Higher serum testosterone levels predict poor prognosis in castration‐resistant prostate cancer patients treated with docetaxel

Ando, Koji; Sakamoto, Shinichi; Takeshita, Nobushige; Fujimoto, Ayumi; Maimaiti, Maihulan; Saito, Shingo; Sanjyon, Pae; Imamura, Yusuke; Sato, Nobuo; Komiya, Akira; Akakura, Koichiro; Ichikawa, Tomohiko

doi:10.1002/pros.23938

Cited by 8 publications

(11 citation statements)

References 25 publications

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“…These studies showed that CRPC patients with suboptimal testosterone serum levels had significantly shorter progression-free survival following docetaxel treatment. 22,23 Our data strongly suggest that taxane efficacy can be optimised by maintaining suppression of testosterone levels in order to minimise interference with docetaxel tumour accumulation and block AR-driven prosurvival signalling. Several phase II/III trials are currently combining (novel) AR-targeted therapies with taxanes in mCRPC.…”

Section: Discussionmentioning

confidence: 86%

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Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

et al. 2020

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Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

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Section: Discussionmentioning

confidence: 86%

“…These studies showed that CRPC patients with suboptimal testosterone serum levels had significantly shorter progression-free survival following docetaxel treatment. 22 , 23 …”

Section: Discussionmentioning

confidence: 99%

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

et al. 2020

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“…The high‐testosterone (TST) group had significantly shorter OS and PFS than the low‐TST group. Furthermore, a high serum TST predicted poor post‐docetaxel survival in patients who received subsequent therapy, including ARAT and/or cabazitaxel [ 44 ]. A serum testosterone level of 5 to < 50 ng/dl was a significant predictor for determining the efficacy of AR-targeted therapy [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

Clinical implication of prognostic and predictive biomarkers for castration-resistant prostate cancer: a systematic review

et al. 2020

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Background: Diagnosis of metastatic castrate resistant prostate cancer (mCRPC) with current biomarkers is difficult and often results in unnecessary invasive procedures as well as over-diagnosis and over-treatment. There are a number of prognostic biomarkers for CRPC, but there are no validated predictive biomarkers to guide in clinical decision-making. Specific biomarkers are needed that enable to understand the natural history and complex biology of this heterogeneous malignancy, identify early response to treatment outcomes and to identify the population of men most likely to benefit from the treatment. In this systematic review, we discuss the existing literature for the role of biomarkers in CRPC and how they aid in the prognosis, treatment selection and survival outcomes. Methods: We performed a literature search on PubMed and EMBASE databases from January 2015 through February 2020 in accordance to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Articles were assessed to identify relevant observational studies and randomized controlled trials regarding biomarkers which aid in identifying progression to mCRPC as well as predictive biomarkers which help in treatment selection. Results: We identified 3640 number of hits of which 58 articles were found to be relevant. Here we addressed biomarkers in the context of prognosis, prediction and patient selection of therapy. These biomarkers were found to be effective as prognostic or predictive factors under variety of conditions. The higher levels for all these biomarkers were associated with shorter median OS and sometimes PFS. Lower amounts of biomarkers in serum or urine were associated with prolonged survival outcomes, longer time to CRPC development or CRPC progression and longer median follow-up irrespective of any therapy. Conclusion: We observed that the biomarkers included in our study predicted clinically relevant survival outcomes and treatment exposure. Though the current biomarkers are prognostic when measured prior to initiating treatment, not all are validated as predictive markers in post treatment setting. A greater understanding of biomarkers in CRPC is need of the hour for development of more personalized approach to maximize benefit and minimize harm in men with CRPC.

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“… 29 Higher serum TST values have been reported to be more responsive to novel ARAT, whereas lower TST values to be more responsive to docetaxel. 30 , 31 …”

Section: Discussionmentioning

confidence: 99%

Revision of CHAARTED and LATITUDE criteria among Japanese de novo metastatic prostate cancer patients

Kanesaka

Sakamoto

Yamada

et al. 2021

Prostate International

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Background To identify the real high-risk group among Japanese de novo metastatic prostate cancer patients who fit CHAARTED or LATITUDE criteria. Methods We retrospectively studied patients who fitted CHAARTED (292 patients) and LATITUDE (294 patients) criteria from Japanese multi-institutions. All patients received androgen deprivation therapy with bicalutamide as an initial treatment. Factors related to overall survival (OS) and progression-free survival were statistically analyzed. Results The median OS was 55.5 months and 60.0 months in patients who met the CHAARTED and the LATITUDE criteria, respectively. In patients who met CHAARTED criteria, lactate dehydrogenase (LDH) (hazard ratio (HR) 2.63, P < 0.0001) and C-reactive protein (CRP) (HR 1.65, P = 0.042) were independent risk factors for OS. In patients who met the LATITUDE criteria, Gleason score (GS) ≥9 (HR 1.77, P = 0.0326) and LDH (HR 2.62, P < 0.0001) were independent risk factors for OS. Modified CHAARTED criteria by adding LDH and CRP showed a significant difference in OS (HR 2.55, P < 0.0001) with a comparative median OS (31.8 months) to placebo of CHAARTED trial (32.2 months). Modified LATITUDE criteria by adding GS ≥9 and LDH showed a significant difference in OS (HR 2.66, P < 0.0001) with a comparative median OS (32.7 months) to placebo of LATITUDE trial (34.7 months). Conclusion Modified criteria may potentially elucidate the true “high volume” and “high risk” patients in the Japanese cohort who require early intensive therapy.

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Higher serum testosterone levels predict poor prognosis in castration‐resistant prostate cancer patients treated with docetaxel

Cited by 8 publications

References 25 publications

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

Clinical implication of prognostic and predictive biomarkers for castration-resistant prostate cancer: a systematic review

Revision of CHAARTED and LATITUDE criteria among Japanese de novo metastatic prostate cancer patients

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