Impact of DNA damage repair defects on response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer

Privé, Bastiaan M.; Slootbeek, Peter H. J.; Laarhuis, Babette I.; Naga, Samhita Pamidimarri; Doelen, Maarten J. van der; Kalmthout, Ludwike W. M. van; Keizer, Bart de; Ezziddin, Samer; Kratochwil, Clemens; Morgenstern, Alfred; Bruchertseifer, Frank; Ligtenberg, Marjolijn J. L.; Witjes, J. Alfred; Oort, Inge M. van; Gotthardt, Martin; Heskamp, Sandra; Janssen, Marcel J.R.; Nagarajah, James; Mehra, Niven

doi:10.1038/s41391-021-00424-2

Cited by 25 publications

(18 citation statements)

References 46 publications

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“…In an observational cohort study carried out by Privè and colleagues, the response to PSMA-RLT with beta or alpha emitters ([ 177 Lu/ 225 Ac]-PSMA-617 or PSMA-I&T) was assessed through a minimum 6 weeks’ follow-up in an overall number of 40 mCRPC patients [ 22 ]. Seventeen of 40 subjects harbored mutations and were classified as DDR+, being BRCA1/2 the most commonly registered mutated genes.…”

Section: Resultsmentioning

confidence: 99%

DNA Damage Repair Defects and Targeted Radionuclide Therapies for Prostate Cancer: Does Mutation Really Matter? A Systematic Review

Filippi

Palumbo²,

Bagni³

et al. 2022

Life

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The aim of the present review was to assess the impact of DNA damage repair (DDR) mutations on response and outcome of patients (pts) affected by advanced prostate cancer (PCa) submitted to radionuclide therapies with [223Ra]RaCl2 (223Ra-therapy) or prostate specific membrane antigen (PSMA) ligands. A systematic literature search according to PRISMA criteria was made by using two main databases. Only studies published up until to October 2022 in the English language with ≥10 enrolled patients were selected. Seven studies including 326 pts, of whom 201 (61.6%) harboring DDR defects, were selected. The majority of selected papers were retrospective and four out of seven (57.1%) had small sample size (<50 pts). Three out of seven (42.8%) studies reported a more favorable outcome (overall or progression free survival) after therapy with alpha emitters (223Ra-therapy or [225Ac]Ac-PSMA-617) in subjects with DDR defects with respect to those without mutations. In two studies employing alpha or beta emitters ([177Lu]/[225Ac]-PMSA), no significant benefit was registered in pts harboring DDR defects. In all but one paper, no significant difference in response rate was reported among pts with or without DDR mutations. Although preliminary and biased by the retrospective design, preliminary data suggest a trend towards a longer survival in PCa pts harboring DDR defects submitted to radionuclide targeted therapy with alpha emitters.

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Section: Resultsmentioning

confidence: 99%

DNA Damage Repair Defects and Targeted Radionuclide Therapies for Prostate Cancer: Does Mutation Really Matter? A Systematic Review

Filippi

Palumbo²,

Bagni³

et al. 2022

Life

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“…Nevertheless, the results were limited by the lack of a control arm 14 . In another series with PSMA‐RLT by Privé et al, 27 the authors included a larger number of patients along with a control arm, and did not report any significant difference in outcomes between the mutation‐positive and mutation‐negative patients. This is in line with our own observations.…”

Section: Discussionmentioning

confidence: 99%

Genomic characterization of metastatic castration‐resistant prostate cancer patients undergoing PSMA radioligand therapy: A single‐center experience

