From Mesopotamia to the Great Lakes “The 6000 Miles Journey”: Prostate Cancer Then & Now
PCF Women in Science Lifetime Achievement Award Lecture: From Mesopotamia to the Great Lakes “The 6000 Miles Journey”: Prostate Cancer Then & Now
Maha Hussain (Northwestern University)
Introduction by Andrea Miyahira (Prostate Cancer Foundation)
View the Transcript Below:
From Mesopotamia to the Great Lakes “the 6000 Miles Journey” Prostate Cancer Then & Now
Andrea Miyahira, PhD [00:00:07] So good morning, everyone. I’m honored to be up here today to not only present an award to one of the most consequential women in prostate cancer research, Dr. Maha Hussain, but also to recognize and celebrate all of the women in our field and in this room. Over the years, we’ve continued to see the number of women in the PCF community increase, culminating in this year being the first ever where we not just achieved parity, but we actually had more women than men in the incoming Young Investigator class. So, I think that’s something that we should all be proud of and continue to push forward. And for the 10th year now, PCF has hosted the Gender Equity Network Initiative. We call it GENI. It was formerly called the Women in Science Forum. And this was us 10 years ago in 2016 on the left, and yesterday on the right. And the GENI Forum is a half-day event that brings together women and allies to really grow and nurture the pipeline of women in prostate cancer research and medicine. And so, I thank everyone who attended yesterday, and I encourage everyone to attend next year. This year we actually had something like over 30% men in the room. So, I think that’s another sort of great achievement that I’m proud to see, you know, we’re pushing to the other side. And in fact, Dr. Hussain, was the first keynote lecturer at our very first GENI Forum. And so, it feels full circle to be coming around and presenting her with this award today. And so, Dr. Maha Hussain is a GU Medical Oncologist at Northwestern University, Feinberg School of Medicine, where her titles include the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Deputy Director and Leader of the GU Oncology Program at the Robert H. Lurie Comprehensive Cancer Center. She received her medical degree from Baghdad University and completed her residency and HemOnc fellowship at Wayne State University. She has trailblazed over the years, leading and participating in much of the most consequential GU clinical research, including multiple phase three trials that have changed standards of care, for instance, PROSPER, PROfound and ARASENS. She’s an author of over 325 scientific publications and book chapters and has received numerous national and international leadership roles, such as serving as chair for many years of the SWOG Advanced Prostate Cancer Subcommittee, chair of the DOD PCRP Integration Panel, chair of U.S. FDA Oncology Drug Advisory Committee. Her CV is incredibly extensive and inspiring and includes numerous awards for scholarship and patient care. And so, I’m so honored to present to her today the PCF Women in Science Lifetime Achievement Award.
Maha Hussain, MD, FACP, FASCO [00:03:36] Great, thank you very, very much. I am absolutely honored and it’s really an incredible recognition award and I have to be very grateful for the PCF, Mike and the team because they have really provided wonderful opportunities and resources for the investigators in the field starting from the days when actually. For a long time, prostate cancer wasn’t hitting the radar screen for people for research. So, with that, I’m gonna move on with my presentation. I called it From Mesopotamia to the Great Lakes, the 6,000-mile journey, and prostate cancer, where it was and where it is. And just to Mike, I come technically from Mesopotamia, which is supposed to be the cradle of civilization, and the cycle of life. You can see how it went under. The beauty of this country, I am hoping that as an immigrant that the spirit of the country, the laws of the county will hopefully keep us sustaining this country forever. So here are my disclosures. So basically, I wanted to begin first with showing the information where I come from. So as many of you know, I was born and raised in Baghdad and Baghdad was actually established in the eighth century. And while Iraq is technically a new country, the area has existed for literally thousands of years and was known Mesopotamia, the cradle of civilization. In fact, if you travel around Iraq, What you will see is, and I don’t know if I can use the pointer, but you will see all of these historic areas in there. This is civilization that existed literally thousands of years ago, and many of you would know is the Babylon and the Lion of Babylon that’s in the middle up there. Now the history is very rich in the region and there are arts, science, legacy of medicine and educational institutions. And what you’ll see here on the left-hand side is the canon of medicine, which is the laws of medicine which was, I’m sure you will be aware, Avicenna wrote that part in there and laid the foundation for, believe it or not, experimental therapy even at the time, amazingly similar to principles in there. And then the other one to the right-hand side is the Madrasa