Neoadjuvant Apalutamide Leads to Reduced Tumor Volume in High-Risk Prostate Cancer

Interim results of a phase 2 trial suggest that neoadjuvant hormone therapy (NHT) administered prior to radical prostatectomy (RP) reduced tumor volume in men with high-risk prostate cancer. Investigators also reported positive trends supporting increased sexual potency preservation without an adverse effect on positive surgical margin rates.¹

Although neoadjuvant systemic therapy is a widely accepted treatment paradigm in many malignancies, the use of androgen deprivation is not widely endorsed in the localized disease setting of prostate cancer. The use of NHT was initially studied in the 1990s where results by Labrie et al demonstrated an improvement in pathologic outcomes, but follow-up data failed to show improvement in overall survival.^1,2

“Historically, [NHT] has been shown to improve pathologic outcomes,” lead study author Joshua Sterling, MD, said during a podium session as part of the American Urological Association (AUA) Virtual Experience platform for the 2020 AUA Annual Meeting.2 “Therefore, neoadjuvant androgen deprivation therapy may allow a nerve-sparing surgical approach to increase post-surgical quality-of-life outcomes without compromising oncologic outcomes.”

Although surgical techniques have improved throughout the years, the prognosis for men with high-risk prostate cancer is poor. “Around 50% of patients who undergo [RP] alone will recur biochemically after follow-up between 10 to 15 years,” said Sterling, a senior resident in the Department of Surgery, Division of Urology at Robert Wood Johnson Medical School in New Brunswick, New Jersey. For men with high-risk localized prostate cancer who choose to have surgery, wide resection of the neuromuscular bundle leads to best oncologic control, but this aggressive tumor control approach comes with adverse effects. “Impotence and possible decreased rate of postoperative continence can significantly affect postoperative quality of life,” he said.

The prospective 3-arm study (NCT02949284) has enrolled 42 patients to date. Patients are randomized to receive either apalutamide (Erleada; arm 1); apalutamide plus a gonadotropin-releasing hormone, abiraterone (Zytiga), and prednisone (arm 2); or surgery alone (arm 3). Three months after completing treatment, patients in arms 1 and 2 undergo RP. Follow-up for all 3 arms is for 2 years. Sterling said the target accrual is 90 patients and includes those with a Gleason score of higher than 8 on biopsy or a prostate-specific antigen (PSA) score greater than 20 ng/mL. Patients should have an ECOG performance status of 0 to 1 or clinical stage disease of T3 or less.

The primary outcome measure is the post-surgical potency rate at 12 months, which is defined as being able to penetrate and complete sexual intercourse satisfactorily in more than 50% of attempts. Secondary outcomes include change in tumor volume, biochemical recurrence rate, positive surgical margins rate, postoperative continence rate, and quality-of-life assessment.

Thirty-two patients were included in this current analysis. Four patients withdrew from study following randomization, 1 patient was declared ineligible, 3 patients continue to receive neoadjuvant treatment, and 24 patients are in the follow-up phase. Arm 1 consisted of 10 patients and arms 2 and 3 had 7 patients each.

There was a median reduction of tumor volume in arm 1 of 32.4% and in arm 2 of 55.7% and there was no pathological complete response, Sterling said. Surgical margins were positive in 3 patients in arm 1, 1 patient in arm 2, and 3 patients in arm 3. Potency was achieved in 50% of patients in arm 1, 14.2% of patients in arm 2, and 28.5% of patients in arm 3.

All groups were well balanced with median highest measured PSA of 11.8 ng/mL (range, 8.8-16.7), 19.9 ng/mL (range, 15.6-25.0), and 8.9 ng/mL (range, 7.7-17.8), in arms 1, 2, and 3, respectively. Median PSA reduction after neoadjuvant therapy was 11.2 ng/mL (range, 8.5-15.2), 19.8 ng/mL (range, 15.4-24.8), and not available, in arms 1, 2, and 3, respectively. Serum testosterone recovered to baseline postoperatively.

“The median follow-up time for arms 1 and 2 has not reached maturity to appropriately assess continence or potency rates,” Sterling said. “However, at the time of analysis, 5 patients in arm 1 [P = .25] and 1 patient in arm 2 [P = .21] have achieved potency compared with 2 patients in arm 3,” he said.

Seven patients in arm 1 (P = .14) and 5 patients in arm 2 (P = .22) have achieved continence compared with 3 patients in arm 3. Three patients have experienced a biochemical recurrence to date. This was reported in 1 patient in arm 1 and 2 patients in arm 2.

“These interim results are promising,” Sterling concluded. “However, complete accrual will be necessary to confirm these early observations.”

_References:

_{1. Sterling J, Chua K, Patel HV, Kim I. Interim analysis of phase 2 randomized apalutamide/abiraterone acetate with prednisone and the feasibility of performing nerve-sparing radical prostatectomy in men with high-risk prostate cancer (NCT02949284). J Urol. 2020;203(suppl 4):PD10-09. doi:10.1097/JU.0000000000000844.09}

_{2. Labrie F, Cusan L, Gomez JL, et al. Downstaging by combination therapy with flutamide and an LHRH agonist before radical prostatectomy. Cancer Surv. 1995;23:149‐156.}