Daniel P. Petrylak, MD
Much progress has been made in the treatment of castration-resistant prostate cancer (CRPC) in recent years. New agents, such as sipuleucel-T, and in the second-line setting, abiraterone acetate, cabazitaxel, and enzalutamide, are now part of the treatment arsenal for this disease.
In addition, the novel alpha radiation-emitting agent radium-223 for patients with bone metastases from CRPC received FDA approval this year for both pre- and post-docetaxel patients. Daniel P. Petrylak, MD, discussed these and other developments at the 6th Annual Interdisciplinary Prostate Cancer Congress™ (IPCC®), where he served as co-chair. He is director of Genitourinary Oncology at the Yale Comprehensive Cancer Center in New Haven, Connecticut, and co-director of the center’s Signal Transduction Research Program.
Yet, despite the advent of these new agents, said Petrylak, “chemotherapy is still an important part of our management of prostate cancer,” and challenges remain regarding the mechanisms of docetaxel resistance, whether combination studies continue to make sense, and how the sequencing of docetaxel may impact toxicity and efficacy.
Docetaxel as first-line therapy in CRPC emanates from pivotal trials leading up to its approval by the FDA for CRPC in 2004,1,2
including the TAX 327 study confirming a clear survival benefit with administration every three weeks.3
“About 17% of patients treated with docetaxel and prednisone every three weeks were alive after three years, compared to about 12% of those who were treated with mitoxantrone,” noted Petrylak.
“That 5% difference is significant; nonetheless, we certainly want to do better than that,” he said.
Rapid Evolution of CRPC Therapy Sequencing
CRPC indicates castration-resistant prostate cancer.
Adapted from Petrylak DP. Advances in chemotherapy for castration resistant prostate cancer.
Presented at: 6th Annual Interdisciplinary Prostate Cancer Congress; March 16, 2013; New York, NY.
A Role for Angiogenesis?
Efforts to improve on the docetaxel-based regimen, he said, have understandably included targeting angiogenesis, in part because vascular endothelial growth factor (VEGF) is expressed in CRPC, and higher levels of VEGF correlate with poor outcomes. However, results of the multicenter, international, phase III VENICE trial reported earlier this year at the 2013 Genitourinary Cancers Symposium, comparing the addition of zivaflibercept to the docetaxel/prednisone regimen, versus docetaxel/prednisone and placebo in CRPC, did not lead to an improvement in survival. In addition, there was added toxicity and lower dose intensity in the experimental arm.4
Data that Petrylak presented at the 2012 European Society for Medical Oncology Meeting on the MAINSAIL trial,5
comparing the addition of lenalidomide versus placebo to the docetaxel regimen, again yielded “the same disappointing result,” he said. “In fact, it could be a little bit worse.” He noted that patients in the experimental arm had both lower overall survival (OS) and progression-free survival than those in the control arm, and adverse events such as neutropenia and febrile neutropenia resulted in less treatment exposure for patients receiving the combination therapy.
“Unfortunately, from these data, it is apparent that the single-agent angiogenesis approach combined with chemotherapy is not effective in this disease,” said Petrylak.
Targeting Bone and Biomarkers
Petrylak said that there also was good reason to expect that the addition of atrasentan, a selective endothelin receptor antagonist, to the docetaxel regimen might improve survival in CRPC, with the former targeting the bone and docetaxel targeting the tumor itself. However, a phase III trial (S0421) by the Southwest Oncology Group, comparing docetaxel plus placebo with docetaxel plus atrasentan in patients with hormone-refractory prostate cancer, again resulted in no difference in the control arm versus the experimental arm.
As to why this may have occurred, Petrylak suggested that more attention be focused on baseline biomarkers, for example, N-telopeptides, which are expressed in lung, breast, and prostate cancers.6,7
“We know that these particular bone markers correlate with a poorer overall prognosis.”