Read the Full Video Transcript

Alicia Morgans: Hi, and welcome to UroToday, and our online medical education program, Beyond Androgen Blockade: New Pathways and Novel Treatments in Metastatic Hormone-Sensitive Prostate Cancer and Metastatic Castration-Resistant Prostate Cancer. My name is Alicia Morgans and I have the honor to moderate today's discussion following a presentation by Dr. Andrew Armstrong. His topic is the Clinical State of Metastatic Hormone-Sensitive Prostate Cancer, Current Treatment Landscape and Clinical Trials and Progress in mHSPC. Thank you so much, Dr. Armstrong.

Andrew Armstrong: Thank you, Alicia. It's a real honor to be with you, and this is a disease state where there's much to be learned in an ever-evolving landscape. So like Alicia mentioned, I'm going to talk to you about the landscape of metastatic hormone-sensitive prostate cancer, a rapidly changing field, and so I hope the next couple minutes will bring you up to speed in the clinical management of these patients.

As I've traveled around the world learning about this disease state from different parts of the world, I've seen that about five or 10% of men in the US present with metastatic disease, but outside of the US this is actually really common. Somewhere between a third and 70% of patients will present with metastatic disease de novo, including China and India. And so this is a really important disease state to cover globally.

We have many treatment options to offer patients. It's really no longer standard of care to offer ADT alone to these patients that have metastatic hormone-sensitive prostate cancer. And the landscape has been informed by really impactful trials like STAMPEDE, LATTITUDE, CHAARTED, ARCHES, ENZAMET, TITAN, more recently ARASENS and PEACE-1. All of these data suggests that treatment intensification with the early use of potent AR inhibitors is improving survival, deepening remissions, and is much better than waiting for castration resistance to occur. And even triple therapy is really changing our paradigm to further improve survival.
When patients do progress, we have many weapons in the castration resistance setting to talk about, but that's going to be a subject for another talk. As a nice summary slide, in hormone sensitive disease, we have many level one evidence clinical trials. They're all shown right here for your reference. We have radiation, we have the potent AR inhibitors, and we have docetaxel as part of triplet therapy, each of which have extended the lives of patients.

The AR inhibitors are largely effective regardless of disease volume, but triplet therapy has largely been seen to improve survival in men with high volume disease, at least as of this time point. In addition, radiation to the prostate for men with de novo disease can improve survival but largely restricted to patients with low volume disease by conventional imaging. This is the data for the STAMPEDE trial and radiation to the primary, where you see that radiation to the primary does improve survival, actually to the same degree as some of our best systemic therapies.

But there's heterogeneity in that benefit where patients with a high burden of disease based on conventional imaging, again, have no benefit from radiation to the primary. Just to show you some new data from the ARCHES study we recently published in European Urology, data around enzalutamide in men with metastatic hormone-sensitive prostate cancer, where we show that the overall and progression-free survival benefits of potent AR inhibition are there regardless of how many metastases you have.
So unlike radiation to the primary where there's increasing benefits with lower volumes of disease, these potent AR inhibitors are very effective, even with just a solitary or two metastases, suggesting that our standard of care for treatment intensification with an ARSI should apply to men even with oligometastatic prostate cancer.

Others in the field are also studying oligometastatic prostate cancer by applying radiation, metastasis-directed radiotherapy to avoid systemic therapy. And this is an alternative, a parallel approach where some studies like STOMP have shown in some patients a significant ability to delay the need for ADT. However, most patients fail this approach, suggesting that most metastatic prostate cancer is a systemic disease, and that we should be applying our best principles of systemic therapy, maybe in conjunction with metastases-directed therapy to further improve outcomes. However, some patients can successfully delay systemic therapy with metastases-directed therapy by a few years, if that's the goal.

The ORIOLE study out of Johns Hopkins also confirmed that stereotactic body radiation in some men can successfully delay the need for systemic therapy over observation alone. These studies have not been compared with our best systemic therapy. The only study to really show that combined systemic therapy with metastasis-directed therapy may be effective is called the EXTEND study, where this randomized trial of men with metastatic hormone-sensitive prostate cancer got combined hormonal therapy, not with an ARSI, but just ADT, and then they took a break, so intermittent therapy.

The combined group got metastasis-directed therapy, while hormone therapy alone was given to the control group. And you can see that the combined group had a significantly longer time to enjoy their break from intermittent therapy. However, for men with high volume disease, we don't really talk about intermittent therapy, and these men have a pressing life-threatening prostate cancer that needs therapy.

