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Neal Shore: Hi, everybody. I'm Neal Shore, and I'm super excited to be here today with my dear friend and colleague, Rana McKay. We're on UroToday, and we're setting the stage of how we got to where we are in 2024 for prostate cancer treatments. Gosh, the landscape has just exploded over the last 10, 15 years, and this is our second module in a series of 10 for this educational programming on prostate cancer treatment. And so, it's such a great honor to have Dr. Rana McKay talk to us and discuss an overview of advanced prostate cancer. No easy task. Thanks, Rana.

Rana McKay: Oh, it's my absolute pleasure. We've definitely come a long way over the last decade from where we've been and honestly where we're going with regards to trials that are currently in progress and new therapies. And while the majority of patients who have prostate cancer are cured with definitive local treatment or salvage treatment, there are a subset that go on to develop recurrence and subsequently develop metastatic disease. And some patients actually develop metastatic disease right at the time of diagnosis, and the proportion of those patients presenting with metastatic disease right upfront has actually been increasing recently with decreased PSA screening rates.

And so, our treatment paradigm for metastatic mHSPC has really turned on its head in 2015 when we started integrating escalated therapy. Prior to that time, the backbone of treatment was androgen deprivation therapy given as monotherapy, and we really did not escalate treatment until patients became castration-resistant.

And now we're learning that actually early intensification for those high-risk individuals actually improves outcomes for patients. And we have looked at doublet therapies, we've looked at triplet therapies, and we're going to go through some of that data. Additionally, there have been a lot of new kids on the block for metastatic CRPC, and what's really exciting is actually the breadth of different types of therapeutics has really expanded from hormonal agents, targeted agents, immunotherapy agents, radioligands. And so, the number of different drugs in our armamentarium has expanded, and we're starting to develop more precision medicine strategies, targeted therapy strategies based on patients' molecular predisposition and baseline biomarker status. So, I think that's been a great win for patients, but we'll dive right in.

So, as we think about the metastatic mHSPC setting, really now the standard of care has been ADT with an ARSI, whether that be abiraterone, enzalutamide, or apalutamide or ADT with abiraterone and docetaxel or darolutamide with docetaxel. We've moved away from ADT docetaxel alone with the data from PEACE-1 and also data from the ARASENS study, which looked at triple therapy compared to a backbone of ADT docetaxel.

So, we've moved away from just ADT docetaxel alone to triple therapy when docetaxel is needed to be used, and then ADT plus an ARSI. We do not yet have the answer for what is the contribution of docetaxel when you're using the backbone of ADT and an ARSI. There are several cooperative group studies that are actually being designed to investigate that question upfront or utilizing six-month PSA as a determination for escalating therapy. And then in the CRPC setting, we've got non-metastatic CRPC, which I will say is an increasingly dwindling population of patients. The integration of PSMA PET imaging has been highly disruptive in staging patients with metastatic disease, particularly in the biochemically recurrent setting, and we've certainly seen stage migration with earlier detection of metastatic disease with the introduction of PSMA PET imaging. But in the context of individuals having non-metastatic and mCRPC treatments like apalutamide, enzalutamide, darolutamide have all demonstrated delayed time to metastasis development and improvement in overall survival.

And additionally, we've even seen the integration of ADT with enzalutamide and enzalutamide monotherapy for those patients with high-risk biochemically recurrent disease that is non-metastatic on conventional imaging, given a rapid PSA doubling time of less than nine months. Data from the EMBARK trial demonstrated the utilization of those agents in that setting. And then we'll kind of highlight all the different agents that have recently been approved in the mCRPC setting, metastatic castration-resistant prostate cancer. You can see a plethora of different drugs that have been approved and doublet therapy as well, with the PARP-ARSI combinations.

So, first, let's delve into the data around metastatic hormone-sensitive prostate cancer. As I've told you, the field really began to turn in 2015, where we saw landmark data of a really simple question: We know docetaxel makes people live longer in the metastatic CRPC setting. What about just using it earlier on? Why wait until the patients get castration-resistant?

