The addition of 6 months of oral daily enzalutamide to standard salvage radiation and hormone therapy is safe and may improve prostate cancer remission rates at 2 and 3 years postoperatively among patients with high-risk disease, according to a recent paper in European Urology Oncology.
The addition of 6 months of oral daily enzalutamide (Xtandi) to standard salvage radiation and hormone therapy is safe and may improve prostate cancer remission rates at 2 and 3 years postoperatively among patients with high-risk disease, according to a recent paper inEuropean Urology Oncology.
In STREAM, a single-arm phase II trial conducted at three leading medical centers, 65% of patients achieved the primary endpoint of 2 year progression-free survival (PFS; 95% Confidence Interval [CI], 47-78). This compared favorably with the historical control rate of 51% (95% CI, 33-67) in a similar population of men with high-risk biochemically recurrent prostate cancer. The 3 year PFS was 54% (95% CI, 37- 68).
Additionally, 11 patients (29%) developed grade 3 toxicities, and there were no grade 45 or unexpected toxicities. In an exploratory analysis, quality-of-life data suggest modest worsening of bowel, bladder, and hormonal symptoms at 3 months. However, most men recovered baseline function by 24 months.
“Salvage enzalutamide and ADT [androgen deprivation therapy] for 6 months with RT [radiation therapy] following prostatectomy for men with PSA-recurrent, high-risk prostate cancer are safe and demonstrate encouraging efficacy at 2 and 3 years,” wrote the authors, led by Rhonda L. Bitting, MD, of Wake Forest School of Medicine, Winston-Salem, North Carolina. “These data warrant prospective controlled phase 3 trials to assess the long-term efficacy, safety, and clinical impact of potent AR [androgen receptor] inhibition in this curative-intent setting.”
Patients were eligible if they had Gleason 710 prostate adenocarcinoma and PSA recurrence within 4 years of radical prostatectomy. The authors defined recurrence as a detectable and rising PSA level of >0.2 ng/ml, with two consecutive rises over the post-prostatectomy nadir, or failure to obtain the PSA nadir of <0.2 ng/ml after surgery. Node-positive men were eligible if fewer than 3 positive nodes required resection and trial screening revealed no lymph nodes >2 cm. Participants were also required to have a Karnofsky performance status of 70 or higher and adequate renal, hepatic, and hematologic function.
Primary exclusion factors were metastatic disease, baseline PSA of >4.0 ng/ml and testosterone of 100 ng/dl or more. Additionally, patients could not have received prior pelvic radiation, hormonal therapy, chemotherapy, or immunotherapy.
In addition to the primary endpoint of 2-year PFS, the authors included several secondary objectives, among them 3 year PFS, the proportions of men at 1, 2, and 3 years with undetectable PSA, and safety, feasibility and tolerability. As an exploratory endpoint, the Expanded PC Index Composite (EPIC) Short Form was used to measure patients’ quality of life over time.
The trial regimen consisted of 6 months of enzalutamide 160 mg daily plus ADT and 2 months of radiation. Patients started the oral therapies 2 months before starting radiation, and continued for an additional 2 months following radiation completion. ADT was given in the form of a GnRH agonist according to institutional standard.
Bitting et al defined unacceptable toxicity as the inability to tolerate radiation in combination with enzalutamide that resulted in a delay of 5 days or more in radiation therapy. Enzalutamide-related toxicities were managed by dose adjustments or interruptions of up to 21 days. Baseline monitoring include CT, bone scan, PSA and the EPIC Short Form. All were repeated at predetermined intervals, except for imaging, which was repeated only as needed.
Study enrollment consisted of 38 men, 90% of whom were white. Eight percent were black and 2% Asian. Nearly all patients (n = 37, 97%) completed therapy and were evaluable with testosterone recovery at 2 years. A single patient could not receive radiation due to postoperative scar tissue development and was excluded from further analysis.
The median patient age was 64 years and the median PSA at the time of study entry was 0.4 ng/ml, with salvage treatment starting approximately 1 year after surgery. “This was a high-risk population, with 87% of men having high- or very-high-risk disease as per NCCN risk classification, nearly half with a Gleason score of 8 or more, nearly half with positive margins, 79% with T3 or higher disease, and 21% with node-positive disease at the time of surgery,” Bitting et al wrote. “Thus, our patient population and outcomes are not comparable with those of published phase 3 salvage RT studies that included mostly intermediate- to high-risk men.”
Median follow up was 37.5 mo (95% CI, 26.2 - 41.7). Bitting et al found that men with node-positive disease at the time of surgery (n = 8) had poorer outcomes, with a 2-yr PFS rate of 25% (95% CI, 3.7 - 55.8). Additionally, node-negative patients had improved PFS relative to the entire study population, with PFS rates of 76% (95% CI, 54 - 88) at 2 years and 64% (95% CI, 42 - 79) at 3 years.
Bitting et al noted the small sample size and lack of a control group as study limitations. “In addition, PFS at 2 or 3 years may not be an optimal surrogate for overall survival in this setting, and metastasis-free survival is likely a more appropriate endpoint. Longer-term follow-up is needed to assess the durability of the remissions observed,” they wrote. “However, these results support the safety and efficacy of combining potent AR inhibition with salvage RT and provide critical benchmarks and safety data to support this approach.”
Bitting RL, Healy P, George DJ, et al. Phase II Trial of Enzalutamide and Androgen Deprivation Therapy with Salvage Radiation in Men with High-risk Prostate-specific Antigen Recurrent Prostate Cancer: The STREAM Trial. Eur Urol Oncol. 2020 Feb 13. pii: S2588-9311(20)30020-1. doi: 10.1016/j.euo.2020.01.005. [Epub ahead of print]