et al. 2022

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Background Genomic defects in DNA‐damage repair (DDR) mechanisms have been proposed to affect the radiosensitivity of prostate cancers. In this study, we intended to evaluate the prevalence of genetic alterations in a cohort of metastatic castration‐resistant prostate cancer (mCRPC) patients undergoing radioligand therapy (RLT) with prostate‐specific membrane antigen (PSMA)‐inhibitors as well as the impact of such mutations on treatment outcomes. Methods Data of consecutive mCRPC patients from 2017 to 2021 who were treated with PSMA‐RLT and underwent next‐generation sequencing (NGS) were collected and analyzed for response and survival outcomes. Results In 95 patients of mCRPC treated with PSMA‐RLT, 15 patients (median age: 66 years, range: 50–73 years; [177Lu]Lu‐PSMA‐617, n = 12; [225Ac]Ac‐PSMA‐617, n = 3) underwent NGS. The median progression‐free survival (PFS) of this cohort was 3 months (95% confidence interval: 1.6–4.4 months). On NGS, 21 genetic alterations were reported in 10/15 (67%) patients, of which 13 were DDR‐associated alterations involving the genes: ATM (n = 3), BRCA2 (n = 3), TP53 (n = 2), PTEN (n = 2), FANCD2 (n = 1), FANCM (n = 1), and NBN (n = 1). Overall, 5/15 (33%) patients harbored six pathogenic variants (BRCA2, n = 2; ATM, n = 1; TP53, n = 1; PTEN, n = 2). No significant difference was noted for the biochemical response, radiological response, PFS, and overall survival between the patients with and without genetic alterations. Conclusions Patients of mCRPC undergoing PSMA‐RLT were frequently seen to harbor DDR‐associated aberrations, albeit with no significant impact on treatment outcomes. Large prospective trials comparing PSMA‐RLT‐related outcomes in DDR‐deficient and ‐proficient patients are required to bring out the differences, if any, in a more observable manner.

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“…Further evaluation of transcript variation analysis for identification of potential biomarkers of radiosensitivity to 177 Lu‐DOTATATE therapy is ongoing (NCT03667092). Pharmacogenomic data of PSMA radioligand therapy is currently limited to a few studies in small series of patients, evaluating possible associations of mutations in DNA damage‐repair‐associated genes and response to PSMA radioligand therapy, which yielded inconsistent results 101,102 . Systematic inclusion of pharmacogenomics in future prospective trials with large patient cohorts is needed for identification of genomic changes predictive of response and toxicity for individual patient selection.…”

Section: Strategies To Improve Efficacy Of Radioligand Therapymentioning

confidence: 99%

Clinical Pharmacology of Radiotheranostics in Oncology

Beek

Burggraaf

Teunissen

et al. 2022

Clin Pharma and Therapeutics

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The combined use of diagnostic and therapeutic radioligands with the same molecular target, also known as theranostics, enables accurate patient selection, targeted therapy, and prediction of treatment response. Radioiodine, bone‐seeking radioligands and norepinephrine analogs have been used for many years for diagnostic imaging and radioligand therapy of thyroid carcinoma, bone metastases, pheochromocytoma, paraganglioma, and neuroblastoma, respectively. In recent years, radiolabeled somatostatin analogs and prostate‐specific membrane antigen ligands have shown clinical efficacy in the treatment of neuroendocrine tumors and prostate cancer, respectively. Several candidate compounds are targeting novel theranostic targets such as fibroblast activation protein, C‐X‐C chemokine receptor 4, and gastrin‐releasing peptide receptor. In addition, several strategies to improve efficacy of radioligand therapy are being evaluated, including dosimetry‐based dose optimization, multireceptor targeting, upregulation of target receptors, radiosensitization, pharmacogenomics, and radiation genomics. Design and evaluation of novel radioligands and optimization of dose and dose schedules, within the complex context of individualized multimodal cancer treatment, requires a multidisciplinary approach that includes clinical pharmacology. Significant increases in the use of these radiopharmaceuticals in routine oncological practice can be expected, which will have major impact on patient care as well as (radio)pharmacy utilization.

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Impact of DNA damage repair defects on response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer

Cited by 25 publications

References 46 publications

DNA Damage Repair Defects and Targeted Radionuclide Therapies for Prostate Cancer: Does Mutation Really Matter? A Systematic Review

DNA Damage Repair Defects and Targeted Radionuclide Therapies for Prostate Cancer: Does Mutation Really Matter? A Systematic Review

Genomic characterization of metastatic castration‐resistant prostate cancer patients undergoing PSMA radioligand therapy: A single‐center experience

Clinical Pharmacology of Radiotheranostics in Oncology

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