What are the remaining challenges for all of us who treat advanced prostate cancer patients and who undergo testosterone [T] suppression? We have learned a lot over the years to become better stewards of the multitude of adverse reactions that occur with T suppression for these men, including loss of sexual function; thermoregulatory discoordination; in terms of hot flashes, which can be very debilitating; bone demineralization; and the quasi-metabolic syndrome, which can also lead to cardiovascular events.

Cardio-oncology, which has gained great importance throughout cancer oncolytics, has something that urologists, medical oncologists, and radiation oncologists need to be aware of: the opportunity to start a patient, who may be at increased risk for cardiovascular events, with a potentially safer drug, a more convenient drug, and 1 that has demonstrated its T-suppressive benefit. That is the goal of all androgen deprivation therapy [ADT] when it’s appropriate. This augments our treatment toolbox.

There are some additional data points that we need to get a better handle on; drug-drug interactions with other molecules that always have a possibility. We see this in various other oral oncolytics that we’re using throughout GU [genitourinary] oncology, and certainly in prostate cancer. Those studies are ongoing. We had a nice presentation at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] this year looking at the safety and efficacy of combining relugolix with radiation therapy patients, as well as docetaxel and enzalutamide.

Testosterone suppression is remarkably effective and powerful for many of our patients with advanced prostate cancer throughout their treatment journey; however, maybe 1 day we’ll be able to treat patients with other alternative modes of therapy that don’t require testosterone suppression. But for now, the approval of relugolix for our patients with advanced prostate cancer who require androgen deprivation at the appropriate time is a most welcome option, especially with the enhanced cardiovascular safety profile.

 Going forward, we are going to continue to have challenges in managing our patients with advanced prostate cancer with ADT; some of which relugolix can help. There is a concern of the cumulative effects of antigen deprivation therapy in patients with cardiovascular risk. We’re beginning to recognize more on how prevalent this is, particularly in our real-world populations.

One of the things that stands out from the HERO study is how frequent lifestyle cardiovascular risks, including smoking and obesity, were in our patient population; and how frequent comorbidities were, including preexisting hypertension, diabetes, and prior history of stroke or heart attack. When we get into our real-world patients, we expect these rates to be even higher. Recognizing what the effects antigen deprivation therapy has on cardiovascular risk is going to be increasingly important. Identifying therapies that carry a low burden of cumulative risk of cardiovascular events is going to be vitally important to the long-term survival of our patients, especially as they live longer, as we treat older men, and as we combine our antigen deprivation therapies with other treatments that also increase the risk of major cardiovascular events, like stroke, heart attack, and sudden death.

These include, as a class, the novel antigen receptor antagonists, our chemotherapies, and even some of our systemic radiotherapies—all could increase some of these risks. We are going to see more of this risk evolve. Having a baseline therapy that is associated with the lowest cumulative risk of these events is an unmet need and something that the HERO data, relugolix in particular, address.

When thinking about the remaining challenges and unmet needs in this patient population, 1 is whether the antagonists are really better. We have this strong signal, and hopefully we will have that answer someday. It looks promising that the antagonists are going to be more heart-healthy.

Even with that, even if they’re more heart-healthy, being castrated has its effects. It increases the risk of diabetes, which in turn is a major risk factor for cardiovascular events. How can we do even better? What is the right lifestyle approach to get these men to combat the cancer and reduce the adverse effects of cardiovascular and diabetes risk, weight gain, and fatigue? These are the effects that men get that make hormonal therapy unpleasant for some. How can we bring in lifestyle and pick the right ADT, and maybe other agents, to minimize those risks but get improved cancer control?

The data that we have in this disease space is from white men. We don’t understand the impact of our treatments well on minorities, particularly the African American population, which is at an increased risk of having aggressive prostate cancer. We know little about Hispanics. It appears that they have similar outcomes, in terms of cancer, to non-Hispanic whites, but country of origin makes a difference. Puerto Rico has higher risks than some of other places. Understanding how hormonal therapy works, how agonists and antagonists work in these populations, and how our lifestyle interventions work in these other populations remains a great unmet need in this field.

*Dr Freedland receives consulting honorarium from Astellas, Pfizer, Janssen, Clovis, Merck, AstraZeneca, Sanofi, Bayer, and Myovant. He is a speaker for AstraZeneca and Sanofi.

