Deborah A. Bradley, MD, discusses how recent clinical trials have impacted patients with nonmetastatic castration-resistant prostate cancer and what the future holds for them.
Deborah A. Bradley, MD
Recent FDA approvals in the setting of nonmetastatic castration-resistant prostate cancer (CRPC) continue to propel the field in the right direction, but there are still unanswered questions, said Deborah A. Bradley, MD.
Most recently, the FDA approved enzalutamide (Xtandi) in July 2018 as a therapy for this patient population. The decision was based on data from the double-blind, phase III PROSPER trial, in which the combination of enzalutamide and androgen deprivation therapy (ADT) reduced the risk of metastases or death by 71% compared with ADT alone.1 Median metastasis-free survival (MFS) was 36.6 months with enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P <.0001).
In February 2018, apalutamide (Erleada) became the first drug to be FDA approved for use in nonmetastatic CRPC, following the results of the phase III SPARTAN trial. This study showed a 72% decrease in the risk of metastases or death with apalutamide versus placebo.2 Median MFS was 40.5 months versus 16.2 months in the apalutamide and placebo arms, respectively (HR, 0.28; 95% CI, 0.23-0.35; P <.0001). Treatment with apalutamide was also not associated with a significant impact on quality of life.
In an interview during the 2018 OncLive® State of the Science Summit™ on Genitourinary Cancers, Bradley, a medical oncologist at the Levine Cancer Institute, Atrium Health, discussed how recent clinical trials have impacted patients with nonmetastatic CRPC and what the future holds for them.Bradley: For many years, we didn't have many options once patients became castration-resistant without evidence of metastases. With the drugs we had…we would see the prostate-specific antigen (PSA) go down maybe for a few months, but with some significant toxicity in a lot of cases. We needed more options in this space.
When abiraterone acetate (Zytiga) and enzalutamide were proven to improve overall survival in the metastatic castration-resistant space, it became very interesting to us. We figured if patients with metastases respond to this therapy, so should patients without them. However, we never had any data to stand on until February 2018, when both the SPARTAN and PROSPER studies were presented. Each of these trials looked at separate agents, apalutamide and enzalutamide, [respectively], and they were amazingly similarly designed. They were both randomized, placebo-controlled trials looking at MFS as a primary endpoint, and both trials met their endpoint by significantly improving MFS. It seemed to benefit all patients when you look at the subgroup analyses. If you look at the survival curves and PSA response curves, you can almost line them up.
These are 2 different agents with 2 different trials, but [they showed] 2 very similar and exciting results. It makes us feel good that we've got not 1, but 2 drugs for this patient population now. One thing that's important to consider is these were high-risk patients. We know if the PSA doubling time is greater than 10 months, then those are the patients at risk of developing metastases and dying from prostate cancer.It would be answering the question of, "Do you combine these agents with other agents?" Deciding between enzalutamide and apalutamide is also something that can be a challenge. In my opinion, I don't think one is better than the other. There was an interesting secondary exploratory endpoint in the SPARTAN trial looking at a second disease-free survival. Actually, the patients who received apalutamide and then went on to receive another therapy versus placebo did better. That makes me question, "When do we treat these patients? Is sooner better?" Pinning down when to treat these patients is going to be the biggest next step.
Another question is understanding why patients respond in 1 situation and not in the other. For example, in the metastatic setting, if you take a patient from enzalutamide and move them to abiraterone, you won't see much of a benefit. In the nonmetastatic setting, you would see a much higher benefit if you did this.You have to focus on QoL and prolonging survival. I always tell my patients, "If I can't cure your disease, my goal is to make you live longer and better." Certainly, OS is important so that we're addressing the living longer part. However, you have to help patients maintain their QoL. I tell patients all the time that if I'm prolonging your survival but putting you in bed all day, I'm not doing my job. It's important to look at these factors.What we also saw in the trials is that fatigue is a big thing. It's very common in all of our patients with prostate cancer. Part of it is that ADT itself is lowering testosterone. With apalutamide, we saw some cases of rash and some hypertension. Another risk associated with these drugs is the risk of falling. There is increased central nervous system penetration, so we're seeing an increased fall rate. Since we're seeing this in both groups, we could hypothesize that this is just associated with the patient population. As you're getting older and have more comorbidities, you might fall more.Probably. In prostate cancer, we've been behind on many things. For many years, we never thought chemotherapy was going to have a role, but certainly now we use it in the nonmetastatic CRPC setting. We know that docetaxel has improved survival. Therefore, for immunotherapy, it's just about continuing to test this. It might have a future role in combination.An area near and dear to my heart is more of a survivorship issue—side effect management. A lot of patients get very fatigued, so I have a lot of interest in getting them moving, up and exercising. We know that with chemotherapy and other treatments, exercise improves fatigue. Patients tell me all the time, "I'm so tired; I have no energy." Their “get-up-and-go routine” has gotten up and left. The other thing I worry about when moving these agents earlier is cardiac-associated toxicity. We need to be more proactive about getting patients into programs to assess this.In the United States in general, myself included, we aren't getting enough exercise. What I find is that when you tell patients they need to be more active, but they just don't know what to do. This is especially for patients with bone metastases—they've gone through so much treatment and they've lost a lot of muscle mass. They just don't know where to get started. Everybody should get moving; I would love to have a supervised exercise program for my patients. Once they get going, they'll be motivated and keep it up.