr. Sweeney gives an in-depth look at approved therapies and emerging treatments for various stages of prostate cancer, and describes the movement of drugs from the late stage setting to the early stage setting. Dr. Sweeney also discusses factors to consider when choosing the best course of care for individual patients.

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Thanks so much for sharing this event online. I just started my third year of fighting advanced prostate cancer and the content of this event is really encouraging.

— Ken, via Facebook

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Transcript |

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That's how you’ll get care that's most appropriate for you.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrea Hutton:                      

Hello, I’m Andrea Hutton, the community manager for breast and prostate cancer for Patient Power, and we are taking today with Dr. Christopher Sweeney.            

He’s a medical oncologist at the Dana-Farber Cancer Institute in Massachusetts, and we are very lucky to have him with us today talking about advanced prostate cancer. Dr. Sweeney, thank you for joining us.

Dr. Sweeney:             

It’s my pleasure and I have the great opportunity to describe on this Patient Power forum the various advances and progress that we’re making in metastatic prostate  cancer, specifically cancer that has spread from the prostate  to the bones or the lymph nodes and what treatment options  we have and what treatment options may emerge over time.  First of all, let’s have a historic context. For the longest time, patients were treated with just testosterone       suppression or hormonal therapy for metastatic prostate cancer when they start their hormones, and we have had that treatment for about 70 years. 

In about 2004, we then had a new drug that was shown to prolong survival. A drug called docetaxel (Taxotere) for patients who have got cancer growing with a            low testosterone, a condition we call castration-resistant prostate cancer.

A lot of us would like to change that name and we’re working towards that, but that’s what you’ll see the condition of cancer growing on testosterone suppression called. And the one drug we had was docetaxel which modestly prolonged overall survival. Now, fast forward until about 2010. More drugs were developed in the castration-resistant setting and what we learned is that targeting the androgen receptor was able to have men live longer and feel better and these drugs are called abiraterone which blocks extra testicular production of androgen and another drug called enzalutamide (Xtandi).

Various versions of those drugs are also in development and the most recent drug in that class is called darolutamide (Nubeqa).

So, they’re approved to patients with cancer that’s growing on a scan despite a low testosterone where darolutuamide has only been approved for patients who have a rising PSA without any disease on a scan and you might ask how that would happen. So, let’s go back and just go through the different patient journeys. A patient may relapse after their radiational surgery and have a rising PSA and they get put on hormones and they’ve never been found to have cancer on a cat scan or a bone scan. But after variable time which can be three years and sometimes ten years their PSA goes up and that’s a condition called M0CRPC so M0 meaning nothing metastases on a scan and CRPC castration-resistant prostate cancer.

Daralutuamide is approved there and enzalutamide is approved there and another drug called apalutamide (Erleada). So, if you’re reading about new drugs that are emerging for prostate cancer, the M0CRPC; it’s that setting. Rising PSA, put on hormones, second rise with a low testosterone and    these three drugs have been shown to delay progression on a scan quite substantially. So, that’s new area of treatment   that we now have drugs that delay symptoms, delay         progression, and we’re hoping with time we’ll see    prolonged overall survival. So, that’s one recent advance.

But I’m now going to focus on the M1 castration-resistant prostate cancer, mainly the disease seen on a cat scan and again, we have the drug enzalutamide, abiraterone (Zytiga), docetaxel all approved as potential options. The hormones are given to patients that have disease that looks like it’s going to be sensitive to hormone manipulation, but there    are some patients who may have a low PSA, lots of cancer in their liver, and not ones that tend to respond to targeting the androgen receptor and we might reach for chemotherapy as well instead of the hormones. So, when the patient has castration-resistant disease we say, “Do we   think we’ll be able to manage them with another hormone on top of the leuprolide (Lupron) or the goserelin (Zoladex) shots, or should we reach for chemotherapy?”

That’s the state of play. Another drug that has emerged is a drug called Radium and this is for patients who have disease that’s limited to the bones and it’s an injection of radiation by vein and Radium is like calcium on the periodic table if you remember and the Radium deposits where there’s bone turnover, and it emits a small amount of radiation where there’s calcium turning over in the bone metastasis. So, that’s another drug that we have in our armamentarium and oftentimes most patients are treated with a  hormone treatment first for castration-resistant disease; abiraterone (Zytiga) or enzalutamide, have a small amount of progression in their bones.