Al-Mustansiriyah, as in Al-Mustansiriyah school, which was established in 1200 and one of the first universities that were established. When I came to the U.S. and with my last name, Hussain, of course nobody would call it Maha. People look at it and they say Meha and I wouldn’t recognize that that was me. And now our government uses my name, Maha, make America happy and healthy again. And I’m getting zero dollars for that. but basically, we get asked about what it must have been like to live there. As long as you stayed outside the politics of the government, life was actually fun. We basically, as young adults, growing up in the 70s, we have fun despite all of the political boundaries. The culture socially was fairly, I’m going to say very liberal, but liberal. Very cultured, education was very important, arts were very important and so on. And in fact, we did sports, we did music, my parents took us to dance classes and stuff like that. And I would say my generation, what I would call it is the ABBA and the Tom Jones generation. Remembering those of us, Elvis did not hit our radar screen as much. It was the European sort of crowd. College was a fantastic time. A medical education, actually all college education in Iraq is free. So, the people who make it into the school has nothing to do with how much money they have but rather by the score of an exam that we all have to take at 12th grade basically. And that’s how we would enter there. And as you can see. This is University of Baghdad College of Medicine. This, the university was one of the first universities in the Middle East. It was established in 1927 at the time there. And the building continued to be there. I have never been back since I left the country a long time ago. But basically, as you can see here, it’s a big class, over 300 students. Over a third were actually girls, women in that class. And it was really very, very fun time. And we’ve had till today, by the way, we have a Facebook and we have a WhatsApp link that we exchange stuff in. And periodically we have get togethers of those of us who are outside the country. Now after three years, we left Iraq literally five weeks after I graduated and got married. And we went to England because historically in the Middle East, for certain countries that are connected to the UK, like Iraq, we go there for our education. However, from the 60s, I’m proud to say that I have actually three uncles who are physicians. All of them went to the Western World for education and stayed. Two of them actually were in the U.S. And one was in Detroit and one was in San Diego, believe it or not, from that time. And they kept telling me come over, come over from the UK and when I looked at the map, Detroit seemed closer to Baghdad than San Diego. And I had no idea what the weather was like, just to be clear. So, it was not easy to adapt to the winters. Let me tell you, it’s just when it gets cold. We saw snow in the movies. We’ve never seen it in real life. So anyhow, I did my training at Wayne State, and I actually loved my training at Wayne state, it was a very nurturing environment. The beauty of Wayne State, while it’s a public institution, it had five associated hospitals. And so, from one end you could see the inner city homeless, and the other end you literally see the auto executive and all kinds of shades of gray in between. And it was a pretty exciting time during our residency and fellowship. And what you see here, and again, I don’t know if I can do the pointer, but there are many people in several of our classes. That were really moved on to do major impact. So, you see me on the right-hand side there. You see Pat LoRusso, who became the AACR president on the left side. Dr. Larry Baker, who was fantastic, he was our division chief, very supportive of clinical translational and basic science research, and went on to be the SWOG chair. And Dr. Rick Pazdur, who was our fellowship director there and he really did an amazing job. And as of course you know, Rick now is the oncology branch head at the FDA. So, it was a very, very nurturing environment. And then I joined the faculty at Wayne State. And there I was not a mouse doctor. I couldn’t touch mice, they scare me. So, I got into doing sort of translational work under the supervision and mentorship of John Ensley. He is one of the first people to actually come up with detection of micrometastatic disease using flow cytometry. And so that was a project. And originally, I was being groomed to be a breast oncologist, but then when I started working in the VA hospital, it was really very clear that that’s not, you know, something that I could do with the breast cancer, switched to prostate cancer and got one of my first projects in there. At the time when I actually entered, I call it the 80s girl generation, when I entered, I finished my fellowship in 89 and I joined faculty in 1990. And at the time, there were really in the GU field, by the way, was predominantly urologist, running the sort of the different research and activities, whether it’s clinical or otherwise. There were very few medical oncologists in the GU field, and when it comes to women, there was less than a handful. And so, when I entered, I call it the class of the late 