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SAN FRANCISCO -- An investigational anti-androgen failed to improve overall survival in a randomized trial of men with docetaxel-treated metastatic castration-resistant prostate cancer (CRPC).

Patients who received orteronel plus prednisone had a median overall survival (OS) of 17 months versus 15.2 months for patients treated with prednisone alone. Orteronel did lead to significantly better progression-free survival (PFS), a secondary endpoint of the trial.

The results showed variation in survival outcomes by geographic region. The subgroup of patients treated outside of Europe and North American obtained a statistically significant 5-month gain in survival with orteronel, whereas smaller differences were seen in North American and European patients, as reported here at the Genitourinary Cancers Symposium.

One possible explanation for the geographic variation is that "38% of the non-European, non-North American population received subsequent therapy compared with more than 50% of patients in either Europe or North America, including abiraterone in 28% and 26%, respectively," said Robert Dreicer, MD, of the Cleveland Clinic.

"Abiraterone was available in the U.S. and Canada through an expanded access program at the time of the study initiation."

The orteronel trial was one of several in metastatic CRPC reported at the symposium.

Orteronel and OS

Like abiraterone (Zytiga), orteronel targets 17,20-lyase, an enzyme involved in steroidal hormone biosynthesis and upregulated in metastatic CRPC. Laboratory studies have demonstrated that orteronel, as compared with abiraterone, has greater specificity for 17,20-lyase and more potent inhibition.

Phase I-II clinical trials provided evidence of safety and efficacy for orteronel, leading to an international phase III trial reported for the first time by Dreicer. Men with metastatic CRPC that had progressed on as many as two prior regimens (including docetaxel) were randomized 2:1 to prednisone plus orteronel or placebo and treated until progression or unacceptable toxicity.

After a second planned interim analysis, the trial was stopped because of futility. Dreicer reported data for 1,099 patients recruited at 260 centers in 42 countries. Geographically, the study population comprised 590 patients from Europe, 112 from North America, and 397 from Australia, South America, and Asia.

The 1.8-month survival differences translated into an 11% reduction in the hazard ratio, which did not achieve statistical significance (HR 0.886, 95% CI 0.739-1.062). In an analysis by geographic region, patients treated outside of Europe and North America had a median OS of 15.3 months with orteronel versus 10.1 months with prednisone alone (HR 0.709, P=0.019).

By comparison, European patients had a median OS of 18.3 months with orteronel and 17.8 months without, and the medians for North American patients were 20.9 versus 16.9 months.

Analysis of radiographic PFS showed a 24% reduction in the hazard for progression, associated with a median PFS of 8.3 months with orteronel and 5.7 months without (HR 0.76, P=0.00038).

Similar to the geographic variation in OS, the PFS difference was driven by patients outside of Europe and North America, who had a median PFS of 6.7 months with orteronel versus 5.2 months with prednisone alone (HR 0.660, P=0.00076). Orteronel-treated patients in North America and Europe did not have significant improvement in PFS.

The orteronel results may reflect an emerging issue that could become clearer as several ongoing trials in prostate cancer reach completion. Invited discussant Michael Morris, MD, summarized the design of several ongoing trials, noting that they involve different types of patients (localized disease, CRPC, castration-sensitive metastatic disease, pre-chemotherapy/post-chemotherapy). Yet, they all have the same primary endpoint of OS.

"We may be approaching the point where OS is losing its interpretability," said Morris, of Memorial Sloan-Kettering Cancer Center in New York City. "All of the stakeholders in prostate cancer developmental therapeutics need to work together to develop alternative endpoints.

"Timing really is everything," he added. "It is incumbent on us, if we have a good question and a good drug, to ask that question, get the trial open, and not unduly delay the trial, because if this [orteronel] trial had come 1 year earlier, we might well have had a positive trial and another drug to treat these patients."

Radiopharmaceutical Results

The 18-month follow-up data from a randomized trial of radium-223 dichloride (Ra-223, Xofigo) in CRPC showed a low incidence of myelosuppression (<3%) and no reports of acute myelogenous leukemia, myelodysplastic syndrome, or primary bone cancer, all of which have been at least theoretical concerns with the bone-targeted agent.

Aplastic anemia has occurred in one patient treated with Ra-223, and two patients have developed other cancers considered unrelated to treatment, as have three patients in the placebo group, reported , of Karolinska University Hospital in Stockholm.

Primary results from the trial showed that Ra-223, as compared with placebo, improved median OS by 3.8 months in patients with CRPC and bone metastases. Time to first symptomatic skeletal event improved by 5.8 months versus placebo.

Follow-up will continue for 3 years in 574 patients (of 921 total) who entered the long-term follow-up phase of the trial.

Dialing Down ADT Duration

Another follow-up report from a clinical trial added to evidence that reducing the duration of androgen deprivation therapy (ADT) from 36 months to 18 months does not adversely affect outcomes in patients with high-risk localized prostate cancer.

The data showed that an 18-month course of ADT after definitive radiation therapy was associated with significantly better patient-reported quality of life, with no decrement in survival, as compared with men who continued ADT for 36 months after radiotherapy.

Quality-of-life assessment included 21 domains and a total of 55 items, said Abdenour Nabid, MD, of Sherbrooke University Hospital in Montreal. Patients completed the questionnaire before starting ADT, every 6 months during treatment, 4 months after completing ADT, and then annually for 5 years.

Results showed significantly higher higher scores (P=0.01) in six domains and 14 individuals items for patients treated with the short course of ADT. However, none of the differences in domain scores met the clinically relevant threshold of 10 points. Two of the individual items (hot flashes and enjoyable sex) met the threshold after 3 to 4 years.

Personalized Vaccine Progress

Interim data from a phase II randomized trial showed a threefold increase in the time to PSA failure in patients with metastatic CRPC treated with major histocompatibility class I personalized vaccines plus dexamethasone compared with dexamethasone alone. Median time to PSA failure (the primary endpoint) was 602 days with vaccine versus 203 days with dexamethasone and placebo (HR 0.641, P<0.001).

The median times to radiographic progression and to initiation of chemotherapy were 16 to 17 months in the placebo group but have yet to be reached in patients who received the vaccine, reported Hirotsugu Uemura, MD, of Kinki University in Osaka, Japan. Thus far, five of 37 patients in the vaccine group have died versus 11 of 35 in the placebo group.