Enzalutamide Reduces Risk of Disease Progression in Low- and Intermediate-Risk Prostate Cancer

Joseph Renzulli, MD, associate professor, Department of Urology, Yale School of Medicine, New Haven, CT, discusses the results of the open-label, randomized, phase 2 ENACT clinical trial comparing enzalutamide monotherapy vs active surveillance for patients with clinically localized low-risk or intermediate-risk prostate cancer. The data showed that enzalutamide was well-tolerated and demonstrated a treatment response, suggesting that enzalutamide may be an alternative treatment for those patients undergoing active surveillance.

Transcript:

I'm excited to present to you today the data on the ENACT trial, which was recently published in JAMA Oncology. The ENACT trial is the first trial to evaluating an androgen receptor antagonist for patients in active surveillance. We evaluated an additional group of patients, both low-risk and intermediate-risk patients with prostate cancer. And these patients were, as per NCCN guidelines, either in a low-risk category, for which the preferred treatment option is active surveillance, or they were in the intermediate-risk category where NCCN deems this an acceptable option for patients that have intermediate-risk disease, in addition to standard therapy such as surgery or radiation therapy.

We modeled this trial on the REDEEM trial, which looked at dutasteride in patients with prostate cancer and demonstrated a reduced risk of progression in up to 30% of the patients who were treated with dutasteride. We asked the question, are there other pharmacologic interventions that may also delay progression in patients on active surveillance?

ENACT was a multicenter, randomized, open label phase 2 trial. All patients knew whether they were being treated with the drug or not. We enrolled 227 patients overall between June 2016 and August 2020. Patients had to have a biopsy that diagnosed prostate cancer, and it had to be low-risk or intermediate-risk but could not be very low risk. And surprisingly, we were able to enroll a very large number in the intermediate group, much more than we thought we would be able to enroll. The randomization was to standard of care active surveillance, or 1 year of enzalutamide 160 mg daily. Patients were monitored over 24 months and they received biopsies at both 12 months and 24 months.

The primary end point evaluated was pathologic progression or definitive therapy. We looked for an increase in Gleason score or volume of disease on subsequent biopsies. Of the 227 patients enrolled, 53% were actually low risk. 47% were intermediate risk, representing Gleason 3+, 4 disease. Of the biopsies that were performed, roughly 76% were MRI-targeted biopsies, representing more of the common biopsies being performed now.

In the treatment arm, 75% were able to complete the full course of enzalutamide therapy for 1 year, and only 13% actually had to stop the medication. Therefore, this represents a well-tolerated treatment arm. 47% of the patients in the enzalutamide group were able to complete follow up on trial, while only 35% of those on active surveillance completed the trial. Disease progression in the enzalutamide group was 28% versus 37% in the active surveillance arm. Therefore, that conferred a 46% reduced risk of progression on the enzalutamide treatment.

At 1 year, the pathologic or treatment progression was lower in those who received enzalutamide. Only 8% of patients progressed, whereas 23% of the patients on the active surveillance arm either progressed or decided to move forward with treatment. Now, by 2 years, the biopsies had returned to equivalent, and there was no difference conferred — each group had about 16% progression at year 2. The odds ratio for a negative biopsy was 3.5% if on the treatment arm at 1 year. But again, at 2 years, this was not reproducible, so the drug effect clearly was most profound in the first year.

92% reported side effects on enzalutamide, which we are well aware of in clinical medicine, sexual side effects, breast side effects, and fatigue were the most common. By year 2, again off treatment after 1 year, by year 2, we saw resolution in all these patients. About 55% of patients had fatigue. There was 37% gynecomastia, 30% nipple or breast tenderness, and erectile dysfunction in approximately 18% of patients.

2.7% of the adverse events were considered serious. 7% of the adverse events led to discontinuation of the drug. Therefore, about 93% of patients were able to stay on and tolerate any adverse events they were experiencing, which were considered minimal. There were no deaths related to treatment or to disease progression on the ENACT trial.

We concluded that enzalutamide monotherapy significantly reduced the risk of prostate cancer and PSA progression compared to active surveillance in low- and intermediate-risk prostate cancer. The odds ratio of having a negative biopsy if you were treated with enzalutamide was up to 3.5% compared to the active surveillance arm, which is quite significant. And the 46% risk reduction observed on treatment was similar to that observed on the REDEEM trial, with dutasteride in the same patient population at 38%. Enzalutamide clearly may offer alternative options for patients on active surveillance, potentially reducing and certainly delaying need for more aggressive treatment in the future. We're excited to see how this will be able to be further studied and possibly implemented in clinical practice. Thank you.

Source:

Shore N, Renzulli J, Fleshner N, et al. Enzalutamide monotherapy vs active surveillance in patients with low-risk or intermediate-risk localized prostate cancer: The ENACT randomized clinical trial. JAMA Oncol. 2022;8(8)1128-1136. doi:10.1001/jamaoncol.2022.1641