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Apalutamide Improves Survival Outcomes in Castration-Sensitive Metastatic Prostate Cancer in TITAN Trial


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Adding apalutamide to androgen-deprivation therapy (ADT) significantly improved survival in men with metastatic castration-sensitive (also termed hormone-sensitive) prostate cancer, according to the results of the phase III TITAN trial, which were presented at the 2019 ASCO Annual Meeting and simultaneously published in The New England Journal of Medicine.1,2 Treatment with apalutamide was tolerable and comparable to other next-generation nonsteroidal antiandrogens.

For the dual primary endpoints of radiographic progression-free survival and overall survival, apalutamide significantly reduced the risk of progression by 52% and reduced the risk of death by 33% compared with placebo.

The TITAN trial joins the ENZAMET trial, another phase III study presented at the ASCO meeting, in demonstrating the benefits of earlier, more aggressive treatment with apalutamide or enzalutamide, respectively, when prostate cancer is still hormone-sensitive.3 Previous phase III trials have also shown longer survival with both abiraterone acetate plus prednisone and with docetaxel in metastatic hormone-sensitive prostate cancer, particularly patients with high-volume or high-risk disease, so clinicians now have expanded options for treatment beyond ADT.

“These results support the addition of apalutamide to ADT for a broad range of patients with metastatic castration-sensitive prostate cancer, such as those included in the TITAN study (patients with high-volume and low-volume disease, who had prior docetaxel treatment, who had metastatic disease at diagnosis or relapsed metastatic disease, and who had received prior treatment for localized disease),” said lead author Kim. N. Chi, MD, of the BC Cancer Agency, Vancouver, Canada.

Kim. N. Chi, MD

Kim. N. Chi, MD

At the ASCO meeting, Dr. Chi presented the final analysis of radiographic progression-free survival and the first planned interim analysis of overall survival. Based on these results, the study’s independent review committee recommended unblinding and allowing patients receiving placebo to cross over to apalutamide.

Study Details

The TITAN trial was designed to evaluate the addition of the androgen receptor inhibitor apalutamide vs placebo in a broad population of men with metastatic castration-sensitive prostate cancer regardless of disease burden who were treated with continuous ADT. The hypothesis was that more complete suppression of androgen signaling would improve outcomes.

A total number of 1,052 patients with documented metastatic castration-sensitive prostate cancer were randomly assigned 1:1 to apalutamide at 240 mg/d orally (n = 525) or matched placebo (n = 527) in 28-day cycles. Patients were stratified by Gleason score, geographic region, and prior treatment with docetaxel.

The median age of study patients was 68 years. A total of 16.4% had prostatectomy or radiation therapy for localized disease; 10.7% received previous docetaxel; 62.7% had high-volume disease, and 37.3% had low-volume disease. At a median follow-up of 22 months, 66% of patients in the apalutamide group and 46% of those on placebo were still on treatment.

Improvement in Survival Outcomes

Apalutamide reduced the risk of radiographic disease progression by 52% compared with placebo. The rate of 2-year radiographic progression-free survival was 68% for the apalutamide-treated group vs 48% for the placebo group—an absolute difference of 20% (P < .0001). Apalutamide reduced the risk of death by 33%. The 2-year overall survival was 82% in the apalutamide arm vs 74% in the placebo arm (P =.005). For both the radiographic progression-free survival and the overall survival analyses, the benefits of apalutamide over placebo were evident across all subgroups.

For the exploratory endpoint of second progression-free survival (defined as the time from randomization to disease progression on the next subsequent treatment), apalutamide reduced the risk by 34% compared with placebo (P = .0026). The 2-year rate of second progression-free survival was 75% with apalutamide and 36% with placebo. “This further supports the earlier use of apalutamide," Dr. Chi told listeners.

Toxicity

THE OCCURRENCE of side effects was not substantially different between the two treatment arms. Grade 3 or 4 adverse events were reported in 42.2% of the apalutamide group and 40.8% of the placebo group. Rash was more common in patients treated with apalutamide (27%, mostly grades 1 and 2).

However, there were numerically more treatment discontinuations with apalutamide: 8% vs 5.3%, respectively. “The difference in treatment discontinuation for adverse events between the arms was mostly due to rash in 2% of patients,” Dr. Chi explained. “Health-related quality of life according to the FACT-P (Functional Assessment of Cancer Therapy–Prostate) subscale was preserved on both arms,” he added.

Additional Commentary

Michael Carducci, MD

Michael Carducci, MD

FORMAL STUDY discussant Michael Carducci, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, questioned the survival benefit of apalutamide across all subgroups, including those with visceral disease and low-volume disease. “We need to put these data together with other study data to decide who should get what drug. There is a clear benefit in overall survival with apalutamide in patients with high-volume disease, but there may be subpopulations that may not derive benefit,” Dr. Carducci indicated.

“This disease state of metastatic hormone-sensitive prostate cancer is broadly heterogeneous. The treatment benefit is not consistent in all subsets, and we need to do a better job with molecular taxonomy and we need better predictors for which drug to use in which patient,” Dr. Carducci stated.

 

DISCLOSURE: Dr. Chi has received honoraria from Sanofi, Janssen, Astellas Pharma, and Bayer; is a consultant with ESSA, Astellas Pharma, Janssen, Sanofi, Amgen, Bayer, AstraZeneca, and Roche; and has received institutional research funding from Janssen, Astellas Pharma, Bayer, Sanofi, Tokai Pharmaceuticals, Lilly/ImClone, Bristol-Myers Squibb, Merck, and Roche. Dr. Carducci is a consultant/advisor with Astellas Pharma, AbbVie, Roche/Genentech, Pfizer, and Foundation Medicine and has received institutional research funding from AstraZeneca, Bristol-Myers Squibb, eFFECTOR Therapeutics, EMD Serono, Gilead Sciences, and Pfizer.

REFERENCES

1. Chi KN, Agarwal N, Bjartell A, et al: First results from TITAN: A phase III double-blind, randomized study of apalutamide versus placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy. 2019 ASCO Annual Meeting. Abstract 5006. Presented, May 31, 2019.

2. Chi KN, Agarwal N, Bjartell A, et al: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. May 31, 2019 (early release online).

3. Sweeney C, Martin AJ, Zielinski RR, et al: Overall survival results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer: ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. 2019 ASCO Annual Meeting. Abstract LBA2. Presented June 2, 2019.


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