Agents that improve survival in metastatic castration-resistant prostate cancer when added to background androgen-deprivation therapy (ADT) are showing success in treating metastatic prostate cancer earlier while it is still hormone-sensitive. These agents include docetaxel (chemotherapy) and hormonal therapies such as abiraterone acetate, enzalutamide, and ­apalutamide.

Two phase III studies presented at the 2019 ASCO Annual Meeting add to the mounting evidence for use of these newer agents in this hormone-sensitive space: ENZAMET (enzalutamide) and TITAN (apalutamide). 

ENZAMET Trial

The addition of enzalutamide to standard therapy in men with metastatic hormone-sensitive prostate cancer extended survival compared with treatment with other nonsteroidal antiandrogens, including bicalutamide, nilutamide, or flutamide, added to standard therapy, according to the interim results of the phase III ENZAMET trial, which was one of four studies selected for the Plenary Session at the ASCO meeting and was published online simultaneously in The New England Journal of Medicine.^1,2 The study was conducted by the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group.

At 3 years, 80% of men with metastatic hormone-sensitive prostate cancer were alive when treated with enzalutamide along with standard therapy, whereas 72% of men who received other nonsteroidal antiandrogens along with standard therapy were alive at that time point.

Christopher Sweeney, MBBS

“Physicians and patients with prostate cancer now have a new treatment option with enzalutamide, and this is especially relevant for men who cannot tolerate chemotherapy and have a lower burden of disease on scans,” said study co-chair Christopher Sweeney, MBBS, a medical oncologist at the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston.

“ENZAMET is the first study in metastatic hormone-sensitive prostate cancer to report survival data on enzalutamide and testosterone suppression and outcomes if patients also received concurrent docetaxel,” Dr. Sweeney emphasized. (However, the use of concurrent docetaxel and enzalutamide is controversial.)

Study coauthor Ian D. Davis, MBBS, PhD, of Monash University and Eastern Health in Melbourne, Australia, commented: “Enzalutamide and docetaxel are both active and are reasonable alternatives for men with metastatic prostate cancer starting testosterone suppression, but they have different side effects, costs, risks, and benefits.”

Ian D. Davis, MBBS, PhD

Neeraj Agarwal, MD

Commenting at a press briefing where these data were discussed, ASCO expert Neeraj Agarwal, MD, of the Huntsman Cancer Institute, Salt Lake City, said: “We see here that giving enzalutamide early can offer worthwhile benefits, especially for certain groups of men. In addition to helping men live longer, this overall approach means they can likely go longer without having to take steroids [with abiraterone acetate] or receive chemotherapy [with docetaxel].”

In the United States, initial treatment of metastatic hormone-sensitive prostate cancer is typically medical castration (testosterone suppression) with ADT. Other drugs can be added as well, depending on the circumstances, including abiraterone acetate plus prednisone or docetaxel. There are a number of other options if the cancer progresses on these drugs. Enzalutamide is approved by the U.S. Food and Drug Administration for men with progressive prostate cancer previously treated or untreated with docetaxel.

Study Details

Between March 2014 and March 2017, the phase III ENZAMET trial randomly assigned 1,125 men with metastatic hormone-sensitive prostate cancer in a 1:1 ratio to receive enzalutamide vs bicalutamide, nilutamide, or flutamide with or without docetaxel. All men also received background ADT. Randomization was stratified by disease volume (high or low), planned early docetaxel, planned antiresorptive therapy, comorbidity score (Adult Comorbidity Evaluation-27), and study site. Prespecified planned subgroup analyses included planned early docetaxel (yes or no) and disease volume (high or low).

The median follow-up for the first interim analysis was 34 months. At 3 years, 62% of those who received enzalutamide vs 34% of those who received other nonsteroidal antiandrogens were still on assigned study treatment.

Key Findings

At 3 years, 80% of men treated with enzalutamide with or without docetaxel were alive compared with 72% of men who received one of the three standard nonsteroidal antiandrogens (P = .002). Overall, enzalutamide reduced the rate of death by 33% compared with the comparator antiandrogens.

