ASCO 2019: TITAN: Apalutamide Meets Dual Primary Endpoints, Shows Good Tolerability in Metastatic Hormone Sensitive Prostate Cancer

Chicago, IL (UroToday.com) Men with low or high-volume metastatic hormone-sensitive prostate cancer who received androgen deprivation therapy (ADT) plus once-daily oral treatment with apalutamide were approximately 52% less likely to die or experience radiographic progression than were patients who received placebo plus ADT in the global phase III TITAN trial.1

After a median of 22.7 months of follow-up, rates of radiographic progression-free survival (rPFS) were 68% in the apalutamide plus ADT arm, versus 48% in the placebo plus ADT arm (hazard ratio [HR] for rPFS, 0.48; 95% CI, 0.39 to 0.60; P<.0001), said principal investigator Kim N. Chi, MD, of BC Cancer in Vancouver, Canada, during an oral presentation at the 2019 ASCO Annual Meeting in Chicago, IL.

Apalutamide also met its dual primary endpoint, overall survival (OS), in a pre-planned interim analysis that coincided with the rPFS readout. At 2 years, apalutamide plus ADT was associated with a 33% lower risk of death than was placebo plus ADT (OS rates, 82% vs. 74%, respectively; HR for death, 0.67; 95% CI, 0.51 to 0.89; P = .0053). 

“Whether patients had a high or low volume of metastatic disease did not affect these findings—there was a survival benefit across pre-defined subgroups,” Dr. Chi said during an interview with UroToday.
The only exception was patients who had previously received docetaxel—this subgroup was too small for the OS difference between arms to reach statistical significance.

Apalutamide (Erleada) binds the androgen receptor, thereby preventing its activation by testosterone and other androgens. Currently, the drug is approved in the United States only for treating non-metastatic castration-resistant prostate cancer (nmCRPC). The TITAN data, which were selected for inclusion in Best of ASCO 2019 Meetings, formed the basis for a supplemental New Drug Application (NDA) submitted in April 2019 by Janssen Pharmaceutical Companies of Johnson & Johnson seeking U.S. Food and Drug Administration (FDA) approval of apalutamide for use in treating metastatic hormone-sensitive prostate cancer (mHSPC).

Metastatic HSPC has a relatively poor prognosis, with a median OS of less than 5 years. Until recently, patients with mHSPC usually received continuous ADT alone, but trials such as CHAARTEDSTAMPEDELATITUDEARCHES, and ENZAMET2-6 are demonstrating superior outcomes when patients also receive docetaxel, the novel hormonal agent abiraterone acetate (plus prednisolone), or docetaxel plus enzalutamide, another novel hormonal agent.

“At this point in time, we can conclude that ADT alone is no longer sufficient and that the standard of care [for mHSPC] should be to consider adding a next-generation androgen receptor pathway inhibitor or chemotherapy,” Dr. Chi said. “We are seeing that earlier treatment is better.”
Unfortunately, side effects can sometimes limit the use of these life-prolonging therapies. A substantial proportion of patients with mHSPC cannot tolerate docetaxel, while abiraterone increases the risk of mortality in patients with significant baseline cardiovascular disease or hypertension.7 All patients on abiraterone, regardless of risk factors, require monthly monitoring for hypertension, hypokalemia, and fluid retention.8 Meanwhile, enzalutamide can cause fatigue that diminishes the quality of life and sometimes leads to treatment discontinuation.

For this reason, it was notable that both arms of the TITAN study had similar overall rates of grade 3-4 (moderate to severe) adverse events (42% vs. 41%, respectively), Dr. Chi said. Both arms also had similar rates of clinically important events, such as fatigue, falls, and fractures, even though duration of exposure to treatment was longer with apalutamide plus ADT versus placebo plus ADT. Adverse events leading to treatment discontinuation occurred among 8% of patients on apalutamide plus ADT versus 5.3% of those on placebo plus ADT. Rash accounted for most of this discrepancy, affecting 27% versus 9% of patients, respectively, Dr. Chi said. However, most cases of rash were asymptomatic. Likewise, although hypothyroidism affected 8% versus 2% of patients in the respective arms, nearly all cases were grade 1, meaning that they were asymptomatic and required no intervention.

Quality of life was “essentially preserved” throughout the TITAN study, with no significant change from baseline or between treatment groups, Dr. Chi said. Patients were in good shape to begin with. They reported having no cancer-associated pain and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. “Therefore, the quality of life data attest to the tolerability of apalutamide,” Dr. Chi said. “Given its tolerability and the lack of monitoring required, earlier treatment with apalutamide is probably better.”

The double-blind, randomized, phase III TITAN trial (NCT02489318) enrolled 1,052 patients with mHSPC who were randomly assigned (1:1) to receive continuous ADT plus either apalutamide (240 mg) or placebo. “The study was designed to include a broad spectrum of patients,” Dr. Chi said. Participants had both low and high-volume metastatic disease, and while some had been newly diagnosed with prostate cancer, others had previously received ADT, docetaxel, or definitive local therapy. Patients resided in 23 countries and were treated at 260 sites in the Americas, Europe, and the Asia Pacific region. 

Apalutamide not only significantly improved rPFS and OS, but also produced statistically significant improvements across secondary and exploratory endpoints, Dr. Chi reported. Levels of prostate-specific antigen (PSA) became undetectable in 68% of men receiving apalutamide plus ADT versus 29% of those receiving placebo plus ADT. At 2 years, 75% of men on apalutamide plus ADT had not biochemically relapsed, versus 36% of men on placebo plus ADT. Apalutamide also produced a 71% decrease in the likelihood of receiving cytotoxic treatment and a 33% reduction in risk of death or progression on first subsequent therapy. “This was an exploratory endpoint with a lot of clinical relevance,” Dr. Chi said. “It suggests that earlier treatment with apalutamide is better than waiting until castration-resistance. At the time of data cutoff, the majority of patients in the placebo plus ADT arm were receiving subsequent therapy.” 

Based on these findings, investigators have unblinded TITAN, and patients on placebo have been permitted to cross over to the apalutamide arm. 
“The TITAN trial demonstrates yet again that the addition of highly potent androgen receptor targeting to standard ADT improves the survival of patients with metastatic prostate cancer, and does so with a favorable safety profile,” said Charles J. Ryan, MD, director of the Division of Hematology, Oncology and Transplantation at the University of Minnesota, Minneapolis, who was not involved in the study. “Clinicians and patients now have several options for effectively initiating systemic therapy in this disease,” he added. “Additional research will hopefully extend these benefits even further.”


Written by: Amy Karon, DVM, MPH, MA, Karon Medical Writing, San Jose, California

References
  1. 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). Accessed May 30, 2019.
  1. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373(8):737-746.
  1. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017; 377(4):352-360.
  1. James ND, Sydes MR, Clarke NW, et al; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387(10024):1163-1177.
  1. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. Phase III study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. J Clin Oncol 2019;37, no. 7_suppl (March 1 2019) 687-687.
  1. Davis ID, Stockley MR, Martin A, et al. Randomised phase 3 trial of enzalutamide in first line androgen deprivation for metastatic prostate cancer: ENZAMET (ANZUP 1304) Ann Oncol. 2015;25(Suppl 4):804TiP. iv278.
  1. Moreira RB, Debiasi M, Francini E, et al. Differential side effects profile in patients with mCRPC treated with abiraterone or enzalutamide: a meta-analysis of randomized controlled trials. Oncotarget 2017;8(48):84572-84578.
  1. HIGHLIGHTS OF PRESCRIBING INFORMATION ZYTIGA® (abiraterone acetate) Tablets Accessed May 30, 2019. 
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