Expert Discusses Degarelix and Other Developments in Prostate Cancer

Guru Sonpavde, MD

The question of when to administer the LHRH receptor antagonist degarelix (Firmagon) to patients with castration-sensitive prostate cancer versus an agonist still remains to be answered, according to Guru P. Sonpavde, MD.

“Unfortunately, it looks like we may never have—at least with the trials ongoing and that have been done—a definitive answer to the question of whether we should be using degarelix for all patients,” said Sonpavde. “At the moment, all we can say is high-volume disease and in patients with a history of cardiovascular events, it might make sense to use degarelix based on the data we have.”

OncLive: What did you focus on in your presentation on prostate cancer?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Genitourinary Cancers, Sonpavde, director of Bladder Cancer at the Dana-Farber Cancer Institute, discussed degarelix, androgen-deprivation therapy (ADT), and ongoing trials with immunotherapy that are crucial to advancing the treatment of patients with prostate cancer.Sonpavde: In the talk, I focused on degarelix, which is an LHRH receptor antagonist as opposed to the LHRH agonists that are in use for a longer time. Essentially, the data right now for degarelix are that this drug suppresses testosterone more rapidly and might have some benefit in patients with a history of cardiovascular events. It seems like patients who have had cardiovascular events might have fewer cardiovascular events on degarelix as opposed to LHRH agonists. There might also be a benefit in terms of prostate-specific antigen progression-free survival, but we’re not quite sure about the efficacy yet because these trials were not designed to look at efficacy as the primary endpoint.

What questions do we still have with agonists and antagonists?

How can community oncologists manage comorbidities that these patients might have? Is there any chance that you might need to switch therapies because of them?

You also spoke about the STAMPEDE and LATITUDE trials. What questions do we still have following the results of these studies?

At this time, it will be reasonable to use degarelix in patients with cardiovascular events based on the lower cardiovascular event rate with degarelix compared with LHRH agonists and in patients with high-volume disease, especially spine metastasis where you want to have rapid control of the disease to prevent cord compression. However, we don’t have a phase III trial looking at efficacy. There is a trial going on that is looking at…[an] LHRH agonist verus degarelix, with cardiovascular events as the primary endpoint. That will answer that question more definitively regarding cardiovascular events.What is not clear is, should we be giving the antagonists to all patients with castration-sensitive disease? This is not clear. The phase III trial that’s been done so far focused on testosterone suppression as the primary endpoint and not antitumor efficacy. The trial going on now—the PRONOUNCE trial—is looking at cardiovascular events as the primary endpoint.ADT does lead to some adverse events—impotence, bone loss, bone thinning, dyslipidemia, glucose intolerance, and a slight increase in cardiovascular events. We are not sure about cardiovascular mortality, but there is an increase in cardiovascular events. Therefore, you have to pay attention to weight, lipid control, blood pressure control, and perhaps aspirin prophylaxis in patients at high risk for cardiovascular events. A lot of these common-sense things should be paid attention to, as well as modify the cardiovascular profile before you even start ADT. For example, you might want to get control of the blood pressure and lipids, or at least start controlling these comorbidities, when you’re about to start ADT.Both the STAMPEDE and LATITUDE trials looked at the value of adding abiraterone acetate (Zytiga) plus prednisone to patients with castration-sensitive disease. LATITUDE was focused on patients with high-risk metastatic castration-sensitive disease; whereas, STAMPEDE was a more heterogeneous patient population of both metastatic and nonmetastatic patients. Both trials looked very similar. The addition of abiraterone plus prednisone to ADT improves survival with a hazard ratio that was very similar, around 0.63, for both trials.

The lingering doubt remains whether the nonmetastatic patient should get abiraterone, and the issue is in the STAMPEDE trial that included these patients. There were not a lot of mortality events in the nonmetastatic population. The survival difference here was driven by the metastatic patients. The investigators did look at the interaction of metastasis versus no metastasis and they showed there was no interaction. Their position is that both metastatic and nonmetastatic patients should receive abiraterone; however, the fact is that the number of events in the nonmetastatic population was low for mortality events.

You probably have 2 camps right now. One camp suggests that everyone, metastatic or nonmetastatic, should get abiraterone; the other camp says that only patients with metastatic disease should get abiraterone acetate.

Will we start seeing bigger breakthroughs with either PARP inhibitors or immunotherapy for prostate cancer in the next year?

On the other hand, you also have the extreme of the LATITUDE trial, which was in high-risk metastatic patients. There is not a right or wrong answer. I tend to fall right in the middle, which is the metastatic patients. That’s right in the middle between nonmetastatic patients and high-risk metastatic patients.That could be. The trials are ongoing. A phase III trial is now ongoing, looking at olaparib (Lynparza) as second-line treatment in select patients post one of the androgen inhibitors. We'll have to wait and see. I’m not sure we'll have an answer next year.

If these checkpoint inhibitors one day get FDA approval, how could we try to fit them into the paradigm in terms of sequencing?

[Regarding immunotherapy], checkpoint inhibitors are being looked at and it seems like patients that are exposed to enzalutamide might have an upregulation of PD-L1 in the tumors. There was some activity shown in this population in a small cohort. There is hope that there will be benefit with the checkpoint inhibitors in selected patients. We'll have to wait and see for both the PARP inhibitors and the checkpoint inhibitors. There is pembrolizumab (Keytruda) and atezolizumab (Tecentriq) being looked at in this population, as well.The sequencing question is getting more and more complicated, so all of these drugs are now moving up to the castration-sensitive phase, as we saw in docetaxel now in the castration-sensitive phase. There are trials looking at the combination of enzalutamide (Xtandi) and abiraterone acetate with ADT in castration-sensitive disease and multiple combinations are being looked at.

What ongoing research are you a part of that you would like to share?

Right now, both [the PARP inhibitor] olaparib, for example, and PD-1/PD-L1 inhibitors, like pembrolizumab or atezolizumab, are being looked at in the castration-resistant phase. That actually is a space that might warrant looking at this because it looks like the older agents, like docetaxel, abiraterone, and enzalutamide, are all moving to the castration-sensitive space. It might make sense anyway to look at these more novel agents, such as olaparib or pembrolizumab, for castration-resistant disease. The field is evolving very quickly. In the space of prostate cancer, we have a phase I, investigator-initiated trial that is looking at a combination of abiraterone, enzalutamide, and cabazitaxel. This is a triplet combination. We're looking at it in the castration-resistant space of the disease. Cabazitaxel is also a taxane like docetaxel, but it’s not as neurotoxic. It has more myelosuppression but, given the lack of neurotoxicity, you can give it for a prolonged period of time. We'll wait and see what the trial shows.