ONCOLOGY® sat down with Leonard G. Gomella, MD, professor and chair of Thomas Jefferson University Hospital’s Department of Urology and clinical director of the Sidney Kimmel Cancer Center Network, to discuss 10 years of breakthroughs for patients with prostate cancer and the hope that continued research will fully transform prostate cancer from a deadly disease into a chronic, manageable condition.
The past decade has seen a sea change in the treatment of prostate cancer. The implementation of genetic sequencing and the rise of targeted therapies have led to tailored treatment regimens and positive outcomes for often even the most advanced disease.
Ahead of the 14th Annual Interdisciplinary Prostate Cancer Congress, ONCOLOGY® sat down with Leonard G. Gomella, MD, professor and chair of Thomas Jefferson University Hospital’s Department of Urology and clinical director of the Sidney Kimmel Cancer Center Network, to discuss 10 years of breakthroughs for patients with prostate cancer and the hope that continued research will fully transform prostate cancer from a deadly disease into a chronic, manageable condition.
Q: Can you discuss some of the recent advances in prostate cancer, and in genitourinary (GU) cancers as a whole?
Gomella: It’s been an amazing 10 years, particularly in prostate cancer, where we’ve had so many new FDA approvals. But we’ve also had approvals in other areas—in bladder cancer, [certainly], and of course we now have so many different drugs in kidney cancer.
At the upcoming [New York GU®] meeting, we’ll talk a little bit about what’s happened over the past year in prostate cancer. The developments in biomarkers and genetics have been explosive. We now have circulating tumor DNA that can be evaluated in patients with prostate cancer to determine genetic susceptibility not only to the disease but to new medications. This is a big breakthrough. We have PARP inhibitors now that were just approved for advanced metastatic castration-resistant prostate cancer (mCRPC), opening up a whole new spectrum of oral agents for the management of prostate cancer. We’ve also had FDA approval for an oral agent, a luteinizing hormone-releasing hormone (LHRH) antagonist, for the treatment of advanced prostate cancer. So, many men who didn’t like their shots will now be able to take a pill when they’re undergoing androgen deprivation therapy.
Another big area in prostate cancer, which we’ll discuss at our meeting, is the new PET imaging: the prostate-specific membrane antigen (PSMA)-PET scan. PSMA-PET scan is designed to pick up metastases from prostate cancer at a very low prostate-specific antigen (PSA) level, so it’ll be really taking off, [especially sbecause] it is now FDA approved. Right now, outside a clinical trial, the only place in the United States you [can] get those PSMA scans is at the University of Southern California or the University of California, Los Angeles, but it’s very important for our colleagues who work in prostate cancer to understand these PET imaging technologies, [to understand] what we have available today and what we’ll have more widely available in the next year or 2.
Also very interesting in this area is theranostics—meaning therapeutics plus diagnostics—in which you combine a PET imaging study with a lethal radionuclide like lutetium . Essentially, what happens is when you have a prostate cancer, an avid tracer finds the [cancer] cell and [delivers] the radioactive payload that’s associated with it. Once that antibody goes to the cell, it’s connected to something like lutetium, which is a destructive nuclide, and it kills the cancer cells. Theranostics is a growing area in prostate cancer. The PSMA lutetium studies are not yet FDA approved, but [this therapy] has worked its way through the system quite far. And at some point, it will be evaluated by the FDA in the United States.
There have also been some very interesting developments in bladder cancer. In particular, we had one of the first agents—pembrolizumab (Keytruda)—
approved for non–muscle-invasive bladder cancer (NMIBC). It’s administered systemically, and it’s for NMIBC refractory to BCG. What was particularly fascinating about this approval, and perhaps even exciting, is the fact that it’s a systemic therapy for NMIBC, not an intravesical agent. In that regard, it’s a first-in-class [therapy]. Several other new medications had very prominent clinical trials reported for NMIBC as well, including nadofaragene firadenovec; clinical trial results showed that this was a very effective intravesical gene therapy for NMIBC. It’s currently being evaluated by the FDA, but trial data reported in 2020 were very promising.
Q: How big of an innovation is having PARP inhibitors available to treat patients with advanced mCRPC?
Gomella: Since 2010, we’ve had an amazing run of approvals of new agents for advanced mCRPC. The latest entries into that category are the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca), approved in May 2020 within 5 days of each other. Essentially, you consider them to be second-, third-, or fourth-line therapies; [a patient has] to have failed other therapeutic interventions for mCRPC to be eligible for olaparib or rucaparib. But further, the way the FDA labels are written, you actually have to identify a problem with the DNA repair pathway genes. So, it’s not only failing therapies, but also identifying that you have what are known as homologous recombinant repair gene abnormalities in the DNA repair pathways. Those [abnormalities] tend to be in genes such as BRCA1, BRCA2, ATM. When 1 gene is mutated, and certainly when 2 are mutated, the body can’t do a normal repair of the DNA, and then the [cancer] cells become very aggressive, very metastatic. Not all patients with advanced prostate cancer have these DNA repair pathway abnormalities, but those who do can actually add several years to their life using these oral PARP inhibitors. Medical oncology has been using these for several years—different ones for breast cancer, different ones for pancreatic cancer. But now we have them available to use as an oral agent in advanced mCRPC.
