Apalutamide Maintains Health-Related QoL in Nonmetastatic CRPC

Fred Saad, MD

Treatment with apalutamide (Erleada) was not associated with a significant impact on health-related quality of life (HRQoL) in patients with high-risk nonmetastatic castration-resistant prostate cancer, according to patient-reported outcome (PRO) data from the phase III SPARTAN trial.

In the study overall, patients treated with the addition of apalutamide to standard hormone therapy also had an improvement in metastasis-free survival (MFS) and longer time to symptomatic progression compared with those who were treated with placebo.

“These findings completely surpassed the improvement we predicted we would see with the addition of apalutamide,” said lead study author Fred Saad, MD.

HRQOL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires. Results showed that the FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group. The data were similar for EQ-5D-3L.

At baseline, the mean for FACT-P total score in both the apalutamide and placebo arms were consistent with the FACT-P general population norm for adult men in the United States. Moreover, the group mean PRO scores show that HRQOL was maintained from baseline following the start of apalutamide therapy and was similar over time among patients receiving apalutamide versus placebo.

As a result of the MFS findings, the FDA approved apalutamide for the treatment of this patient population, becoming the first available drug in that setting, in February 2018.

In SPARTAN, which was a randomized, double-blind, placebo-controlled study, 1207 patients were randomized to receive 240 mg/day apalutamide plus androgen deprivation therapy (n = 806) or placebo (n = 401) between October 2013 and December 2016. Each treatment cycle was 28 days. Results also showed that MFS was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm.

OncLive: Please provide some background to the SPARTAN trial.

In an interview with OncLive^®, Saad, professor and chief, Urology, director of Genitourinary Oncology, University of Montreal Hospital Centers, discussed the clinical significance of the SPARTAN trial, the HRQoL data, and remaining steps in the treatment of patients with nonmetastatic CRPC.Saad: SPARTAN was one of the first clinical trials done in patients with nonmetastatic CRPC using an extremely effective class of agents that we use in metastatic disease. Apalutamide is a new-generation androgen receptor (AR) inhibitor that was tested in patients with high-risk CRPC. We defined high risk by prostate-specific antigen (PSA) doublet time. This is the best predictor of how quickly patients will become metastatic and likely die from their disease.

Approximately 1200 patients were randomized 2:1 to either apalutamide or placebo. Obviously, we have many treatment options for patients with metastases, but unfortunately, it was an unmet need for what to do in a patient with a rising PSA who we know is destined to become metastatic. Therefore, clearly, there was a need for us to do something here.

SPARTAN, which was published in the New England Journal of Medicine in February 2018, showed that apalutamide significantly delayed the time to first metastases compared with placebo. It was in the range of about 40 months to the first development of metastases compared with 15 to 17 months for placebo. This, in a nutshell, was the most important finding of the SPARTAN trial.

What adverse events (AEs) are associated with apalutamide?

It seems like PROs are becoming increasingly important in clinical trials. Is this a fair assessment?

It clearly met its primary endpoint and all of our planned secondary endpoints. It delayed symptoms, PSA progression, and PSA response. However, in terms of survival, it's still too early to know whether we see an improvement here. This is important because for the patients on the placebo arm, when they developed metastases, they had very early access to effective therapies. In the case of SPARTAN, they were offered abiraterone acetate (Zytiga) earlier than they would in the real world.There is a class effect with AR inhibitors. We've seen it with enzalutamide (Xtandi), which has been around for a long time. There is a risk of fatigue. There's a risk of hypertension, which requires intervention to normalize. There is also the potential risk of seizures, which fortunately was rarely seen in the study. You sometimes also see a rash associated with apalutamide. Usually these don't require intervention, but they sometimes become severe. Another issue that sometimes arises is hypothyroidism. Importantly, severe AEs were very infrequent.Absolutely. Society as a whole—and us as physicians—have really stopped being obsessed with only survival and symptoms. We have recognized that quality of life (QoL) is as important, if not more important, than just living longer at all costs. It's definitely safe to say that we are relying more and more on PROs. It's not enough to say, "Well, we increased survival by ‘X’ number of months or years." You have to consider what we actually did to achieve that survival in terms of quality of life.

What is an area of prostate cancer you would like to see addressed?

It's not just about P values and survival data. This is especially true in prostate cancer, where the average patient is not 40 or 50 years. The average age in SPARTAN was about 70 years old; we had patients up to 93 years old. Clearly, QoL is important. Patients aren't willing to just accept anything in order to live longer.We would all like to see ways of being able to predict response and resistance. This is where we lack, in a sense. As clinicians, patients are asking us, "Is this drug going to work for me?" It's not enough to just say, "Yes, it works in 80% of patients." They would like to know ahead of time that this treatment will work specifically for their disease. None of us are happy just trying the standard frontline therapy, then checking 3 months later and seeing if it worked. It can be a waste of precious time and money. We use the word personalized a lot, and it's definitely appropriate.

We need to develop more tools to know what treatments work best for each individual patient. In prostate cancer, there are multiple lines of therapy. How to sequence these therapies is critically important.

Saad F, Cella D, Basch E, et all. Effect of apalutamide on health-related quality of life in patients with nonmetastatic castration-resistant prostate cancer: an analysis of SPARTAN, randomized phase III trial [published online ahead of print September 10, 2018]. Lancet Oncology. doi: 10.1016/S1470-2045(18)30456-X.