A majority of men in active surveillance (AS) for early prostate cancer had negative biopsies after a 90-day course of apalutamide (Erleada), a small phase II trial showed.

Follow-up pathology showed no evidence of residual cancer in 13 of 22 evaluable patients following treatment with the androgen receptor inhibitor. The median time to a positive biopsy was 364 days, and the treatment was associated with favorable pathologic changes in patients with higher-risk features, such as grade group 2 (GG2) disease and high genomic risk.

The treatment was well tolerated and had minimal impact on patients’ quality of life (QoL), reported Michael T. Schweizer, MD, of the University of Washington in Seattle, and colleagues, in the Journal of Urology.

“While we acknowledge that a negative biopsy is not a validated proxy for long-term outcomes, this was felt to be a reasonable primary endpoint given that the majority of AS programs rely on pathological changes as a trigger to recommend definitive local treatment,” the authors stated. “We acknowledge that the small sample size of this study is one of its primary limitations, which was further challenged by its premature termination. However, in spite of this shortcoming, we still detected a robust efficacy signal.”

“Ultimately, large, randomized studies will be needed to evaluate if systemic therapies are useful in the management of patients with prostate cancer followed on AS.”

Not Active Surveillance

The results added to evidence of potential benefits for hormonal therapy in active surveillance. The results compared favorably with previous studies of dutasteride (Avodart), leuprolide, and enzalutamide (Xtandi), showing negative biopsy rates at 12-18 months of 28%-45%.

Authors of an accompanying editorial maintained that active surveillance is no longer active surveillance when a therapeutic intervention is introduced.

“The publication of these studies raises some critical questions about therapeutic intervention in men on AS,” wrote Peter Lonergan, MD, and Louise C. McLoughlin, MBBCh, both of St. James’s Hospital and Trinity College in Dublin. “First AS with a therapeutic intervention, such as an ARAT [androgen receptor axis-targeted agent], is active treatment, not surveillance. This strategy is, therefore, inconsistent with the principles of AS.”

They also pointed out that a negative biopsy has yet to be proven as a valid surrogate endpoint for long-term outcomes in active surveillance. Finally, they asserted that androgen receptor-targeted therapies have “considerable financial- and treatment-related toxicities.”

“However, we have to acknowledge that AS is not perfect,” Lonergan and McLoughlin added. “Despite a large body of evidence supporting this strategy in low-risk disease, there remains significant regional variation in the uptake of AS, particularly in the U.S. Therefore, we should direct our attention to initiatives which increase the utilization of AS and decrease the overdiagnosis of low-risk disease.”

Studies of active surveillance for low-risk prostate cancer have shown that 20%-50% of patients subsequently convert to local therapy (radiation or prostatectomy). Medical therapies offer an “appealing” option to decrease the rate of attrition, Schweizer’s group noted. Apalutamide is an “ideal compound” to evaluate as a means of prolonging time to positive biopsy and associated dropout from active surveillance.

The authors reported findings from a phase II trial that evaluated the pathologic effects of a 3-month course of apalutamide on men with low- or intermediate-risk prostate cancer enrolled in active surveillance. Risk was determined by clinical stage T1c disease, PSA <15 g/mL, GG2 in ≤50% of one core/site, and GG1 disease in all other cores.

Repeat MRI- or transrectal ultrasound-guided biopsies was performed at the treating physician’s discretion. Prostate biopsies were mandated at 365 and 730 days from enrollment. The primary endpoint was negative repeat biopsy at the end of the 90-day apalutamide treatment course.

Key Findings

The study had an accrual goal of 33 patients, but the enrollment ended prematurely because of slow accrual. Investigators enrolled 23 patients, who had a median time on active surveillance of 10.4 months at enrollment. A majority (n=13/23) of the patients had two or more prior positive biopsies while on active surveillance. All 23 participants completed the 90 days of treatment with apalutamide, and 22 underwent post-treatment biopsy.

Pathology results showed that 59% of the post-treatment biopsies showed no evidence of residual disease, significantly higher than an estimated rate of 20% predicted by statistical modeling (P<0.001). If 33 patients had been enrolled and all remaining patients had residual disease, the resulting negative biopsy rate (13/33, 39%) still would have exceeded the hypothesized rate (P=0.008).

All but one patient had a biopsy at day 365, and seven of 21 (33%) had no evidence of residual disease. Additionally, 19 patients had biopsies at day 730, and four (19%) had no residual disease. One patient had a positive biopsy at day 365 and a negative day-730 biopsy.

At day 91, all patients had a PSA decline exceeding 50% from enrollment and 15 (65%) had reductions of 90% or greater. PSA levels increased in all patients after discontinuation of apalutamide, and at 365 days, the median PSA value did not differ significantly from the baseline value. The median testosterone level increased significantly from baseline to day 91 (+275 ng/mL, P<0.001).

During a median follow-up of 753 days, five patients underwent definitive local therapy, four who had GG reclassification and one who opted for prostatectomy despite stable GG2 disease.

Adverse events were generally mild and consistent with known effects of apalutamide, the authors reported. Transient declines in several QoL scores occurred during the treatment period but returned to near baseline by day 180. No “clinically meaningful” changes in QoL occurred with the exception of a 13-point decline in the median score for energy/fatigue (P=0.01).

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