San Francisco, CA—Two treatments significantly extended survival in men with metastatic castration-resistant prostate cancer (CRPC) in separate phase 3 clinical trials reported at the 2012 Genitourinary Cancers Symposium.
The hope is that the 2 treatments, one an injectable alpha pharmaceutical (radium-223 chloride) and the other a novel antiandrogen drug (MDV3100), can be used either sequentially or in combination to further boost survival in men with CRPC and bone metastases.
In the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, radium-223 chloride improved overall survival (OS) by 30% compared with placebo. Mean survival in men randomized to radium-223 chloride was 14.0 months compared with 11.2 months in the group receiving placebo. Radium-223 chloride also cut the risk of pathologic bone fracture and spinal cord compression in half while also reducing the need for external beam radiation by one third, reported A. Oliver Sartor, MD, Professor of Cancer Research at Tulane University and Medical Director of the Tulane Cancer Center, New Orleans.
“We believe this novel alpha-pharmaceutical—the very first one to be tested in phase 3 in all of medicine—may provide a new standard of care for the treatment of patients with bone metastases in advanced prostate cancer,” said Dr Sartor.
Radium-223 is an alpha particle emitter that binds to stroma adjacent to bone metastases. The short range of the alpha emitters enables highly localized tumor cell death with minimal damage to surrounding normal tissue.
The ALSYMPCA investigators randomized 922 men with confirmed symptomatic CRPC and at least 2 bone metastases, but no visceral metastases, in a 2:1 ratio to radium-223 chloride or placebo. Most participants had disease progression after treatment with docetaxel or were considered unfit for docetaxel, a group often excluded from clinical trials, noted Dr Sartor. Both groups received best supportive care.
After a planned interim analysis, the Independent Data Monitoring Committee recommended stopping the trial early because of evidence of a significant benefit with radium-223 treatment.
The time to a first skeletal-related event (SRE) was extended from 8.4 months in the placebo group to 13.6 months in the radium-223 chloride group, corresponding to a 39% relative improvement.
Compared with placebo, treatment with radium-223 resulted in a 55% reduction in pathologic bone fracture (6.7% vs 3.6%), a 56% reduction in spinal cord compression (6.0% vs 3.1%), and a 35% reduction in the need for external beam radiation (26.9% vs 22.6%). There was no significant difference between the 2 groups in the rate of surgical intervention for SREs.
Radium-223 chloride was “very well tolerated,” said Dr Sartor. The rates of grade 3 or 4 events, including anemia and other hematologic events, were not different with radium-223 than with placebo, except for a lower rate of bone pain in those treated with radium-223. The lack of toxicity is evidence that the short tract of the radium particle spares the bone marrow, he said.
Based on the ALSYMPCA results, the US Food and Drug Administration has agreed to a fast-track review of radium-223.
The other phase 3 data presented here involved MDV3100, the first in a new class of oral hormonal agents that affects multiple steps in androgen-receptor signaling, a key driver of prostate cancer growth.
It was studied in 1199 patients with progressive CRPC in whom docetaxel chemotherapy failed. The patients were randomized in a 2:1 ratio to daily MDV3100 or placebo.
The double-blind trial was unblinded early after the Independent Data Monitoring Committee determined that the risk:benefit ratio with MDV3100 was favorable.
OS, the primary end point of the trial, was extended by an average of 4.8 months in the MDV3100 arm, from 13.6 months in the placebo group to 18.4 months in the MDV3100 group—a 37% relative reduction in the risk of death, said lead investigator Howard I. Scher, MD, Chief of the Genitourinary Oncology Service and Chair in Urologic Oncology at Memorial Sloan-Kettering Cancer Center, NY.
A significantly higher proportion of patients treated with MDV3100 had shrinkage of soft tissue tumors demonstrated on imaging studies—28.9% of patients randomized to MDV3100 versus 3.8% of patients randomized to placebo. The median progression-free survival on imaging was extended by approximately 60% with MDV3100.
A higher proportion of patients also had a decline of at least 50% in their blood level of prostate-specific antigen (PSA). A ≥50% reduction in PSA level from baseline was seen in 54.0% of patients randomized to MDV3100 and only 1.5% of placebo recipients. A ≥90% reduction in PSA level from baseline occurred in 25% of the MDV3100 group and 1% of the placebo group.
MDV3100 increased the time to PSA progression by 5.3 months—from 3.0 months with placebo to 8.3 months with MDV3100. The time to disease progression was 5 months longer on average in those receiving MDV3100 versus placebo.
MDV3100 was well tolerated. Mild fatigue, diarrhea, and hot flushes were more common with MDV3100 but did not necessitate a reduction in dosage.
“The benefit:risk profile [of MDV3100] will likely position it as the first frontline agent after docetaxel therapy,” said Dr Scher.
An 18.4-month median survival rate, with 25% of patients having a 90% decline in PSA is “unprecedented,” commented Nicholas J. Vogelzang, MD, Medical Director of the Developmental Therapeutics Committee of US Oncology.
These drugs will probably be used in sequence, said Dr Vogelzang. “In a simple, additive way, we would expect the survivals to be fairly dramatically pushed forward,” but it is impossible to know because they have not yet been tested in sequence.
The drugs are mechanistically different and both have favorable safety profiles and have shown a survival benefit. “Seeing these effects and effects on survival in drugs that seem like they can be given in sequence or even together…will clearly benefit patients going forward,” Dr Scher pointed out.
“These mechanistically distinct therapies will probably be combined,” agreed Dr Sartor, and combinations or sequences “may add even more value than what we see here.”—WK