80s here. As you can see, Nancy Dawson, Tia Higano, myself, and Cora Sternberg, who is here. And we were all young women, and again, for the new generation, by the way, sleep is overrated, you’re gonna parallel your life and your profession all at one time. Because, you know, time runs. And so, this was really a wonderful group of ladies. So, this is really when I met the deadly prostate cancer and literally from residency. So, on the right-hand side is the Ellen Park Veterans Administration Hospital which was one of the oldest hospitals, VA hospitals in the country, built before World War II, in fact. And then Detroit Receiving Hospital was like, this was like a more an open hospital, anybody who was ill or something acutely gets in. And what we see is, used to see literally prostate cancer and its ugliest faces, court compression, brain metastasis, renal failure, bleeding and things like that. And then when you evaluate the patient, you discover that they had prostate cancer. This is really what prompted one of my first projects that I had worked with Dr. Ensley on. Trying to see can we pick up bone metastasis, micrometastatic disease in the marrow long before the disease is spread in the context of high-risk disease. So, this is the prostate cancer story. Then, at the time, bilateral orchiectomy was the primary treatment. DES was another medical treatment, but I’ll tell you, again, in my residency, we used to see people coming in with all kinds of PEs and DVTs and stuff like that with the treatment. Then LHRH agonists were being tested. Only FDA approved a drug at the time for hormone refractory prostate cancer was actually estramustine. And then patients progressing on first-line treatment. Basically, the concepts were, or the dogma of the time, that they’re not likely to respond again to any other hormone treatment, and chemotherapy basically has no role. These were like the principles when we started. So, these are, I’m not gonna go through all of them, examples of the questions that were asked in the 1980s and the 1990s. And one of the different issues were different concepts that I think some of which we still apply at this point, including bone targeted therapy, combination with chemotherapy, combined endocrine deprivation, intermittent therapy, do you continue the drug when people progress to castration-resistant and so on, and of course also questions for the early-stage relapse. In summary of where we are now, compared to when we started, going back all the way to the days of bilateral orchiectomy, as you can see, there’s been a significant evolution of the treatment, but the principles in terms of intensification of therapy and multi-targeted strategies were concepts that were tested a long time ago, and now I would say entering 2015. We’ve really entered a much better era in terms of success with therapy intensification. Now, this is from a publication with one of my ex-fellows, Tony Seritella, who is in Wisconsin right now. What we looked at, you know, summarizing the different successes with sort of level one and what I call tailwind, level one evidence of efficacy. As it relates to systemic therapy in prostate cancer with doublet treatments, with either chemotherapy or with AR inhibitors, and circling there are all the trials that showed level one evidence and support. The triplet therapy, again, basic principles of oncology in general is a multi-targeted strategy, and so the concept of adding chemotherapy or AR inhibitor to ADT and chemo and so on, was a concept that was being investigated a long time ago. PEACE 1 and the ENZAMT were two of the first trials that actually showed benefit for the triplet therapy including docetaxel and an AR inhibitor. And then we transitioned to the third triplet which I was involved in the trial design and conduct, the ARASENS trial. And I know Matt Smith is around here too. And basically, this was a trial that was designed looking at a combination of doublet with chemotherapy versus triplet with adding darolutamide. And the primary data was reported, and as you’ll see, clearly there was an overall survival advantage. We did a post-hoc analysis looking at volume of disease because then we had the data from the CHAARTED and so on as to the impact of triplet therapy in the context of the disease volume, high-volume, low-volume, or high-risk and low-risk. And what you’ll see here, the trends are favorable in both these groups. Now one of the questions that I get asked about, and certainly when I’m seeing my patients, do you have to give triplet to every patient? And if you’re gonna do a doublet, who do you choose, and do you use chemo, do you do AR inhibitors, and so on? So, this is from actually a paper that we put together, and we published in JAMA Oncology, where basically kind of providing just an outline with regard to what we would recommend there. The basic principle in my practice is anytime I think I’m gonna harm a patient, I’m not gonna go with something that’s gonna be harmful. That really is gonna be the priority. I have to say, in literally 99% of patients, when you counsel them with what you think what it is, and they’ll say, Dr. Hussain, what do you think? I’m gonna say, this is what I think. I would say 99.9% of the patients