Background: Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis. The Cancer of the Ovary Abiraterone (CORAL) trial was designed to evaluate the clinical activity of abiraterone in EOC. Patients & Methods: CORAL was a multi-centre, open-label, non-randomised, 2-stage phase II clinical trial. Eligible patients had progression within 12 months of last systemic therapy and no prior hormonal anti-cancer agents. Patients received abiraterone 1000 mg daily plus 5 mg prednisone until progression. The primary endpoint was objective response rate (ORR) according to combined Response Evaluation Criteria in Solid Tumours/Gynaecological Cancer Intergroup (RECIST/GCIG) criteria at 12 weeks. Secondary endpoints included clinical benefit rate (CBR) at 12 weeks. Results: A total of 42 patients were recruited; median age 65 (range 34–85) years; 37 (88.1%) had high-grade serous tumours; 20 (48%) had at least three prior lines of therapy; 29/40 (72.5%) were AR+. In stage 1, 1/26 response was observed (in an AR+, low-grade serous EOC); response lasted 47 weeks. Overall, 12 week ORR was 1/42 (2%), CBR was 11/42 (26%) (8/29 (28%) in AR+ patients). Disease control was ⩾6 months for 4/29 (14%). One patient (AR+, low-grade serous) had a RECIST response at 82 weeks. Four (10%) had grade ⩾3 hypokalaemia; 11 (26%) had dose delays. Conclusions: CORAL represents the first trial of an AR targeted agent in ovarian cancer. While responses were rare, a subset of patients achieved sustained clinical benefit. Targeting AR in EOC including low-grade serous cancer warrants further investigation. Trial registration: CORAL is registered on the ISRCTN registry: ISRCTN63407050; http://www.isrctn.com/ISRCTN63407050
Although platinum chemotherapy remains the standard treatment for ovarian cancer, recent advances in novel targeted drugs have generated anticipation and excitement. In addition, alternate administration schedules of already established cytotoxics have shown promise in both front line and recurrent disease settings. In this review, we outline the seminal trials that influenced our current management as well as introduce recent trials that have provided intriguing results to aid the understanding of ovarian tumour biology.
Previous reports suggest that weekly paclitaxel (WP) treatment has significant activity in patients having ovarian or primary peritoneal cancer, and also that its toxicity profile is relatively favorable. This retrospective study audited the use of WP in 47 patients with recurrent ovarian cancer and 6 with primary peritoneal cancer who were cared for at a tertiary cancer center. All patients had previously received a platinum cytotoxic agent and 24 had received a taxane as well; the median number of treatments was 3. WP was given in a dose of 80–100 mg/m2; the median number of weekly doses was 13. Toxicity was estimated using Common Toxicity Criteria, and the response by radiological findings and levels of cancer antigen-125 (CA-125). The overall response rate was 48% using radiological criteria and 69% based on CA-125 levels. Of 46 patients with measurable disease, 20 had a partial, and 2, a complete response. Five patients (11%) had progressive disease during WP treatment. The median progression-free survival time was 4.8 months, and the median overall survival time, 13.5 months. The use of taxanes did not influence the efficacy of WP therapy, nor were platinum-free or treatment-free intervals less than or greater than 6 months a factor. The most common grade 1–2 toxic effects were anemia, noted in 81% of patients, neutropenia in 57%, and peripheral neuropathy in 47%. Grade 3 toxicity included fatigue, peripheral neuropathy, and neutropenia—none affecting more than 15% of patients. No patient had grade 4 toxicity. The investigators conclude that WP therapy is a highly active and relatively well tolerated approach to relapsed ovarian cancer. Its use for treating recurrent disease is likely to increase.
<p>Supplementary Materials Table 1. Ratio of area under the curve during the time interval between consecutive dosing (AUCtau) on day 3 to AUCtau on day 1 (schedule 1 [S1]) Table 2. Ratio of area under the curve during the time interval between consecutive dosing (AUCtau) on day 5 (S2) or day 7 (S3) to AUCtau on day 1.</p>
<div>Abstract<p>A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4 mg/m<sup>2</sup>. Dose escalation in cohorts of at least three patients proceeded according to the worst toxicity observed in the previous cohort. Twenty-eight patients were treated with 72 courses of ES-285 across eight dose levels. No dose-limiting toxicities were seen between 4 and 128 mg/m<sup>2</sup>. Two of four patients treated at 256 mg/m<sup>2</sup> had dose-limiting reversible grade 3 transaminitis; one patient at 256 mg/m<sup>2</sup> also had transient grade 3 central neurotoxicity. One of three patients subsequently treated at 200 mg/m<sup>2</sup> died following drug-related central neurotoxicity. Other toxicities included phlebitis, nausea, fatigue, and fever. Pharmacokinetic studies indicated dose proportionality with high volume of distribution (median <i>V</i><sub>ss</sub> at 256 mg/m<sup>2</sup> was 2,389 liters; range, 1,615–4,051 liters) and long elimination half life (median <i>t</i><sub>1/2</sub> at 256 mg/m<sup>2</sup> was 28 h; range, 21–32 h). The three patients with dose-limiting toxicity had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Disease stabilization for 6 to 18 weeks was recorded in nine patients. Using this schedule, 128 mg/m<sup>2</sup> was considered safe and feasible. At this dose, pharmacologically relevant concentrations of the drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential mechanistic relevance. [Mol Cancer Ther 2009;8(6):1430–7]</p></div>
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