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Experts discuss challenges and unmet needs in men with advanced prostate cancer who are undergoing treatment with androgen deprivation therapy. 

Advanced Prostate Cancer: Remaining Challenges

We’ve been hearing about cardiovascular events for a long time in prostate cancer, but as we’re getting better at keeping these men alive, and not dying of their prostate cancer, we are seeing an increased risk of cardiovascular events. We know that men with cardiovascular disease are more likely to develop prostate cancer. This is a group of men who walk in the door and are at a higher risk of having cardiovascular disease and developing cardiovascular events: MI [acute myocardial infarction], stroke, or heart failure. We need to be careful with these men and thoughtful in terms of treating them with ADT [androgen deprivation therapy]. There is overwhelming observational data that androgen deprivation therapy, at least via GNRH agonist, which is what’s largely been done for the last several decades, does increase the risk of cardiovascular events.

When we think about the comorbidities we’re looking for, a lot of men will have hypertension, and that is a cardiovascular risk factor. In some of the data sets I’ve looked at, upward of 70% to 80% of men with advanced prostate cancer will have hypertension. Obesity is another cardiovascular risk factor, it’s about one-third of the men we see. We try to do clinical trials of statins; however, they’re tough to do because so many men are already on statins to begin with. If you lump some of those together, you end up with a metabolic syndrome. Many men will have diabetes as well. Certainly, if they’ve had a cardiovascular event, an MI, they’ve had stents placed, they’re on anticoagulants for the stents, or they’ve had a stroke, those men are at particularly high risk of developing another cardiovascular event from the ADT. We need to be cognizant of that. This is not to say that we should avoid ADT, but we should use it carefully. Does this patient really need hormonal therapy in the first place? If yes, they have metastatic disease, or symptomatic—in certain circumstances we’ll know it has tremendous benefits. We have to be thinking, what can we do to reduce the risk of having new cardiovascular events in these patients?

One thing I spend a lot of time talking with my patients about is lifestyle interventions: getting exercise and losing weight. Invariably the question is, what’s the best way to lose weight? When I talk to different dietitians and experts in the field, there’s only 1 thing they can all agree on: that simple sugars are bad—cookies, cakes, candies, and soda. That’s what I focus on, which is trying to eliminate the simple sugars. Within that, if patients are interested in a vegan, Mediterranean, or ketogenic diet, I’m happy to work with them. But I make sure they’re aware that diet is important, but exercise—particularly vigorous weight-bearing exercise—is important in terms of reducing osteoporosis.

Moving on from lifestyle, is there anything we can do drug-wise to try to reduce those risks? There are some exciting data with a new oral GNRH antagonist, relugolix. In a randomized trial, a secondary outcome was a reduced risk of MACE [major adverse cardiovascular event]. It wasn’t the primary outcome of the study. It’s consistent with some of the older data we saw with degarelix, but that was never the primary outcome of a study. There are increasing data that this may be a class effect of the GNRH antagonist. At this point, we don’t know that for sure, but it does seem quite promising.

Almost everyone is hypertensive, needs to lose a little weight, and has some high lipids. But the strong risk factors would be if they’ve had a MACE event before, they’ve had stents, they’ve had a CABG [coronary artery bypass grafting], they’re on blood thinners because of the stents they have, or they’ve had a stroke or TIA [transient ischemic attack]. With those patients, we have to be thoughtful and say, “They need hormonal therapy, but is putting them on an agonist the right answer?” I’m not here to say yes or no, but it’s something we need to pause to think about. What is the way that I’m going to protect this patient from getting into trouble with this prostate cancer, and also how am I going to prevent him from getting in trouble with his heart?

What’s amazing is that if you look at men with prostate cancer, not necessarily the men getting ADT who are a little more advanced, but in general, men diagnosed with prostate cancer are more likely to die of heart disease than prostate cancer. The patient is diagnosed with cancer, yet they’re more likely to die of heart disease. Heart disease is the No. 1 killer of men in general, so we’ve always got to be thinking heart-healthy. We’ve learned that there’s the suggestion that relugolix, particularly GNRH antagonists, may be more heart-healthy.

