Molecular determinants of castration resistance or survival in patients with mHSPC have been unclear, but the new study sheds new light on molecular alterations associated with poor outcomes in men with mHSPC, particularly alterations in the AR, cell cycle genes, MYC, and TP53 genes, said Joshi Alumkal, MD, the Leader of the Prostate/Genitourinary Medical Oncology Section and Associate Division Chief for Basic Research in the Hematology-Oncology Division at the University of Michigan School of Medicine.

“Several randomized phase 3 clinical trials now show a benefit of escalating treatment in men with mHSPC by adding novel AR-targeting agents or chemotherapy plus medical castration versus medical castration alone,” Dr Alumkal said. “Whether the addition of any of these specific agents to medical castration is associated with improved outcomes in patients with poor-risk molecular alterations identified by the new study is a critical next question,” he said.

Urologic oncologist James Mohler, MD, Senior Vice President for Translational Research at Roswell Park Comprehensive Cancer Center in Buffalo, New York, said the new study found relatively small differences among the clinical phenotypes, but that is not surprising because the temporal differences in the evolution of tumor biology occur over long periods of time, much of which precedes clinical presentation. The hazard ratios for association between mutational analysis and oncologic outcome in some cases were statistically significant, but are so small as to not be clinically significant. “Part of the reason for this may be that prostate cancer, once metastatic, is so complex that no single mutation or single gene pathway is driving growth and hence targetable at a high rate beyond the long proven benefit from androgen deprivation therapy,” Dr Mohler said.

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The results reported by these authors may be disappointing to many clinicians, but are important because they represent a comprehensive analysis of mCSPC. “The authors appropriately acknowledge that better tumor sampling and more comprehensive genetic analysis and larger numbers of patients may be required to find any benefit to genomic or somatic sequencing,” Dr Mohler said. “I am afraid that these limitations are not just of their work but a biological limitation of aggressive prostate cancer, which makes improving treatment of advanced prostate cancer in an individual patient extremely challenging.”

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Stopsack KH, Nandakumar S, Wibmer AG, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer [published online March 27, 2020]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-20-0168

This article originally appeared on Renal and Urology News