Prostate Cancer Therapies: From Fast-Track to Graveyard-Bound

CHICAGO – Updated and final analyses from four phase III prostate cancer trials offer continued support for radium-223, insights into denosumab and multimodal therapy, and an obituary for yet another drug in castration-resistant prostate cancer.

Radium-223 Boosts Overall Survival

Updated results from the phase III ALSYMPCA trial show that radium-223 chloride (Alpharadin) increased median overall survival by 3.6 months, from 11.3 months to 14.9 months (hazard ratio, 0.695; P = .00007), resulting in a 30.5% reduction in the risk of death, compared with placebo, in men with castration-resistant prostate cancer (CRPC) and bone metastases.

Dr. Chris Parker

The experimental alpha-emitting particle also significantly prolonged the time to first skeletal-related event, from 6.7 months to 12.2 months (HR, 0.64; P less than .0001), said Dr. Chris Parker of the Royal Marsden Hospital, London, at the annual meeting of the American Society of Clinical Oncology.

The updated results surpass the overall survival benefit reported for radium-223 chloride in an interim analysis at the 2011 European Multidisciplinary Cancer Congress.

The Food and Drug Administration very quickly granted fast-track designation to radium-223 chloride, and earlier this year agreed that Bayer HealthCare could make the drug available to patients who had CRPC or hormone-refractory prostate cancer with symptomatic bone metastases at qualified clinical sites through its expanded-access program.

Based on the ALSYMPCA data, Bayer is expected to file radium-223 chloride for CRPC with regulatory authorities in the second half of 2012, and is planning trials in earlier-stage disease and other cancers. Recruitment is already underway for a trial of radium-223 in combination with docetaxel (Taxotere) in patients with bone metastasis from CRPC.

Denosumab Data Did Not Sway FDA

The shorter the prostate-specific antigen doubling time (PSADT), the greater the impact is of denosumab (Xgeva) in nonmetastatic CRPC, according to an exploratory, post hoc subset analysis of the denosumab 147 trial.

If the PSADT was 6 months or less, denosumab increased median bone metastasis-free survival by 7.2 months to 25.9 months, from a median of 18.7 months with placebo (HR, 0.77; P = .006), which translates into a 23% risk reduction.

If the PSADT was less than 4 months, the delay increased by 7.5 months, from a median of 18.3 months with placebo to 25.8 months with denosumab (HR, 0.71; P = .004), corresponding to a 29% risk reduction, reported Dr. Fred Saad, professor and chief of urology at the University of Montreal Hospital Centre.

Discussant Dr. Eric Small, codirector of urologic oncology at the University of California, San Francisco, said that the study validates PSADT as an important risk stratifier in this group of patients, but observed that denosumab is not approved for this indication, and it appears to have the greatest benefit in a diminishingly small group of patients with shorter and shorter PSA doubling times.

"This is wonderful hypothesis generation, but cannot be used for the basis of therapeutic decisions," he said.

Bone metastasis–free survival in the entire cohort was 25.2 months with placebo and 29.5 months with denosumab (HR, 0.85; P = .028).

In February, an FDA advisory panel voted that denosumab does not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastasis in high-risk men (defined as those with a PSA level of at least 8.0 ng/mL or a PSA that doubled within 10 months or less).

Multimodal Benefit Goes 10 Years

The survival benefit of adding radiotherapy (RT) to androgen deprivation therapy (ADT) was maintained at 10 years in men with locally advanced prostate cancer, according to the final analysis of a phase III intergroup trial carried out by the U.K. Medical Research Council, the National Cancer Institute of Canada, and the Southwest Oncology Group.

At 10 years, 55% of men who were treated with ADT plus RT were alive, compared with 49% given ADT alone (HR, 0.70; P = .0003). The difference in disease-specific survival was particularly striking at 15% vs. 26%, favoring the combination (HR, 0.46; P less than .0001).

Dr. Malcolm Mason

"That’s more than halving the risk of death from prostate cancer," said Prof. Malcolm D. Mason, head of oncology and palliative medicine at Cardiff (Wales) University.

In an interim analysis reported at ASCO 2010, RT plus ADT provided significant improvements at 7 years in overall survival (HR, 0.77; P = .033) and disease-specific survival (DSS; HR, 0.54; P = .0001).

In the current analysis, bowel and urinary morbidity were transiently elevated with the addition of radiation, most often delivered at a dose of 65-69 Gy, but were no different after 3 years.