Among men with low- or intermediate-risk prostate cancer, those treated with enzalutamide benefit from a significant reduction in the risk for cancer progression compared with those undergoing active surveillance (AS), according to findings from a phase 2 open-label exploratory study (ENACT) reported at the AUA2021 Virtual Experience.

The study is the first to assess the efficacy and safety of a novel androgen receptor antagonist as monotherapy in patients with clinically localized low- or intermediate-risk prostate cancer, said lead investigator Neal D. Shore, MD, medical director for the Carolina Urologic Research Center in Myrtle Beach, South Carolina. Enzalutamide was found to be well tolerated and provided significant clinical benefit compared with AS. “Enzalutamide may therefore offer an alternative treatment option in this patient population,” he said.

The trial included 227 patients (53% with low-risk and 47% with intermediate-risk disease, mainly Gleason pattern 3+4) randomly assigned to receive 160 mg/d of enzalutamide (114 patients) or to undergo AS (113 patients). Baseline characteristics were similar between study arms. Of the 227 patients, 165 (85 in the enzalutamide group and 80 in the AS arm) completed 1 year of treatment. Patients had up to 2 years of follow-up.

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Enzalutamide-treated patients had a significant 46% reduction in pathologic prostate cancer progression risk and 29% decreased risk for PSA progression compared with those undergoing AS, Dr Shore reported. Enzalutamide delayed PSA progression by a median of 6 months compared with AS.

At 1 year, a significantly higher proportion of patients in the enzalutamide group had a negative prostate biopsy compared with the AS group (35.1% vs 14.2%). At 2 years, however, although a higher proportion of enzalutamide recipients compared with the AS group had a negative biopsy (19% vs 12%), the difference between the study arms was no longer significant.

Enzalutamide recipients were 3.5 times more likely than those in the AS group to have a negative prostate biopsy at 1 year. The odds of a negative biopsy at 2 years did not differ significantly between the groups.

The investigators defined pathologic progression as an increase in primary or secondary Gleason pattern by more than 1 or a greater than 15% increase in cancer-positive cores. They defined therapeutic progression as the earliest occurrence of primary therapy for prostate cancer (prostatectomy, radiation, focal therapy, or systemic therapy).

Patients with low-risk cancer had stage T1c to T2a disease, a PSA level less than 10 ng/mL, a Gleason score of 6 or less, and no nodal involvement or metastasis. Patients with intermediate-risk disease had T2b-T2c disease, a PSA level less than 20 ng/mL, or Gleason score of 7 (3+4 pattern), and no nodal involvement or metastasis.

In an interview, Dr Shore indicated that the earlier use of enzalutamide would not necessarily present a problem later on in terms of therapeutic choices if the patient develops castration-resistant-disease. “Ideally, active surveillance patients receiving enzalutamide therapy would potentially decrease their risk for developing advanced disease,” he said. He pointed, however, that as androgen receptor pathway inhibitor therapies have been used earlier for castration-sensitive metastatic disease, their subsequent sequencing and combination use with other approved therapies remains an area of ongoing investigation.

Commenting on the findings, Adam S. Feldman, MD, MPH, a urologic oncologist at Massachusetts General Hospital in Boston, who was not involved in the research, said the study cohort is notable for its relatively high proportion of patients with favorable intermediate-risk disease. As the majority of patients with favorable intermediate-risk disease opt for treatment rather than AS, enzalutamide could possibly be an alternative to radical prostatectomy or radiation, Dr Feldman said. He said he would be hesitant to place patients with low-risk or very-low-risk prostate cancer on a drug with potential side effects when these patients may well be able to avoid treatment anyway.

Dr Feldman also observed that from an oncologic perspective there may be no danger in using enzalutamide for early prostate cancer for a transitory period of 1 year. “I don’t think it would significantly change the biology of the disease, but we don’t know,” he said. An important question, he said, is whether there are long-term health consequences associated with 1 year of enzalutamide treatment.

The finding that 1 year of enzalutamide treatment significantly increased the likelihood of a negative prostate biopsy at 1 year but less so at 2 years suggests that the drug gains patients another 1 year without disease progression, he said. He said he suspects that when treatment is withdrawn after 1 year, the biology of the prostate cancer may go back to where it was before treatment; however, time will tell as this cohort is followed over time.

Disclosure: Astellas Pharma Inc.; Pfizer Inc., the co-developers of enzalutamide, provided funding.


Shore ND, Renzulli J, Fleshner NE, et al. Enzalutamide in patients with localized prostate cancer undergoing active surveillance: ENACT. Presented at: AUA 2021, held September 10-13, 2021. Abstract MP62-17.