Stephen Freedland, MD, discusses risk factors involved in men with advanced prostate cancer who receive androgen deprivation therapy. 

Risk Factors in Advanced Prostate Cancer

The report from ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] 2021 on concomitant medication from the HERO study, men treated with relugolix or leuprolide for advanced prostate cancer was a pivotal trial to study the first oral GNRH antagonist relugolix, Orgovyx, in comparison with leuprolide. In this study, patients were randomized to 1 or the other 2:1 and treated for 48 weeks with continuous therapy. Patients were checked for testosterone suppression continuously, and overall relugolix demonstrated a 97% continuous suppression of testosterone throughout the study period, which was superior to that of leuprolide.

It also demonstrated a 54% reduction in the risk of cardiovascular events, in particular major adverse cardiovascular events, including stroke, heart attack, or sudden death. In recognizing this 48-week period, we anticipated that some patients would have some disease progression. In the HERO study, patients were allowed to have concomitant therapy for disease progression, because it has become common in patients with advanced prostate cancer with a disease progression, and treatments with novel androgen hormonal agents, such as enzalutamide or chemotherapy such as docetaxel.

In the study, roughly 2.7% of the patients on relugolix received concomitant enzalutamide, about 1.9% of those in the leuprolide arm received enzalutamide. Another 1.6% of patients with relugolix received docetaxel chemotherapy concomitantly and 1.9% of the leuprolide patients received docetaxel chemotherapy concomitantly. In addition, patients were allowed to receive radiation therapy, whether it be palliative or localized radiation therapy. In the relugolix arm, 15.5% of patients received concomitant radiotherapy and 18.8% of patients in the leuprolide arm received concomitant radiotherapy. When looking at these results, we recognize these numbers are relatively small for the systemic therapy arms, but with nearly 900 patients treated, there are enough data here for us to get an early look at the results of enzalutamide and docetaxel.

It appears throughout the population receiving those, both ruxolitinib and leuprolide testosterone levels remain suppressed. There is the pharmacodynamics effect with both agents and, in particular for relugolix, we saw over 95% continuous testosterone suppression throughout the study with receiving either enzalutamide and relugolix or docetaxel and relugolix. We also looked at the adverse-effect profiles for these concomitant therapies, including radiation therapy, and saw no new adverse-effect complications or signals. They were comparable in both arms, but there were higher rates of toxicity and grade 3 toxicity with both relugolix and leuprolide in combination with docetaxel or enzalutamide.

Relugolix is an effective agent as an androgen deprivation therapy for patients and can be combined with concomitant systemic therapies, including enzalutamide and docetaxel. Based on these data, a standard of care use of relugolix with radiotherapy is acceptable, given the continuous testosterone suppression effects, as well as the similar safety profiles. More studies will be needed to study combinations up front of relugolix with concomitant therapies to further define the efficacy and safety of these regimens.

It’s important to recognize that more commonly in our practice, antigen deprivation therapies are being combined with both local therapies and systemic therapies. And recognizing that even as patients progress from the castrate-sensitive to the castrate-resistant disease setting, ongoing antigen deprivation therapy is a de facto standard of care. It will be important to recognize that relugolix is highly effective in combination with systemic agents, including enzalutamide and docetaxel.

This can be effective in the castrate-resistant and castrate-sensitive prostate cancer settings. More studies and more data will be needed long term, and other agents will need to be looked at. But it’s promising to see that there doesn’t appear to be any drug interactions that would either elicit unexpected or more severe toxicities or that would affect pharmacodynamically the efficacy of relugolix in suppressing testosterone.

Dan George, MD, reviews new findings in advanced prostate cancer presented at ASCO GU 2021.

Advanced Prostate Cancer: New Findings From ASCO GU 2021

On December 21, 2020, the FDA approved relugolix, commercially known as Orgovyx. This is the first oral GNRH receptor antagonist approved for patients who would benefit from androgen deprivation therapy [ADT]. This is a real breakthrough in the arena of androgen deprivation therapy. All prior ADT has been parenteral, meaning a subcutaneous or intramuscular injection.

