Investigators have identified genomic alterations that appear to be associated with prognosis in men with metastatic castration-sensitive prostate cancer (mCSPC).

A study of 424 patients with mCSPC treated at a tertiary care center revealed that alterations in the androgen receptor (AR), TP53, cell-cycle, MYC oncogenic signaling pathways occur more commonly in tumors with worse overall survival and decreased time to castration-resistant disease, whereas alterations in the SPOP and MNT pathways occur more frequently in tumors with a better prognosis, according to findings published in Clinical Cancer Research.

“The genomics of metastatic castration-sensitive prostate cancer have not been well characterized in the literature, but it is now clear that upfront treatment intensification with taxanes or next-generation AR-directed therapies offer benefit in the overall patient population,” said the study’s co-senior author Wassim Abida, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. “The question remains whether treatment selection or targeted therapies can be employed based on genomic characteristics.”

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The association between alterations in cell-cycle genes and TP53 and MYC pathway genes and worse outcomes “may pave the way for targeted therapy in these higher-risk groups,” Dr Abida said.

The study compared genomic alterations according to clinical phenotypes: high- vs low-volume disease and de novo vs metastatic recurrence. Of the 424 patients in the study, 213 men (50%) had high-volume disease (4 or more bone metastases or visceral metastases) and 211 (50%) had low-volume disease; 65% had de novo metastases and 35% had metastatic recurrence. At the time of sample collection, patients had a median age of 66 years. The investigators conducted gene sequencing from May 2015 to September 2018.

High- vs low-volume disease

In adjusted analyses, men with higher-volume disease had significant 1.8- and 3.7-fold increased risks of castration-resistant disease and death, respectively, compared with men who had low-volume disease. Tumor specimens from men with high-volume disease had more copy number alterations.

Among men with high-volume disease, the highest-ranking pathways were the NOTCH, cell-cycle, and epigenetic modifiers pathways.

Although the prevalence of CDK12 alterations differed between patients with de novo metastatic and those with metastatic recurrences, the groups had similar prognoses. “I was actually surprised there were not more dramatic genomic differences between de novo and relapsed disease,” said study co-senior author Philip Kantoff, MD, a medical oncologist and Chair of the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York.

After adjusting for disease volume and other genomic pathways, the researchers found that the rates of castration resistance differed by 1.5-fold and up to 5-fold according to alterations in the AR, SPOP (inverse), TP53, cell-cycle, WNT (inverse), and MYC pathways. Overall survival (OS) rates varied from 2- to 4-fold according to alterations in the AR, SPOP (inverse), WNT (inverse), and cell-cycle pathways. PI3K pathway alterations were not associated with prognosis.

Docetaxel and next-generation AR axis-directed therapies have been shown to prolong OS, but it remains uncertain which patients benefit the most from intensified therapies. “We did not find any obvious genomic reason to explain the differences in docetaxel sensitivity between high- and low-volume disease,” Dr Kantoff said.

The authors pointed out that genomic landscape studies of tumor DNA profiling in prostate cancer in general have excluded metastatic castration-sensitive tumors. Instead, most studies have focus on localized disease or metastatic castration-resistant disease.

Dr Abida and his colleagues acknowledged that their study has inherent biases because it was hospital based and enrolled patients at an academic referral center.

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.

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