will actually opt to do that. And one thing about these types of treatments, you don’t have to make a decision about triplets right away. You can start with combined androgen deprivation, give the patient two, three months, see how they are doing, and then decide regarding adding the chemo. So here, one of the prognostic factors. For sake of time, I did not include the disease volume and the disease risk, which was something that was SWOG-based, MD Anderson-based and a hybrid was created when we designed CHAARTED. The second prognostic factor was actually nadir PSA because as you know, until we got the PSMA PETs, we had bone scans and CT scans, and the bone scan can be very misleading. Sometimes, because once you treat, things can get worse, even though the patient is responding. And so basically, one thing that we reported from my intermittent trial, the SWOG trial, is the nadir PSA and undetectable PSA, and it’s very clear, it’s a very strong prognostic factor which I actually, we use, and it’s a great opportunity to do that. Just for the fun of it, When PSA came out, for those who are not aware of it, it’s prostate-specific antigen, we used to call it psychosis stimulating agent because when we did the trial, when we do the treatment, no matter what it is, the PSA goes up, immediately the doctor is freaked out, the patient is freaked, so anyhow. So, tailwind number two. This is essentially where we are right now in the setting of castration-resistant prostate cancer. And there’s a long list of life prolonging treatments starting with docetaxel. And I wanna give credit to Dr. Dan Petrylak and SWOG because this is one of the two trials that led to the FDA approval of docetaxel was a trial that Dan led. And the other one was a multi-center sponsored trial. And then we’ve seen all kinds of different agents coming in, and I have to say, in 2000, we’ve entered the era of precision, personalized, and therapy, and all of that is there. And one of the issues come up is, how do you go about choosing what to do? And there’s really several clinical considerations to be included. I think one of the major landmarks that I would personally feel transformed prostate cancer treatment and got us into the precision medicine sort of phase was really the stand up to cancer effort. And this is a work that was led by Arul Chinnaiyan and the Michigan team. I was part of the team at the time at University of Michigan, but there were, it was international, the Marsden. UW, a bunch of other institutions were participating in it. And this was basically one of the first set of data that actually identified the genomic profile based on fresh biopsies of the metastatic disease and identified the mutations in the HRR genes. And as part of the study, part of a project, there was a clinical trial called TOPARP-A, and TOPARP-A basically took all comers. The patients were enrolled in the stand-up to cancer, their tissue got tested, they got olaparib, and when the data was looked at, there was responses in the patients who have HRR mutations that provided the foundation for the PROfound trial, which was really a very exciting time. This was a biomarker pre-selected and stratified clinical trial. We had patients with BRCA1, 2, and ATM as the primary cohort and anybody else with the other HRR mutations as cohort B. And we basically reported the data. It was ESMO 2019, I believe, when I presented it. The first paper came out with the PFS. And then we afterwards reported the overall survival data. And what you can see clearly, because we allowed crossover, the primary endpoint was PFS. And what’s you see here, when you adjust for the crossover, there is really a very big benefit in there. One of the critical things that are there is there is not one pathway that’s going to 100% target prostate cancer. Or any cancer for that matter so multi-targeted strategy is critical and what you’ll see here is pre-clinical data from a group of individuals including Karen Knudsen and her lab regarding the co-targeting of AR and DNA repair which then provided the foundation for once the PARP inhibitors were approved, moving into combination strategies with randomized phase three clinical trials. Many of the leads are in fact here. And basically, what that showed, the bottom line is irrespective of the trial design, when you look at the cohort of patients who have the HRR mutations, these are the ones that tend to benefit the most. Having said that, PROpel and MAGNITUDE, the approval in the U.S. specifically is based on BRCA1 and 2. The talazoparib plus enza was actually a bigger panel and we certainly can discuss that further. One of the questions that started after we had the original stand up to cancer work, which is about the time when I started the BRCAAway trial was the fact that do you have to give actually combination treatment? Can you demonstrate if there is more efficacy that way and what happens if you wanna give sequential therapy? So, this is a trial that I designed. We conducted it through the prostate cancer team and basically taking patients with BRCA1, 2 or ATM, randomizing them to abi with prednisone, olaparib or the combination. And at progression, patients were allowed to crossover. And the other cohort, which is exploratory, was