Management of Advanced Prostate Cancer in Urology: Update on Androgen Receptor Inhibitors - Episode 8
Ashley E. Ross, MD, PhD, discusses challenges and unmet needs in managing nmCRPC and Bobby Liaw, MD, reviews the PROSPER and ARAMIS trials.
Neal Shore, MD, FACS: Let’s transition to nmCRPC [nonmetastatic castration-resistant prostate cancer]. Ash, isn’t it incredible that when the AUA [American Urological Association] Guidelines came out in advanced prostate cancer, they had the 6 index cases? Index case 1 was what we called M0. We regularly refer to it as nmCRPC. It was M0 CRPC [castration-resistant prostate cancer], and there was no level 1 evidence for anything other than PSA [prostate-specific antigen] mitigation concepts. In a short time, we have 3 unbelievable studies: PROSPER, ARAMIS, and SPARTAN. Ash, your thoughts?
Ashley E. Ross, MD, PhD: I have 2 thoughts. And I’ll tell you something that surprised me. Obviously, in nonmetastatic CRPC [castration-resistant prostate cancer], if the PSA doubling time is significant, you inevitably think the guy may have metastasis. One thing I struggled with initially when I was waiting for those trials to come out is that these guys are not usually very symptomatic. The population tends to be older, maybe a little frailer. Are we going to help them by initiating therapy before we see something on conventional imaging?
I was delighted and enthusiastic about seeing the results that Bobby and Vivek are going to talk about from those 3 trials, the intensification of this space where the guys can progress through fairly quickly if they have a faster doubling time, which improves overall outcomes and overall survival and does so without a big detriment to their morbidity. I’ll let them talk about how the space is changing or vanishing in the setting of PET [positron emission tomography] imaging. I’ll pose a question to them that I’m sure you would have posed: if we have level 1 evidence based on conventional imaging, for someone who has PET-only imaging positive, how do you treat them in the CRPC space?... There are great data there. I’ll let you hand it over to 1 of the others to talk specifically about the trials.
Neal Shore, MD, FACS: Yes, I definitely want to talk about the role for PSMA [prostate-specific membrane antigen]–PET, not only in high-risk localized disease and in BCR [biochemical recurrence] but also in nmCRPC. There was a nice paper published on this by the National Cancer Institute CCDR [Cancer Care Delivery Research] Program. Bobby, please review PROSPER and ARAMIS and some of the end points. Then we’ll have Vivek weigh in on SPARTAN.
Bobby Liaw, MD: PROSPER was a double-blinded, randomized phase 3 study in nmCRPC, and all the men who enrolled on the study had a PSA doubling time of 10 months or less. They were randomized 2:1 to get either ADT [androgen deprivation therapy] plus enzalutamide or ADT plus placebo. It’s important to note that the primary end point of the study was metastasis-free survival. It’s the first time we’re seeing this end point peeking into our prostate cancer trials. It’s been found to be a strong surrogate for overall survival. It’s also associated with morbidity and prostate cancer–specific mortality.
Enzalutamide is an active agent in CRPC. We knew this. It demonstrated a very significant improvement in this primary end point of metastasis-free survival: 36.6 vs 14.7 months, which is highly significant. It also showed clear superiority over the placebo in some of the secondary end points of PSA progression and time to first use of a subsequent antineoplastic therapy. With extended follow-up, it was also found that the enzalutamide arm resulted in a significantly longer median OS [overall survival] compared with ADT alone.
While we’re postponing metastasis from developing, it’s intended to improve a patient’s quality of life by preventing bone pain, fractures, and things like this from happening. But we have to take into consideration the ongoing use of an AR [androgen receptor] inhibitor and that can have in terms of long-term adverse effects. People can be on this for years.
There were additional secondary end points of pain progression. Health-related quality of life was looked at. Time to clinically meaningful pain progression was longer with enzalutamide compared with placebo. Compared with placebo, the time to first worsening of urinary symptoms and bowel symptoms was much improved with enzalutamide. The only thing that enzalutamide fell a little short with is worsening of hormone treatment-related symptoms, which makes sense. It also found that both groups maintained a pretty stable quality of life throughout the entire time of the study without any big significant differences between the 2, which is a very important finding.
ARAMIS was a similarly designed randomized phase 3 study, this time looking at ADT plus darolutamide vs ADT plus placebo. We’re seeing metastasis-free survival as our primary end point, for which darolutamide performed admirably: 40.4 vs 80.4 months. In terms of secondary end points, which include time to pain progression, cytotoxic chemotherapy use, and symptomatic skeletal event, these all favored darolutamide as well. Safety was a key concern in this study, especially because this was the debut phase 3 study for darolutamide. But the incidence of adverse events was generally similar in the darolutamide and placebo groups.
There were no significant differences in the key adverse events that we generally associate with next-generation AR inhibitors, such as fractures, falls, seizures, weight loss. And the percentage of patients that discontinued treatment was similar between the darolutamide and placebo arms, which was roughly around the high 8%, so it’s very similar. With longer follow-up, darolutamide also demonstrated superiority in terms of overall survival, which is excellent. With long-term follow-up darolutamide continues to show excellent tolerability, with close to 90% of patients continuing at the recommended dosage of 600 mg twice a day clinically. That’s very important because these patients are generally asymptomatic and have a good quality of life, so finding options that are effective at prolonging survival and minimizing long-term toxicity to help preserve quality of life is extremely important.
Neal Shore, MD, FACS: That’s a great overview of both studies.
Transcript Edited for Clarity