And the data from CHAARTED, from STAMPEDE, from GETUG-15 all really demonstrated the activity of docetaxel in patients with newly diagnosed metastatic castration-sensitive prostate cancer. Along the same time that the CHAARTED study and the STAMPEDE study were being designed and reported, LATITUDE and STAMPEDE also looked at the addition of abiraterone. LATITUDE was specifically in those individuals that had high-risk disease based off of Gleason score, presence of visceral metastasis, or presence of four or more bone mets, and really LATITUDE enrolled a pretty high-risk population, but both LATITUDE and STAMPEDE demonstrated the benefit of abiraterone added to the backbone of just ADT. And we see subsequent studies, the TITAN study looked at apalutamide, and that was approved in 2019, against similar study design: mHSPC patients adding apalutamide to the backbone of ADT, and then several studies looked at enzalutamide, including ARCHES and also the ENZAMET trial, and ENZAMET did allow for concurrent docetaxel.

TITAN did allow for prior docetaxel. So, we have some data about the activity of docetaxel in combination with apa and enza in those trials. In this time as well, we saw data about what is the role of radiation therapy to the primary for those patients that present with de novo metastatic disease? And data from STAMPEDE and the HORRAD trial really highlighted that for those patients that have low-volume disease, actually treating the prostate improves overall survival.

These were radiation studies. There's currently a study through SWOG looking at the role of radiation and also surgery to the primary for patients with metastatic hormone-sensitive prostate cancer that will certainly ask an important question. And then, with regards to triplet therapy, now we've demonstrated that doublets definitely improve survival. PEACE-1 and ARASENS looked at the combination of docetaxel with abiraterone and darolutamide, respectively, compared to the backbone of ADT docetaxel, which as you see here, the standard of care has really been evolving to escalate therapy in the metastatic hormone-sensitive setting.

So, these trials have been really important to highlight that when docetaxel is needed, actually triple therapy should be utilized over just ADT docetaxel alone. I think the biggest question about these studies is who needs what? Does everybody need intensification? How can we better utilize biomarkers to help identify who are those patients that need to be intensified, that need triple therapy? Who are those individuals that do not? And then, with patients being on these agents, they're highly effective. Patients can be on them for a long time. Questions arise, well, how long can patients stay on therapy for those individuals that are four or five years out? Is there an opportunity to ever think about treatment discontinuation or a treatment holiday? And there are certainly clinical trials that are looking at answering that question. The A-DREAM study through the alliance looked at abiraterone discontinuation in abiraterone extreme responders.

And I think this is a question that's certainly relevant for our patient community. A lot of other studies happening in the mHSPC setting. We've got the CYCLONE 3 study looking at abemaciclib. We've got TALAPRO looking at talazoparib with enzalutamide in a biomarker-selected population. PSMAddition is looking at lutetium PSMA in the mHSPC setting. The CAPItello study is looking at capivasertib, an AKT inhibitor, in this setting. So, there's a lot of clinical trials that are currently ongoing looking at escalated therapy in the mHSPC setting that will certainly impact the treatment landscape. So, moving into mCRPC, a lot of what we do in the mCRPC setting is largely dependent on what patients have received previously and categorizing those individuals as, well, have they received prior chemo? Have they seen a prior ARSI? Have they seen both or neither? And so, based off of what patients have received previously, data to support select agents.

So, for those individuals who are docetaxel and ARSI naive, there are a lot of different options that can be utilized from abiraterone, enzalutamide, to docetaxel, which certainly are the preferred treatment strategies. For those individuals who have received prior novel hormonal therapy or an ARSI but have not received prior docetaxel, I think docetaxel is certainly something that can be considered. Additionally, other agents can be utilized like cabazitaxel, carboplatin for patients with select mutations in the DNA repair genes, an ARSI with a PARP inhibitor can be utilized. And we saw data from PSMAfore on the utility and efficacy of lutetium in the pre-docetaxel setting. And no FDA ruling, I guess, on that use pre-chemo, but certainly, there are individuals who are not fit for chemo or different therapies can be utilized. For those individuals who have received prior docetaxel but had not received a prior ARSI, obviously, an ARSI is the top-line choice.

And then for those individuals who have received both an ARSI and docetaxel, that's the classic setting for lutetium PSMA to be considered. Cabazitaxel can also be considered. I think it's critically important to highlight that all patients with metastatic disease should undergo germline and somatic tumor profiling to identify if they have a homologous recombination repair gene alteration, particularly BRCA1 and BRCA2, where there is data for combination PARP inhibitors with an ARSI. And then for the broader HRR population, olaparib monotherapy or rucaparib for those BRCA1, BRCA2 mutated individuals. So, I think that is something to consider. About one to two percent of patients also have MSI high that is found, and those patients could be candidates for pembrolizumab. So, as we think about the treatment selection in the advanced setting, there's a lot of things that we consider from volume of disease, timing of disease, where are the mets, liver, non-liver, Gleason score, and genomic features.