anybody who had other alterations. And what you see here, and even after adjusting for a crossover. The combination up front was much more efficacious. And we just submitted an abstract to ASCO GU. Shockingly, believe it or not, there are many of these men who are alive four, five years after, despite the fact that they really had horrendous cancer, de novo metastatic disease. So, I do think for the scientists in the group here, trying to understand the biology more is going to be very, very critical. You’re all aware of the other sort of targeted therapy, the lutetium-PSMA-based treatment, and this clearly was approved by the FDA, got moved into the earlier stages of castration-resistant disease, and again, got FDA approval. It’s positive with regard to overall radiographic progression-free survival. One of the questions is this, if you’re gonna go with targeted treatment, where are you best targeting this treatment? And this is actually, Arul shared this slide with me. This is actually work from the University of Michigan cohort, and it’s actually a very large cohort of patients, over 1,200 patients actually that were included in this cohort. Essentially looking at the genomics from different phases of the disease. And what you can see here, the reality of it is this, is the earlier stages of disease have much less complicated genomic profile. So potentially this could say that you might be better off if you’re gonna do targeted treatment, you may get better mileage going into the earlier phases of disease. And so, there are several clinical trials right now, summarized in here, shared it from Neeraj Aggarwal, looking at targeted therapies of different kinds. Most recently at ASCO, we got the AMPLITUDE trial reported, which was again frontline hormone-sensitive prostate cancer with niraparib and abiraterone. And patients who are pre-selected for HRR alterations. And what you see here, actually, there is a very strong signal when it comes to radiographic progression-free survival. With that, I’m reaching the end. I wanna highlight the fact that we have come a very, very long way. From the 1940s when testosterone was recognized and its effect on prostate cancer and so on. Until 2004, the disease was very stagnant with regard to treatments that we were doing for the patients. 2004, Docetaxel hit the market because of two randomized phase three trial showing that prostate cancer, in fact, can be impacted. And that really opened up the door for much more involvement in there. We’ve moved all the way down to where we are right now with, again, precision medicine and targeted therapy. And what’s very clear is this, and this is from a paper that Neeraj Aggarwal wrote, but it’s based on several SWOG clinical trials, just looking at overall survival from those trials. And what you’ll see here, and even in the more current, not very current era, but in the sort of beyond the 2010 era, median survival for patients with metastatic hormone-sensitive disease is pretty much over five years, which really is remarkable. And I know many of you may have patients who have lived longer. I actually have men who are literally 10 years out. And guess what? They don’t wanna stop the treatment. And so, there is a lot of things that I think we need to investigate from that perspective. I just wanted to just summarize for the newer generation and the crowd. Basically, everything is possible. As one of my mentors told me, you have a fire in your belly. Everything you wanna do can be done. So go after it. And so, this is just examples of work that I was involved in that actually led to impact the field. I wanna say now we’re passing on the baton to the new generation to cure prostate cancer. This is essentially a summary of where we were and where we are. And I do think one critical area which is what we need to investigate definitely is all of the treatments we’re doing and moving everything into earlier stages of the disease, how will this impact the biology of downstream disease and clearly investment in preclinical translational work is gonna be very critical and also clinical trials in that regard. And I think we’ve come a long way and it’s time to move on for sure. I wanna say, as I showed you earlier, when we entered the field, there were very few medical oncologists and very few women in oncology. Now we’re seeing the field expanding, and I am really delighted to say that a significant percentage of my mentees up there on the two pictures there actually chose GU Oncology as their area of focus. And then of course, as you look at all the pictures, the number of women is increasing. So, this is the APEx meeting. Some of you may be at this upcoming one. So, we’ll see you there. The ASCO AACR workshop, which I have done for many years. All of the people we took pictures here with are focused on GU. The number of individuals with interest in GU is significant, and a good chunk of them are women. And then when you go to international, and this is Morocco, Brazil, and Colombia, basically, just to show you how many women are either in fellowship and or a faculty role that are getting into the field. So, with that, I believe that’s it and thank you so much for the opportunity and the invitation and recognition.