And from both ARASENS and PEACE-1 study, we see that agents like abiraterone significantly improved survival on top of ADT docetaxel, but largely in high volume patients, has ratio 0.72, and with darolutamide with docetaxel concurrently, we again see an overall survival benefit hazard ratio of 0.69, largely restricted to the high volume patients, and the low volume patients we don't see a significant benefit yet, although this is an underpowered analysis and patients are still being followed.

So Dr. McManus and I published in JCO this year a pretty simple algorithm for managing metastatic hormone-sensitive prostate cancer. Again, based on conventional imaging, because that's how all of our trials have been done, and breaking patients by disease volume and whether they have synchronous or De Novo disease or metachronous or relapse disease. You'll see that ADT alone is really not a standard of care for most of these patients, where treatment intensification is the standard of care based on level one evidence, with triplet therapy being reserved for those with synchronous or metastatic high volume disease and treatment of the primary reserve for synchronous low volume patients.

It is important to remember that genetic testing is the standard of care for all men with metastatic prostate cancer. We do this to inform both genetic risk to family members, but also precision medicines down the road. In 2023, we saw the approval of three PARP inhibitors in combination with AR inhibitors, and these are now moving into earlier settings. We have MSI-high disease, which can also inform on pembrolizumab as well as clinical trial eligibility.

There is some suggestion that clinical genomic testing might help with treatment strategies in the hormone-sensitive settings such as SPOP mutations, conferring exquisite hormone sensitivity and sensitivity to potent AR inhibitors, while not conferring sensitivity to docetaxel, suggesting maybe these patients could avoid docetaxel. That's a hypothesis right now.

And then PTEN/RB/P53 loss, these patients do much more poorly and may benefit from triplet therapy. These are patients that are more likely to have high volume disease, visceral metastases, such as liver metastases. There's some really interesting ongoing Phase 3 studies that are testing newer versions of triplet therapy. The TALAPRO-3 trial is testing enzalutamide placebo, ADT plus or minus talazoparib, a PARP 1/2 inhibitor for patients that have DNA repair defects. The AMPLITUDE study is testing niraparib in a similar population with abiraterone, and this is based on the success that's been seen in patients with DNA repair defects in the castration resistance setting.

The CAPItello study is taking patients with P10 deficiency and looking at PI3 kinase, AKT inhibition, and the PSMA Addition study is looking instead at phenotypic precision medicine with radiologic imaging and taking PSMA PET positive patients and randomizing them to standard of care potent ARSI ADT therapy plus or minus PSMA lutetium.

I do want to point out that we do need to do a better job with clinical trial representation. If you look at all of our prostate cancer Phase 3 studies, there is still a disparity in the enrollment of black men in those clinical trials. We do a very good job in federal studies, but in industry and academic studies, we have a long way to go where there's been an over-representation of white men and an under-representation of black men who are disproportionately affected by lethal prostate cancer. So this is a call to action for that.

As you treat these patients and follow them long-term, you start to see patients living five, six, seven years in complete remission from these potent AR inhibitors. Prostate cancer is the number one survived cancer in America, and we're extending life even longer now with these intensive therapies. But you can't forget about the burden of the treatments on our patients' bodies. Obesity, issues with cardiovascular fitness and diet, really important, mental health, preventative vaccination and long-term attention to bone monitoring, exercise and heart health.

So it really takes a team. The medical oncologist along with radiation, nuclear medicine and urologists are at the forefront, but working in conjunction with primary care doctors, nursing, community support, counselors for genetic risk patients. This is just a cartoon showing some of the major side effects of these potent inhibitors, fatigue, fall risk, loss of muscle mass, some cardiovascular risk and bone health. Really important in some of the strategies to reduce the burden of these therapies.
These are just some key survivor tips to getting your patients through this. I provide this as an after visit summary to my patients to educate them and reinforce this at each visit to keep patients healthy long term. So in summary, we've come a long way since the original Nobel Prize winning discoveries in 1941 of just androgen deprivation therapy alone. We're now blocking AR more potently blocking adrenal axis, and patients are living longer because of this.

I think you're seeing new trials of more precision therapies of genetic-guided therapies, of radiographic, radioligand therapies starting to move into earlier disease settings, integrating these AR inhibitors into the non-metastatic hormone-sensitive setting. That's again, probably something for another talk, but a lot of exciting data, certainly a changing field and excited to present this to you. Thanks, Alicia.

Alicia Morgans: Thank you so much for that fantastic conversation and presentation, Dr. Armstrong. I know I can always rely on you to not only level set, but to raise the level, and I wanted to dig in a little bit to one of the things that you raised, and we'll dig into multiple. So first, it sounds like ADT and an androgen receptor signaling inhibitor, generally that's the backbone to which we add multiple other things. Did I understand correctly?