And if that’s only in their bones, then they’re treated with Radium. But they have more marked progression outside of the bones; we would reach for chemotherapy like docetaxel (Taxotere). This has all emerged since about 2010 and what is emerging in the castration-resistant setting is a couple more advances. One old advance that we use in pretty much safe for the latest age, after patients have had docetaxel is a drug called cabazitaxel (Jevtana). Another             chemotherapy but it has significant clinical benefits and prolongs survival after patients have had docetaxel.

So, that’s the list of all the approved drugs and the clinician has to make a decision between one versus the other based on the patient in front of them and the nature of their cancer and how they responded to their prior therapies. Now, the question is are there new therapies that are emerging in this space? Specifically immune based treatments or the targeted therapies. With regards to the immune treatments; we still have one approved and one agent that is very useful for early castration-resistant prostate cancer called sipuleucel-T (Provenge), and that is a drug that should be used early. It doesn’t debunk the disease but it may make the cancer more susceptible to future treatments and prolong survival by juicing up the patient’s immune system.

A lot to be said about that drug. A lot has changed since it was approved, but it was definitely one of the immune options. The other immune options that is proven to work    in melanoma and kidney and bladder cancer have not proven to work in prostate cancer. The PDL-1 inhibitors, the CTLA-4 inhibitors, and similar agents. They have been    evaluated. Some patients have responded but not enough or the studies are too early to say that it is a standard of care.            It’s still very experimental to use the PDL-1 inhibitors, the PD-1 inhibitors, the CTLA-4 inhibitors in prostate cancer.

Where there’s much more promise is the PARP inhibitors. More and more data is emerging that patients who have a  BRCA-1 or BRCA-2 defect have a substantial chance of a good response to a PARP inhibitor. We’ve seen it with olaporib (Lynparza) and similar drugs are being developed in that space as well and with the FDA and hopefully will be able  to be prescribed maybe in the next six months or so but  don’t hold me to that. So, that’s targeted therapy for patients who have a specific mutation.

There is a suggestion that patients who  have a mutation in CDK-12 or marked instability may be candidates for the PD-1 or PDL-1 inhibitors but that’s a            unique group so I’ll just say targeted therapy pairing with immune therapy may be an option for some patients, but it’s a small number of the total patients.

Now, the other major therapy that’s being developed with   some promise is another radiology and, namely a medication  that is made into an injection and there’s a protein called PSMA which is on the tumors and an antibody can recognize the PSMA and it’s coming along and binding to   the PSMA. It has a little bit of radiation called letetium.  So, it’s given by vein and it travels through the body and if the PSMA is present and the tumor is responsive to the radiation; it may shrink. So, there’s been in the early stage   evaluation there have been substantial responses in some patients and the drug has been much more widely available in Australia and in Germany, and some very promising results have been pushed forward and presented and that’s now in a randomized phase three study for the first-time global study.

And then the Australians are doing a comparison study between letetium PSMA and cabazitaxel, that chemotherapy I mentioned earlier. That’s a long way off     for it to be standard of care. The study has just been completed. Even if this study isn’t the perfect study; it is hopeful that it will have enough of a survival benefit that it gets approved and our job will be to work at who are the     patients who actually benefit from that. So, I’ve been talking about the castration-resistant setting and that has two key words in it. It’s castration, namely growing with low testosterone and the resistant setting.

You’re probably naturally asking about, “Well, what if it works somewhat in the resistant setting, what about taking it back to the hormone sensitive setting?” Because the timelines are longer and the pharmaceutical industry need to get their drugs approved in a reasonable time frame; they get evaluated first in the late stage setting and a number of us in the cooperative groups have started to do studies in the hormone-sensitive setting where the studies take longer.

But having shown some benefit there, the pharmaceutical industry is now starting to do studies in that setting as well.  And the first study that came out and showed that using a drug in the late stage setting called docetaxel – if you move it to the earlier setting, metastatic hormone sensitive, it is clear that patients who have a rapidly progressive disease of cancer that when first diagnosed is found to be in the bones and there are a number of bony metastases, patients who get docetaxel in that setting have a marked survival benefit rather than using it later in the disease when they’re resistant.

