Lead Investigator Highlights Apalutamide Efficacy in Metastatic Castration-Sensitive Prostate Cancer

Kim N. Chi, MD

With improvements in radiographic progression-free survival (rPFS) and overall survival (OS), Kim Chi, MD, explained that the next-generation androgen receptor (AR) inhibitor apalutamide (Erleada) in combination with androgen deprivation therapy (ADT) could be a new standard of care for patients with metastatic castration-sensitive prostate cancer.

In the randomized, double-blind TITAN study, investigators compared apalutamide (n = 525) and placebo (n = 527) in patients with metastatic castration-sensitive prostate cancer receiving ADT. At the median follow-up of 22.6 months, 66% of the apalutamide arm and 46% of the placebo arm remained on trial.

Results presented at the 2019 ASCO Annual Meeting showed that there was a 52% reduction in the risk of radiographic progression or death with apalutamide compared with placebo (HR, 0.48; 95% CI, 0.39-0.60; P <.0001). While the median rPFS was not estimable in the apalutamide group, it was 22.1 months with placebo/ADT.

Moreover, there was a 33% reduction in the risk of death with apalutamide versus placebo (HR, 0.67; 95% CI, 0.51-0.89; P = .005). The median OS was not yet reached in either arm.

The rates of grade 3/4 adverse events (AEs) were similar, with 42.2% for the apalutamide arm and 40.8% for the placebo arm. Grade ≥3 AEs of special interest, included rash (6.3% in the apalutamide arm vs 0.6% in the ADT-alone arm), fatigue (1.5% vs 1.1%, respectively), fall (0.8% in each arm), fracture (1.3% vs 0.8%), and seizure (0.2% vs 0).

Following these results, and a recommendation from the Independent Data Monitoring Committee, the study was unblinded to allow crossover of placebo-treated patients to receive apalutamide. In April 2019, Janssen, the developer of the agent, submitted a supplemental new drug application to the FDA for the approval of apalutamide for use as a treatment of patients with metastatic castration-sensitive prostate cancer.

“The next step is, hopefully, apalutamide will be approved by regulatory authorities and will become a standard of care for these patients,” said Chi, a professor at the University of British Columbia and a medical oncologist at BC Cancer Vancouver.

In an interview with OncLive, Chi, who is also lead study author of the TITAN trial, discussed the addition of apalutamide to standard-of-care ADT for patients with metastatic castration-sensitive prostate cancer.

OncLive: Could you discuss this study of apalutamide in patients with metastatic castration-sensitive prostate cancer who are receiving ADT?

Chi: The TITAN study was a randomized, double-blind, placebo-controlled trial that evaluated the addition of apalutamide, which is a next-generation AR inhibitor, to standard ADT in patients with metastatic castration-sensitive prostate cancer. The intent was to accrue a broad spectrum of patients. This included patients with both high- and low-volume disease, as well as those who required prior therapy, including ADT and docetaxel for castration-sensitive disease.

In the trial, 1052 patients were randomized and the dual primary endpoints were rPFS and OS. At the first analysis, the trial was positive. With rPFS, there was a 52% reduction in the risk of progression. For OS, there was a 33% reduction in the risk of death.

In addition, all of the secondary endpoints were in favor of apalutamide and the AE profile was not that dissimilar to placebo. There were the usual AEs that are known with apalutamide, but overall, the treatment was well tolerated. Attesting to that is that the quality of life (QoL) over the course of the study showed that the apalutamide arm had QoL preserved and it was not that much different from placebo.

What were the safety findings of apalutamide in this population?

Apalutamide was well tolerated. The safety profile was not that dissimilar to placebo, but it does have some specific AEs; one of them is rash, which occurred in about 27% of patients. It was typically mild, around grade 1 or 2. It can be managed symptomatically or with creams and so on. Only 2% of patients discontinued treatment because of this rash.

Another specific AE for apalutamide is hypothyroidism, but this was on laboratory tests. It was grade 1 and no intervention was required. Otherwise, AEs, such as fatigue, falls, fractures, and seizures were associated with these next-generation AR inhibitors was no different than placebo.

Was there any difference in efficacy between subgroups?

There was pre-planned subgroup analysis. For rPFS, the results were consistent across all the subgroups. Similarly, with OS, the benefit was consistent across subgroups.

How is apalutamide already making an impact for other patients with prostate cancer?

Apalutamide is currently FDA approved for patients with nonmetastatic, castration-resistant prostate cancer. In the trials, it has shown substantial ability to delay metastases development.

What else should oncologists note about the future of apalutamide?

This adds a new treatment for patients with metastatic castration-sensitive prostate cancer and further establishes that ADT alone for this patients population should be the exception rather than the norm. We should be intensifying ADT for all our patients. Now we have several choices. We have docetaxel, abiraterone acetate (Zytiga), and soon, once regulatory approval is made, we'll have apalutamide.

With several agents available to patients with metastatic castration-sensitive prostate cancer, do you anticipate any sequencing challenges?

This is a key question we need to consider regarding combinations. Should we be doing docetaxel with a next-generation hormonal agent, such as apalutamide? The current evidences suggest there may be some benefit in adding apalutamide in patients who had received docetaxel for castration-sensitive disease. It's a small subgroup; it's not a definitive study. The study wasn't designed to test this; however, with the current evidence, it suggested patients could go on to receive apalutamide after they've had docetaxel.

Chi KN, Agarwal N, Bjartell A, et al. First results from TITAN: A phase III double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). J Clin Oncol. 2019;37(suppl; abstr 5006). meetinglibrary.asco.org/record/172902/slide.