Should the denosumab metastasis prevention trial change practice for men with nonmetastatic prostate cancer?

Presentation of the case. A 68-year-old man presents for management of prostate-specific antigen (PSA)-recurrent prostate cancer. His PSA level had become undetectable after prostatectomy for a high-risk localized tumor but began to rise 8 months later. This later led to the initiation of androgen deprivation therapy (ADT), which he has received for the last 3.5 years. After initially falling in response to ADT, his PSA level again trended steadily upward and is now 13.2. Restaging with an abdominal and pelvic computed tomography scan and a bone scan reveals no evidence of metastases. Is this man likely to benefit from denosumab? Bone is the most common site of metastasis for advanced prostate cancer. Bone metastases can cause considerable morbidity in the form of pain, pathologic fractures, and even spinal cord compression. Two bone-targeted therapies (zoledronic acid and denosumab) have been shown to reduce the risk for skeletal events (SREs) among men with bone metastases and a rising PSA level despite a testosterone level <50 ng/dL (castration-resistant prostate cancer [CRPC]). Until recently, no therapy had been shown to reduce the risk for developing bone metastases for the first time. Denosumab 147 was a randomized, placebo-controlled, phase III trial that enrolled 1,432 men with CRPC, no bone metastases, and at least one feature consistent with a high risk for the development of bone metastases (PSA ≥8 ng/mL or PSA doubling time ≤10 months). Participants were treated every 4 weeks with s.c. denosumab (120 mg) or placebo. The trial was positive because denosumab led to a 4.2-month significantly longer bone-metastasis-free survival time relative to placebo (median, 29.5 months versus 25.2 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73-0.98; p = .028) [1]. The time to first bone metastasis and risk for symptomatic bone metastasis were also significantly better with denosumab treatment. Dror Michaelson and Philip Saylor discuss the potential implications of this trial.

A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524).

PURPOSE: Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. METHODS AND MATERIALS: Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completion rate, and survival. RESULTS: A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. CONCLUSIONS: In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer.

BACKGROUND: Metastatic prostate cancer is characterized by the presence of osteoblastic bone metastases. Bone metastases account for most of the morbidity from this disease. Inhibition of osteoclast activity with the potent bisphosphonate zoledronic acid reduces skeletal complications and decreases serum levels of biochemical bone turnover markers compared with placebo. Atrasentan is an investigational agent that inhibits endothelin-1 receptor, resulting in decreased osteoblast activity. METHODS: The effects of atrasentan alone versus combination therapy with atrasentan and zoledronic acid were investigated on bone turnover markers in men with bone metastases from prostate cancer. Forty-four men were randomized to receive either atrasentan alone or combination therapy, and 33 completed at least 12 weeks of treatment and were included in the primary analysis. RESULTS: Treatment with the combination resulted in significantly lower serum levels of N-telopeptide, a marker of bone resorption, compared with treatment with atrasentan alone. There was no difference between groups in serum levels of bone-specific alkaline phosphatase, a marker of bone formation, at 12 weeks. Commonly observed adverse effects were edema, rhinitis, fatigue, and shortness of breath, most of which were NCI CTC (version 3.0) Grade 1. No Grade 4 or 5 treatment-related toxicities were observed. There was minimal clinical efficacy, with no objective responses and only 1 prostate-specific antigen (PSA) response. CONCLUSIONS: There is no evidence for additive or synergistic effects of combination therapy with atrasentan and zoledronic acid on bone turnover markers in men with metastatic prostate cancer.