Relugolix is a GNRH antagonist, as opposed to all the parenteral LHRH agonists. It’s a similar antagonist to degarelix, which is given via a deep subcutaneous injection. The obvious advantage is the mechanism of action. Within a matter of days, it lowers the testosterone [T] to castrate levels and achieves what you’re trying to do, when appropriate for a patient with advanced prostate cancer.

The LHRH agonist formulations all have a superphysiological surge of LH [luteinizing hormone], FSH [follicle stimulating hormone], and therefore, testosterone. For the first 2 weeks, it’s somewhat counterintuitive to what you’re trying to accomplish. It’s the only pill that’s available. The first day the patient takes 3 pills, then it’s 1 pill once a day; there’s no food-effect requirement. This is particularly advantageous to patients for whom convenience is a concern, an issue of travel, but especially during the pandemic, decreasing exposure for both the patient and his family, as well as the clinic for their exposure.

The HERO phase 3 trial had tremendous global participation and Asian, Latin American, European, and North American sites. A steering committee was designed to look at over 900 patients, a 2:1 randomization for patients who required, through the investigator’s assessment, androgen deprivation therapy. About half the patients had a PSA [prostate-specific antigen] biochemical relapse. About 25% had high-risk, locally advanced disease, who were not deemed appropriate for an interventional treatment, such as surgery or radiation, and another quarter had metastatic disease. Our primary outcome measure was testosterone suppression from day 28 through 48 weeks. Then multiple key secondary end points of profound T suppression, PSA suppression, safety, and tolerability. There was a subset of the population, about 184 patients with a 2:1 randomization, looking at early T recovery at the end of 48 weeks.

We found that the biostatistical analysis demonstrated first a noninferiority to LHRH. Then with a second review, we were able to claim superiority, essentially a near 97% sustained T suppression from day 29 through week 48. The LHRH formulation was approximately 89%. In a subset population, we saw patients had about 53% by day 90 had a testosterone return to u-gonadal levels, whereas only 3% of the LHRH population returned to u-gonadal levels by day 90.

In terms of toxicities, they were consistent in both arms, the relugolix and LHRH agonist arms, consisting of the usual hot flashes and loss of libido. These were not dissimilar in either arm. What was particularly noticeable is that a prespecified safety analysis, there was a 54% decrease in cardiovascular events in the relugolix arm vs the LHRH agonist arm.

Patients who’d had any major adverse cardiovascular event, a myocardial infarction, or a stroke within 6 months of starting the study were excluded from being in the trial. We had 14% of patients who’d had a MACE [major adverse cardiovascular event] prior to the 6-month exclusion, and there was a near 2-fold decrease in cardiovascular events in the relugolix arm. When we looked in the entirety of the population, looking at the patients who had a MACE 6 months prior to entry, it was nearly a 5-fold decreased risk of a MACE, in the relugolix arm vs the LHRH agonist arm.

, and it had 2 plenary presentations at ASCO [American Society of Clinical Oncology Annual Meeting] 2020 and AUA [American Urological Association Annual Meeting] 2020, reviewing the data. There is a unique opportunity to start a patient on a pill formulation, 1 pill once a day, instead of requiring them to come into a clinic to get an injection. There is excellent testosterone suppression, which is the pharmacological end point for all the ADT formulations, and a safety profile that had a 54% decrease in cardiovascular events. Unfortunately, most patients who require ADT have cardiovascular risk, more than 90%. Oftentimes that is by the nature of their older age but also because of issues like obesity, dyslipidemia, hypercholesterolemia, diabetes, hypertension, or prior arrhythmia. It’s not all patients, but it can be upward of 30% in some populations, and even higher, depending upon where you are in the globe and their prior cardiovascular history. This formulation—its convenience, its T suppression, and its cardiovascular safety profile—augments nicely for many patients considering androgen deprivation therapy.

Neal Shore, MD, discusses the recent FDA approval of the first oral GNRH receptor antagonist, relugolix, for men with advanced prostate cancer, along with data from the phase 3 HERO trial.

Stephen Freedland, MD, Cedars-Sinai Medical Center

Articles

Advanced Prostate Cancer: Remaining Challenges

Risk Factors in Advanced Prostate Cancer

Advanced Prostate Cancer: New Findings From ASCO GU 2021

The First Oral GNRH Receptor Antagonist for Advanced Prostate Cancer