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Melanie Cole (Host): Today, we are examining how men with aggressive prostate cancer may get a new powerful drug option. My guest is Dr. Maha Hussain. She’s the Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Dr. Hussain, please tell us a little bit about yourself and how you came to Northwestern Medicine.

Maha Hussain, MD, FACP, FASCO (Guest): Certainly. So, I am a medical oncologist who started early in my career being fascinated with genitourinary cancers in general and the need to develop better treatments in them. I began focusing on that part of the field and over time, subspecialized in mostly bladder and prostate cancer and prostate being the bulk of the care I am involved in and research. I have been part of many different research that has led to impacting standards of care in this disease and in 2016, I was recruited from the University of Michigan to come to Chicago to join the faculty of the Robert H. Lurie Comprehensive Cancer Center. And here I am.

Host: The Northwestern Medicine Robert H. Lurie Comprehensive Cancer Center was recently rated by the NCI as exceptional. What does that mean overall for the work you are doing?

Dr. Hussain: It means we are awesome. So, specifically, I should explain. This ranking happens because of a peer review by independent scientists and researchers and clinical researchers and administrators that the NCI brings to review the science we are doing, the care we are giving, and we have received fantastic rating and exceptional put us - and the score that we received puts us in the top 5 comprehensive cancer centers with NCI designation in the country. So, we are in the top 5. There are 48 that have NCI comprehensive status designation and we are one of the top 5.

Host: That is awesome Dr. Hussain. And you’ve recently published work in the New England Journal of Medicine that will benefit men with aggressive states of prostate cancer. Explain the initial purpose of this research and the trial design used during the study.

Dr. Hussain: Certainly. So, this is a space that up until 2018, there had not been any impactful treatments that are considered standard of care or FDA approved based on clinical benefits. This is a space of men who you look at them and you cannot tell necessarily they have cancer, but when you actually evaluate them, these are men who have had prostate cancer diagnosis, may have received surgery or radiation with or without hormonal treatments and then developed a rising PSA which is something – it’s a blood biomarker that tells us there is cancer activity. And these men have been on treatment with hormone treatment and what we call castration resistance meaning essentially, they are on treatment that suppresses the testosterone production from the testes, which by default will starve the cancer and yet that treatment was not successful, and their PSA is beginning to go up. So, we know that there is cancer activity and yet you do scans for them, a bone scan, a CAT scan, a PET scan and you do not see visible cancer. So, there is an invisible cancer activity.

This is an area that I would call in prostate cancer an unmet need area and there has not been until recently much research happening in it. So, the trial design was to look at men who specifically had an aggressive form of this type of cancer driven by how rapidly their PSA is going up and they were randomly assigned to get either the active treatment which is the drug enzalutamide or a placebo and then they were monitored for disease progression and looking at also their survival. The early results based on the primary end-point which is disease progression by imaging by bone scan or CAT scan or both demonstrated that there was significant delays in developing visible metastatic disease in this patient population which then led to an FDA approval of enzalutamide in this specific space.

Host: Wow. Please describe for us then, the eligibility requirements for participants. What’s the patient selection criteria for enzalutamide?

Dr. Hussain: Certainly. So, every patient who was included had to have at some point, a pathologic confirmation of prostate cancer. This could have been driven by biopsies of the prostate or surgical removal of the prostate or anything like that. They had to have a testosterone of what we describe in the castration range, and castration range is an FDA defined level which basically is below a certain figure and because then that implies that they are “castration resistant.” They had to be on hormonal therapy with either a gonadal suppressing agent like Lupron or zoladex or something of that sort or have had their testes taken out. They had to have evidence of a rising PSA. PSA is a blood test and sometimes you can see fluctuations with it and so to be sure that we are including a relatively speaking, homogenous cohort; the patients had to have a minimum of three rising PSAs at least a week apart to ensure that the trend is upward and of course, there was minimum PSA required for the study.

The study, on purpose, selected patients in this subgroup of the highest risk and this risk is driven by how rapidly the PSA is doubling and that is a doubling time of ten months basically or less. And this was calculated based on a special formula. And then obviously, the patients had to be fit enough, they had to have had scans to rule out any chance of visible metastatic disease. They had to have no significant comorbidities or problems where the treatments can cause negative drug interactions and things of that sort. And basically, the patients were what we call stratified to make sure that we have equal or representative numbers in both arms. They were stratified by the PSA doubling time of less than six months or six months and greater and whether they have had other bone strengthening medications and then the random assignment was 2:1 which specifically means for every two patients being assigned to the enzalutamide arm, one patient was assigned to the placebo. Both patients and physicians were blinded to what type of medication the patient is getting to make sure that there’s absolutely no bias and that this is a very well-controlled study.

Host: Dr. Hussain, speak about some of the meaningful endpoints of your study. What conclusions would you like other providers to take away from this and what type of patient would benefit as providers are looking to refer patients whose PSA levels might be rising? What would you like them to know about this?

Dr. Hussain: Well I think the first thing to understand that an invisible cancer does not kill. Okay so this is really a message to the patients and obviously the physicians know that, but the bottom line is this. A cancer that is not visible, even if the PSA is 500; it doesn’t kill. It’s when the cancer becomes visible, that’s the problem. So, the key endpoint was to delay or prevent the time to developing visible metastases and that was achieved basically in this particular study. So, the thing is that the median metastases - so the average was – the average time to developing metastases was 36.6 months so this is enzalutamide arm versus 14.7 months in the placebo group. So, this is the time to developing – to delaying metastases development which I think is a very, very clinically meaningful part.

We are still in follow up to look at overall survival. There were some trends with regards to reduction of deaths from prostate cancer, but the data is not mature yet. So, there’s more and more follow up that is happening.

Host: Dr. Hussain, What should providers keep in mind when referring patients that may benefit from this new treatment?

Dr. Hussain: So, let me begin first by highlighting the facts. While this particular clinical trial preselected for patients who specifically have more aggressive version of the prostate cancer; the FDA approval for this particular drug in general, was actually all-comers with nonmetastatic but castration resistant prostate cancer. So, I think the point here is this. Any patient who has prostate cancer, who has been on hormonal treatment and despite that, their PSA is rising; should be consulting with an oncologist or an oncologic urologist who are familiar with these types of treatments and drugs for a consultation regarding the pros and cons.

I would say that in general, patients who are in good health, patients who have a rising PSA should be evaluated and referred and discussions that we have usually with the patients, are the pros and cons. Like anything else, every time you have a treatment, there’s going to be some side effects and so in the big picture, the benefit of the treatment must outweigh the potential risks from the treatment. And what I generally recommend for patients is to consult with the appropriate specialists so that they can understand the scope of the benefits, the potential risks including the physical risks, the drug interaction for example medications they are on and things of that sort, what their objectives are and ultimately a shared decision is made to start or hold off and continue to watch there.

I would say in my practice, the vast majority of patients when given the choice and the pros and cons and the issues of benefits versus risks and so on; they tend to want to be on treatment.

Host: It’s great information and what a fascinating study for other providers to hear about. Thank you so much Dr. Hussain, for coming on and explaining it to us. This is Better Edge, a Northwestern Medicine Podcast for physicians. For more information on the latest advances in medicine, please visit www.nm.org, that’s www.nm.orgRelated: First Prostate Cancer Therapy to Target Genes Delays Cancer Progression.This is Melanie Cole. Thanks so much for tuning in.