Q: Looking back, the early 1990’s had chemotherapy, radiation and maybe a little bit of hormonal therapy to treat prostate cancer. Could you have ever foreseen the changes and advances in treatment that we
Gomella: The reality is that for a while, we were pretty quiet in prostate cancer. In the late 1980s, we had the development of the LHRH agonists, where instead of cutting a man’s testicles off, you could give him a shot and turn his testicles off relatively safely. Then we had the amazing discovery of PSA and its association with prostate cancer. That really kicked off in a big way in the early 1990s—but then things got kind of quiet. A lot of work was done with surgery, [though]. Because of the pioneering work of Patrick C. Walsh, MD, in the 1980s, more and more doctors were doing surgery for prostate cancer. At the same time, there were improvements in radiation, with brachytherapy and different ways to deliver radiation. That continued into the 21st century in the treatment of local prostate cancer, with the development of robotic prostatectomy and proton therapy.
In advanced prostate cancer, we didn’t really have a lot until the early 2000s, when we had docetaxel (Taxotere) come out, but again, after that it was quiet. Then 7 or 8 years later, boom! We were hit with sipuleucel-T (Provenge), one of the first immunotherapies for any advanced cancer. Then we [saw the approvals of] enzalutamide (Xtandi), darolutamide (Nubeqa), apalutamide (Erleada), abiraterone (Zytiga), cabazitaxel (Jevtana), rucaparib, olaparib. In just a 10-year period, we had at least 9 or 10 different new drugs available to treat various stages of prostate cancer. And now, of course, we have the oral LHRH antagonists as well. So, yes, it’s been an amazing run, the last 11 years, to see all of these new drugs approved for advanced prostate cancer.
Q: Where is the research headed now?
Gomella: One concept we talk about in prostate cancer is a shift to the left. What do we mean by that? We get drugs that are approved for advanced mCRPC, for the worst-case scenarios; [here,] men are not doing well and have failed [every prior treatment]. Then, once you get that approval, you start to move into earlier and earlier stages to try to delay the spread of cancer. That’s what we’re doing now with drugs such as enzalutamide, apalutamide, and darolutamide. We’re using them to slow the spread of advanced prostate cancer. I think [the research is] moving us back to the left and identifying things that we may be able to do earlier and earlier, to convert prostate cancer from an acute life-threatening disease to, [potentially,] a chronically managed disease like diabetes or hypertension. A lot of the research now is looking at drugs that may alter that trajectory of prostate cancer by understanding the genetic triggers that we may be able to interact with earlier in the course of the disease: to slow it down, or even prevent it from metastasizing, or, if it is metastasizing, to [get it to stay] there in a holding pattern.
Q: Your institution has had great success with the use of a multidisciplinary approach to cancer care. Can you describe the philosophy behind that?
Gomella: We’ve been utilizing a multidisciplinary approach here at the Kimmel Cancer Center since way back in 1996; we [believe no] other center has been doing it as long as we have. We’ve found it to be an amazing experience. Many other centers have started to do it now, because it’s a very patient-friendly and family-friendly approach to prostate cancer.
Most of the men who come to our multidisciplinary clinic have early prostate cancer, and they’re trying to decide between active surveillance and active treatment with something like radiation or surgery. But for those patients who come in with prostate cancer that’s a little bit more advanced, we have a whole team of radiation oncologists, as well as medical oncologists, clinical trials specialists, radiologists, pathologists—and all [of us are] at the same place at the same time to talk to the patient and their family, and to give them our best recommendation for what path they should start on.
With regard to genetic testing, we’re very proud of the fact that in 2014, we incorporated what we believe is the first genetic testing clinic where all patients who come in receive a quick consultation with a genetic testing team. [The team discusses testing, and asks,] “Could this be something you’d be interested in pursuing further?” The focus on that first visit is on treatment, [of course], but if there’s an indication the patient could have a familial form of prostate cancer, the option is there to talk to our genetic counselors after [the visit is] over.
For patients who may have a genetic predisposition, [the consultation] may be important to them, especially when it comes to screening for other cancers, such as pancreatic cancer, melanoma, or male breast cancer. It also might be very important to them, from a perspective of cascade testing, to know if this is something they may need to worry about in their children. Should their children be aware that they might have this inherited gene? Again, this requires a very up-close-and-personal discussion with the patient or family, but we believe this is the future of precision medicine in all of cancer.
Q: Is there a particular achievement in your career of which you are most proud?
Gomella: When it comes to a basic science discovery, something that doesn’t get a lot of attention, that I’m particularly proud of, is the fact that way back in 1993, we described the first molecular test to identify circulating prostate cancer cells. I think that that really laid a lot of groundwork for others who started to look and say, “Hm, can we use these molecular tests to look at circulating tumor cells?” Over the last 25 years, the work that we did has now been eclipsed and expanded dramatically. At the time, it was too early; we didn’t really know what we were doing. We just said, “Hey, we’re doing this RT PCR [reverse transcription polymerase chain reaction] for PSA, and we’re seeing stuff out in the blood that shouldn’t be there.” That was a very early indication that something was going on. The problem was, we didn’t know enough about the circulating cell-free DNA and all the other circulating tumor cells that we actually got involved with about 8 or 10 years later. So, identifying micrometastasis in the early 1990s is something that I was pretty proud of.
But [something else I’m very proud of is] the team building—working with my amazing colleagues in medical oncology, radiation oncology and cancer biology. A lot of the basic science translational things come out of the lab, and we’re able to bring [the results of that work] to our patients.