Dataset Information

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial.

ABSTRACT:

Background

The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined.

Patients and methods

Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC.

Results

The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015).

Conclusion

This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

SUBMITTER: Hamid AA

PROVIDER: S-EPMC8463957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe immunosuppressive cytokine interleukin- 8 (IL-8), produced by tumor cells and some myeloid cells, promotes inflammation, angiogenesis, and metastasis. In our discovery work, elevated serum IL-8 at androgen deprivation therapy (ADT) initiation portended worse overall survival (OS). Leveraging serum samples from the phase 3 CHAARTED trial of patients treated with ADT +/- docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), we validated these findings.MethodsTwo hundred and thirty-three patients had serum samples drawn within 28 days of ADT initiation. The samples were assayed using the same Mesoscale Multiplex ELISA platform employed in the discovery cohort. After adjusting for performance status, disease volume, and de novo/metachronous metastases, multivariable Cox proportional hazards models assessed associations between IL-8 as continuous and binary variables on OS and time to castration-resistant prostate cancer (CRPC). The median IL-8 level (9.3 pg/ml) was the a priori binary cutpoint. Fixed-effects meta-analyses of the discovery and validation sets were performed.ResultsHigher IL-8 levels were prognostic for shorter OS (continuous: hazard ratio [HR] 2.2, 95% confidence interval [CI]: 1.4-3.6, p = .001; binary >9.3: HR 1.7, 95% CI: 1.2-2.4, p = .007) and time to CRPC (continuous: HR 2.3, 95% CI: 1.6-3.3, p < .001; binary: HR 1.8, 95% CI: 1.3-2.5, p < .001) and independent of docetaxel use, disease burden, and time of metastases. Meta-analysis including the discovery cohort, also showed that binary IL-8 levels >9.3 pg/ml from patients treated with ADT alone was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p = .007) and shorter time to CRPC (HR 1.4, 95% CI: 0.99-1.9, p = .057).ConclusionsIn the phase 3 CHAARTED study of men with mHSPC at ADT initiation, elevated IL-8 portended worse survival and shorter time to castration-resistant prostate cancer independent of docetaxel administration, metastatic burden, and metachronous versus de novo metastatic presentation. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.

Project description:BackgroundECOG3805 is a randomized trial of testosterone suppression with or without docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC). Deeper prostate-specific antigen (PSA) suppression is prognostic for outcome. However, the concordance of PSA rise and radiographic progression has not been examined previously in mHSPC, whereas this has been reported in metastatic castration-resistant prostate cancer.ObjectiveTo determine the patterns of progression by PSA and radiographic parameters in patients in ECOG3805.Design, setting, and participantsWe conducted a retrospective analysis of all patients in ECOG3805. Patients were classified according to the PSA level at progression (whether PSA level was below 2.0 ng/mL or not) and the type of progression event in the study (either PSA progression as defined by the study with or without clinical progression, or clinical progression alone). Baseline demographics, clinical outcomes, and patterns of progression were compared between the groups.Results and limitationsOne in eight patients had clinical progression below a PSA level of 2 ng/mL, and approximately 25% developed clinical progression in the absence of confirmed PSA progression. Overall survival from randomization was shorter in patients with clinical progression without confirmed PSA progression than in patients with PSA progression alone as the first progression. Patient demographics at study entry were not predictive of the pattern of progression. Study limitations include its retrospective and post hoc nature.ConclusionsClinical progression prior to PSA rise or at low PSA levels is a relatively frequent phenomenon in mHSPC and is associated with poorer overall survival. Further biological and clinical studies of these patients are warranted.Patient summaryReliance on prostate-specific antigen (PSA) alone is an inadequate strategy to monitor patients undergoing treatment for metastatic hormone-sensitive prostate cancer. Prostate cancer can get worse on scans even with low PSA and/or no or small changes in PSA. Imaging should be added to PSA testing to monitor patients with metastatic prostate cancer.