They have an SPOP alteration, RB, P53; those all matter. Clinical factors like the patient's symptoms, their performance status, their comorbidities, what other medications are they on that could impact drug interactions? And then drug factors from mechanism of action, mode of administration, and cost. So, really, there have just been significant advances in life-prolonging therapies in the metastatic advanced prostate cancer setting. Doublets and triplets are now the new standard of care. Certainly, radiation to the primary for those low-volume patients can be considered. It's recommended that all individuals undergo germline and somatic tumor profiling, and there are lots of treatment options that are expanding in the mCRPC setting, including PARP inhibitors, chemotherapy, radioligand therapy, so lots to look forward to.

Neal Shore: Wow, that was wonderful. That's a real tour de force in this proverbial embarrassment of riches that exists for our patients and for healthcare providers and for the team to figure out what to do. So much great progress in the last 15 years. I got two questions for you, Rana. So, when we say advanced prostate cancer, how do we think about that now? How do we define what does advanced really mean? How do you explain that to our colleagues and trainees?

Rana McKay: Very good question. So, stepping back, I think for me, advanced prostate cancer classically are people who have demonstrated evidence of metastases either on PSMA PET or conventional imaging. I think those would be individuals with advanced disease. There's always a struggle of, well, how do you categorize somebody who's recurred, has a biochemical recurrence, but is non-metastatic? And there can be individuals in that category that are advanced, knowing that they have high-risk features, they've got a rapid PSA doubling time. But in general, it's not every man who has a biochemical recurrence that goes on to actually develop metastases or die of prostate cancer. So, I think it's those individuals who have bonafide evidence of metastases, whether that's detected on PSMA PET or detected on conventional imaging, that I would put into that category of advanced individuals who don't necessarily have curative treatment options or their likelihood of cure is very low.

Neal Shore: I would agree with you, but I would add, and I brought this up once a few years back when we were doing an AUA course on "advanced therapies." This was about eight years ago, and I said, "I think anybody is advanced the moment you start a systemic therapy, as opposed to trying to do an active intervention like prostatectomy or radiation to the prostate." Because to me, at least, once you start systemic therapy, it's a form of advanced management.

Maybe that's a better word, and I realize it's subjective, but I think what's really important in your presentation is the complexity, this embarrassment of riches of options, and the importance of the multidisciplinary team. And my second question, Rana, is so we have this level one evidence for all these life-prolonging therapies from BCR, mHSPC, and in mCRPC throughout the spectrum of mCRPC, but yet many patients will succumb to prostate cancer cause-specific mortality and may receive only one or two therapies. What have been your learnings, because you're at the cutting edge of all this research and education, not just in the US, but globally, how do we enhance the multidisciplinary team so that patients receive the appropriate number of therapies?

Rana McKay: No, I think that's a very good question, and it's a struggle. I think there are many factors that come in the way of patients receiving the gold standard treatment, like getting therapy escalation when they need to get therapy escalation, getting genomic profiling when they need to get genomic profiling. And I know we're an international prostate cancer community, and there are lots of barriers from access to drugs, access to genetic testing, cost, and there's physician bias of not thinking somebody is high risk enough to receive, though the data may have suggested or shown and demonstrated that actually all individuals with metastatic hormone-sensitive prostate cancer benefit from therapy escalation. So, I think a lot of these things play into effect. So, I think the more educational tools such as this one that we can get out there and get it in front of routinely treating clinicians and in front of patients, so they can also be their own advocates asking, "Well, I heard about this drug, or I heard about maybe I should do X."

And I think it's important to just improve education, improve access, knock down walls, barriers that are built regarding social determinants of health. There are a lot of barriers internationally across the globe that really can interfere with people getting therapy. We did a study looking at access to ARSIs in a Brazilian population through the public health system in Brazil, and the rates of ARSI use, they're just non-existent, very, very low, and doing almost a cost analysis that actually if you trade in the Lupron or GnRH agonists for orchiectomy and use once-daily abiraterone with food, it's a negligible financial hit. So, I think there are a lot of things that we need to be creative in thinking about to improve access.

Neal Shore: Well, I couldn't agree with you more, and thank you very, very much for a really comprehensive, concise, and inspiring presentation. I really appreciate it, thank you.

Rana McKay: My pleasure.