 

So, there are two studies that were positive in that setting.  One called CHAARTED run by the Eastern Cooperative Oncology Group, an NCI sponsored study. So, your taxpayer dollars at work doing clinical trials. Another one was a UK-based study called STAMPEDE that showed the drug works in the more rapidly progressive patients and that was proven and shown in about 2015. I also mentioned the drug abiraterone which was shown to work in late stage disease  castration-resistant. It too has been evaluated in hormone-sensitive prostate cancer with disease that’s on the scans but just starting the testosterone suppression. And that too has been shown to prolong survival more than using it later rather than just adding it on later and delaying the time to    progression and substantial improvements.

And in both settings I would say these patients who have the high volume to metastatic. We talk about the chance of being alive on average – let’s keep it simple, at three years going from about 50 percent to 70 percent which is quite substantial. Not good enough. And these are in the patients who have the poorest prognosis who need the most improvements but that’s a good start. The benefit seems to be less but there still seems to be a benefit for patients who have a lower burden of disease who have basically about an 80 percent chance of being alive on just the hormones alone at three years. Then we’re improving their numbers a little bit up to 85, maybe 90 percent at three years so a benefit with abiraterone in both groups, the high volume and the low volume.

The docetaxel benefits seem to be really only in the patients with a higher volume. Now, the next question is, “Well, what about these other drugs I mentioned?”  Enzalutamide and apalutamide have just completed studies under review by the FDA for the hormone sensitive and they too prolong the early survival with patients with high volume and low volume metastatic disease that’s seen on    the scans for the first time and starting testosterone             suppression.

And I’m very sure there are people that are asking the question, “Well, what about adding docetaxel plus one of these new drugs, enzalutamide or apalutamide?” The only   study that has looked at that to some degree is a study called ENZAMET which I should declare I was one of the lead investigators of both the CHAARTED study and the ENZAMET study so that’s declaring it so while I’m talking about them. And they are both investigator sponsored which means we as a cooperative group receive the drug and the funding from the pharmaceutical industry and government funding support and run the trials          independently so I’m very close to this data.

And what we saw is that the docetaxel plus the enzalutamide plus the testosterone suppression delayed the time to progression but it didn’t improve the overall survival of giving say testosterone suppression plus docetaxel and then adding enzalutamide when a patient is    progressing. So, when a patient now presents to a doctor with metastatic hormone sensitive prostate cancer; I think    it’s very fair that they be assessed to whether they have a high burden of cancer or a lower burden of cancer, what their sickness is. Are they someone who can tolerate chemotherapy? And in that case I would give a dose of        chemotherapy, a course of the chemotherapy with the testosterone suppression decreasing the testosterone continuously and then when progressing adding these other drugs on.

Or you can do the testosterone suppression plus the new hormone and then add the docetaxel. Both have pros and cons but if you’re not chemotherapy fit, the options are testosterone suppression plus the drug enzalutamide, abiraterone, or apalutamide and it depends on your   insurance, your co-pays, and being able to have access to these new drugs if you’re in the United States. So, right now in 2019, there’s a lot of movement of drugs from the late stage setting to the early stage setting. Patients are living longer based on the results from the clinical trials and the clinicians and the patients have more choices on how to choose which treatment and when.

So, we’ve made a lot of advances and we will make more advances because we’re getting the tissues from these patients and trying to work out what are the biological causes of the resistance and develop new therapies against those resistance mechanisms. So, I hope is a 20 minute primer on many years of work and many clinical trials, and I thank everyone for their attention.

Andrea Hutton:                      

Thank you so much, Dr. Sweeney. That was incredibly informative and very much appreciated. I just have one additional question. If a patient does not live close to a center of excellence and maybe is in a community doctor setting, how familiar do you think these new drugs are to the doctors in the community hospital settings outside of where you are?

Dr. Sweeney:             

That’s a really really good question. So, many urologists may not be aware of this because they may not see the patients for the metastatic disease often and they go to their tried true and tested of just the testosterone suppression alone. So, I think as much information as we can go do   through education events directly to doctors, but I think also patients being aware of the options and taking those options and saying to their urologists who often are at the forefront of the metastatic hormone sensitive, “What about this option?” And just having them think through that option with them and so I think it’s very fair for the patients to take knowledge that they gain to their physician and just say, “Do you think this is right for me?”     

Andrea Hutton:                      

Great. Thank you so much.

Dr. Sweeney:             

You’re welcome.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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