Andrew Armstrong: I think that's correct. There are certainly patients where maybe you see metastasis on a PET scan like a PSMA PET scan, which is very popular right now. And I see every day in my clinic where we don't yet know if you have to intensify therapy for all patients. Certainly many of my patients will say, "Well, can you just treat that lesion and avoid these very expensive medicines that can cause hormonal side effects?" But I would say for metastatic disease that's on conventional imaging, the standard of care is these potent inhibitors.

Doesn't necessarily mean for the rest of a patient's life. I certainly have patients where I've applied metastasis-directed therapy and then stopped therapy. That's a little bit outside of the evidence that I showed, but there are some patients where taking a break could be considered. But for patients with high volume disease, it's really continuous therapy until disease progression happens. For these patients with very low volume or oligometastatic disease, I think we could start to apply and think about curative intense strategies where you're combining the best of metastasis directed therapy with systemic therapy.

Alicia Morgans: I certainly do the same in my practice. And I do think, as I think you mentioned, that we will see some further evidence hopefully from STAMPEDE iterations and other studies. But one of the things you also mentioned in addition to this is that we really do have a heterogeneous population of cells, particularly most likely in those patients with high volume disease, and that we may need to use different combinations in addition to that backbone of ADT and an ARSI to really hit those targets more effectively. What do you think?

Andrew Armstrong: Yeah, that was the basis for docetaxel. Docetaxel has many mechanisms of action. It's a microtubule poison. It actually can work through androgen receptor signaling, but showing that docetaxel works even better early on than later is very impactful. And I suspect that you'll see that with other therapies like PSMA lutetium. So people are starting to move radioligand therapies and precision inhibitors like PARP inhibitors into this earlier setting. Certainly the AR inhibitors, which work much more effectively, maybe because of the greater homogeneity of the cancer before castration resistance develops, and then it becomes so heterogeneous that it's really hard to get a long-term remission.

Alicia Morgans: Wonderful. Well, as you think about the combinations moving into the metastatic hormone-sensitive setting, as well as those that are newly moving into first line mCRPC, which is sometimes the moving target between these two settings, how do you think about choosing between all of the new combinations that exist now and may exist in the near future, particularly as you think about survivorship, which you also mentioned?

Andrew Armstrong: Absolutely. So largely I communicate to my patients that all these AR inhibitors are equally active. They all improve survival, but the right choice for that individual may be based on simple things like availability and costs, or comorbidities, drug interactions, whether a patient's taking a statin or an anticoagulant or has a cardiac condition. Some of it's based on age. Some of our agents, enzalutamide in particular, and older men can put a patient at more vulnerability to falls, fractures, cognitive effects. Drugs like darolutamide have no effects like that. So in older men, darolutamide is a great option.

Right now it's kind of linked to docetaxel, which is frustrating. So you'd rather have trials like ARANOTE, which I should have mentioned, are undergoing randomized trials right now. We just don't have the level one evidence at this point. That doesn't mean you can't use this agent in that setting if docetaxel is contraindicated, and I do that. It would be a bit off label, but it's still something it can help your patients and you can advocate for.

Alicia Morgans: Wonderful. And I guess final question, you presented multiple trials in progress, and certainly you can't present every trial in progress in the MCSPC or mCRPC setting, but as you think about it, and as you think about combinations that may be effective for the heterogeneity of disease, what are your thoughts on moving effective strategies from the mCRPC setting into the MCSPC setting to try to have more effectiveness perhaps earlier on in the disease?

Andrew Armstrong: I think so far it's been very successful. I do have some concerns. For example, PARP inhibitors can cause DNA damage, so I'm a little concerned about causing that DNA damage early if you're not eradicating the disease, and seeing what evolution of the cancer might look like after a PARP inhibitor, or the bone marrow toxicity from that long-term PARP inhibition. So I'm not sure that that strategy is going to apply to all drugs. PSMA lutetium, certainly it could apply earlier when the PSMA intensity is less heterogeneous.

But then you have the challenge of the disease going away basically on imaging. And so what are you actually targeting? Do you have to give all six doses or are you just basically treating the salivary glands at that point? So could you just give one or two doses and then save more for later? I would also like to highlight the non-metastatic hormone-sensitive trials, ATLAS and ENZARAD and DASL-HiCaP, and certainly STAMPEDE. These agents might be the most effective when used in early disease to cure patients more, for example, with radiation and two years of intensive therapy so that we never have to see metastatic disease.

Alicia Morgans: Well, I sincerely appreciate you walking us through this, and even as you make things more clear, you raised so many more questions for us to investigate, and that is always one of my favorite things about talking to you. So thank you so much for sharing your knowledge and taking the time with us today.

Andrew Armstrong: Thanks, Alicia and to UroToday. Really appreciate it.