Abstract
Although salvage prostate bed radiotherapy is highly effective in biochemically-relapsing prostate cancer patients following prostatectomy, relapses remain frequent and improvements are needed. Randomized phase 3 trials have shown the benefit of adding androgen-depriving therapy to irradiation, but not all patients benefit from this combination. Preclinical studies have shown that novel agents targeting the androgen receptor, DNA repair, PI3K/AKT/mTOR pathways, or the hypoxic microenvironment may help increase the response to prostate bed irradiation while minimizing potential side effects. This perspective review focuses on the most relevant molecules that may have an impact when combined with salvage radiotherapy, and underlines the strategies that need to be developed to increase the efficacy of salvage post-prostatectomy radiotherapy in prostate cancer patients.
Highlights
Despite adequate surgery, biochemical relapse following prostatectomy for locally advanced prostate cancer occurs in up to 50% of cases [1]
Recent transcriptomic analyses have described the first test capable of distinguishing low- and high-risk biochemicallyrelapsing forms of prostate cancer [28]. These genomic and transcriptomic analyses can help identify novel mechanisms in prostate cancer progression, and suggest radiosensitizing drugs that target deoxyribonucleic acid (DNA) repair, survival pathways, or the tumor microenvironment [29]. Based on this better understanding of the mechanisms behind the aggressiveness and radioresistance of prostate cancer, this article describes current and future strategies for drug intensification that aim to improve the efficacy of post-prostatectomy radiotherapy
The randomized phase 3 study that compares salvage prostate bed and lymph node radiotherapy combined with 6 months of androgen-depriving therapies (ADT) +/- apalutamide, combined abiraterone (CARLHA) 2 groupe d’étude des tumeurs urogénitales (GETUG) 33 (NCT04181203), is actively recruiting patients
Summary
Biochemical relapse following prostatectomy for locally advanced prostate cancer occurs in up to 50% of cases [1]. The NRG Oncology/RTOG 0534 SPPORT Trial showed that irradiating the pelvic lymph nodes in addition to the prostate bed improved progression-free survival compared to the prostate bed alone [10] This important result could be interpreted as radiotherapy being capable of reducing local relapses and of slowing down or even blocking the metastatic process. These genomic and transcriptomic analyses can help identify novel mechanisms in prostate cancer progression, and suggest radiosensitizing drugs that target DNA repair, survival pathways, or the tumor microenvironment [29] Based on this better understanding of the mechanisms behind the aggressiveness and radioresistance of prostate cancer, this article describes current and future strategies for drug intensification that aim to improve the efficacy of post-prostatectomy radiotherapy. AR amplification, alternative splicing of the AR, post-translational modifications to the AR, alteration of factors that control AR expression, or somatic gainof-function mutations which are the hallmark of late-stage castration-resistant prostate cancer, are typically absent in Frontiers in Oncology | www.frontiersin.org
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