Subgroup analyses showed that among the 588 men with a high disease burden, 71% of the enzalutamide group vs 64% of the comparator group were alive at 3 years. Of the 537 men with a low disease burden, 90% of the enzalutamide group vs 82% of the comparator group were alive at 3 years. Survival was only improved more markedly with enzalutamide in men who did not receive early docetaxel; among this group, 3-year survival was 83% vs 70%, respectively. In addition, enzalutamide significantly delayed the time to prostate-­specific antigen disease progression, clinical disease progression, or death compared with the comparator group (P < .001).

Looking at the treatment arms according to concurrent docetaxel, enzalutamide delayed clinical progression-free survival in those receiving docetaxel compared with the other treatment arm but did not significantly improve overall survival. However, for those not receiving early docetaxel, enzalutamide reduced the hazard for clinical disease progression by 66% and reduced the hazard for death (overall survival)  by 47% compared with the other treatment. In the group receiving docetaxel, 71% of the men had high-volume disease compared with 37% in the group not receiving docetaxel.

“Most of the men on docetaxel had high-volume disease,” said Dr. Sweeney. “We have to think long and hard about what to give patients with high volume disease wh are fit for chemotherapy. This is because we now have direct evidence of improvement of overall survival when docetaxel, abiraterone, apalutamide and enzalutamide. are each added to testosterone suppression. In contrast, there is no direct evidence of benefit of early docetaxel in patients with low-volume disease and a good prognosis. As such, for patients with high volume disease and not fit for chemotherapy as well as patients with low volume disease we have direct evidence of overall survival benefit from abiraterone, apalutamide and enzalutamide added to testosterone ­suppression. The ultimate choice for an individual patient depends on the physician detailing risks and benefits of each approach and considering the patients other health issues, access, costs, and the patient preference."

Adverse Events

Serious adverse events per year of treatment exposure were similar in both arms of the study. The rates of grade 2 and 3 hypertension (18% vs 9%), grades 2 and 3 fatigue (31% vs 15%), grades 2 and 3 falls (6% vs 2%), syncope (4% vs 1%), and grades 1 and 2 concentration impairment (4% vs 1%) were higher in the enzalutamide arm.

“Enzalutamide is a new option for men with metastatic hormone-sensitive prostate cancer and is superior to the current standard,” Dr Sweeney said.

About ANZUP

ANZUP is the leading cancer-cooperative clinical trials group that brings together all the professional disciplines and groups involved in researching and treating urogenital cancers and conducts high-quality clinical research. ANZUP identifies gaps in evidence and areas of clinical need, collaborates with clinicians and researchers in GU cancer, and communicates frequently and effectively with the broader community along the way. ■

DISCLOSURE: Astellas Pharma provided drug and financial support for the ENZAMET trial but was not involved in study conduct or data analysis. ANZUP is funded by the Australia Government through Cancer Australia. Dr. Sweeney is a consultant with Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, Celgene, and Lilly; has received institutional research funding from Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Sotio, and personal funding from Dendreo; and has received patents/royalties/other intellectual property from Leuchemix, Parthenolide, Dimethylaminoparthenolide, and Exelixis. Dr. Davis has received institutional research funding from Astellas Pharma, Pfizer, Roche/Genentech, MSD Oncology, AstraZeneca, Janssen Oncology, Eisai, Bayer, Amgen, and Bristol-Myers Squibb; and has a patent with Ludwig Institute for Cancer Research. Dr. Agarwal is a consultant/advisor with Pfizer, Exelixis, Medivation/Astellas, Eisai, Merck, Novartis, EMD Serono, Clovis Oncology, Genentech/Roche, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, and Pharmacyclics; and has received institutional research funding from Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, NewLink Genetics, Prometheus, and Sanofi.

REFERENCES

1. 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.

2. Davis ID, Martin AJ, Stockler MR, et al: Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. June 2, 2019 (early release online).