1. Nalley, Catlin

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A real-world analysis of men with newly diagnosed metastatic castration-sensitive prostate cancer undergoing intensified androgen deprivation therapy identified clinical and genomic markers associated with poor overall survival. These findings-after external validation-have a number of potential implications for this patient population, including the development of future risk stratification models, as well as ongoing drug development.

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These data were presented by Nicolas Sayegh, MD, from the Huntsman Cancer Institute at the University of Utah, Salt Lake City, during the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics (Abstract P012).


While there have been advancements in systemic therapy for metastatic castration-sensitive prostate cancer, it remains a fatal disease, Sayegh and colleagues acknowledged. Recognizing the need for the identification of novel genomic and clinical correlates of survival, they sought to fill this gap.


"Androgen deprivation therapy is the standard of care at the onset of metastasis or biochemical recurrence after definitive therapy-radical prostatectomy or radiation therapy-for prostate cancer," Sayegh noted. "In the last years, chemotherapy and novel hormonal therapy agents have been approved in the metastatic castration-sensitive prostate cancer setting, after [demonstrating] to prolong survival when added to androgen deprivation therapy."


Several tumoral genomic biomarkers have been associated with a worse prognosis in prostate cancer. However, according to Sayegh, only limited prognostic or predictive analyses have been initiated among metastatic castration-sensitive prostate cancer patients treated with these recently approved intensification agents.


Study Methodology

In the current study, the researchers explored clinical and genomic factors associated with survival and treatment outcomes in the real-world setting of metastatic castration-sensitive prostate cancer patients undergoing intensified androgen deprivation therapy.


They retrospectively collected patient data using electronic medical records from a single tertiary referral cancer center. Eligible patients included those with newly diagnosed metastatic castration-sensitive prostate cancer undergoing intensified androgen deprivation therapy (ADT plus docetaxel or novel hormonal therapy). Only those with available comprehensive genomic profiling of the primary tumor were included in the analysis.


"Patients treated with androgen deprivation therapy alone and those with a histology showing small cell or neuroendocrine features were excluded," said Sayegh. "All variants of unknown significance were removed and genomic alterations that were included in the analysis were all somatic and were either single nucleotide variants, copy number variants, or fusions."


The researchers used a CLIA-certified next-generation sequencing panel to perform comprehensive genomic profiling and involved the following genes: FAS, KDM6A, MYC1, PTEN, RB1, TMPRSS2, and TP53.


Cox proportional hazards was used to assess relationships between overall survival and multiple variables, according to the study authors. These variables included age at diagnosis, Gleason score, baseline PSA, de novo disease, volume of disease, presence of visceral metastases, and presence of genetic aberrations on comprehensive genomic profiling.


Trial Results

Among the 127 patients included in the analysis, Sayegh reported that most had a Gleason score of 8 or greater and 66 percent had de novo metastatic disease. Fifty-six percent had high-volume disease, with 17 percent having visceral metastases at the time of first metastasis diagnosis.


The most frequently mutated genes included TP53, TMPRSS2, and PTEN. Median follow-up time for overall survival of the entire cohort was 30 months, said Sayegh. Of the 127 patients included, death occurred in 35 subjects at the time of analysis.


"Among the clinical variables, baseline PSA and presence of visceral metastases were significantly associated with a lower overall survival," Sayegh noted during his presentation. "Median overall survival in patients with RB1 mutations was 22.5 months, significantly lower than those that had wild-type RB1 genes. Death rate in patients with MYC1 alterations were significantly higher than those without these alterations."


Discussion & Conclusions

Data from big trials support that baseline PSA values correlate with worse outcomes, Sayegh noted, while highlighting other studies in this patient population.


A single-institution analysis of 97 metastatic castration-sensitive prostate cancer patients, who were treated with androgen deprivation therapy plus abiraterone acetate or androgen deprivation therapy plus docetaxel, found that alterations in RB1, PTEN, or TP53 were associated with lower median overall survival (27.6 vs. 53.3 months).


"A large introspective cohort study enrolling 424 metastatic castration-sensitive prostate cancer patients, regardless of treatment type, reported that alterations in MYC had a negative association with overall survival, but it was not statistically significant," Sayegh said.


He also acknowledged the limitations of their own study, which included the retrospective and single-institution nature of this research, as well as the small sample size.


"In conclusion, we used the real-world patient population of men with metastatic castration-sensitive prostate cancer undergoing intensified androgen deprivation therapy and identified clinical and genomic markers associated with poor overall survival," he summarized.


"We highlight the need for the introduction of a comprehensive genomic profiling-based certification system in clinical trials," Sayegh continued. "These data are only hypothesis generating and upon external validation may aid with development of a risk stratification model, counseling of patients, treatment decision-making in the clinic, as well as further drug development."


Catlin Nalley is a contributing writer.