Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer

Doelen, Maarten J. van der; Velho, Pedro Isaacsson; Slootbeek, Peter H. J.; Naga, Samhita Pamidimarri; Bormann, Maren; Helvert, Sjoerd van; Kroeze, Leonie I.; Oort, Inge M. van; Antonarakis, Emmanuel S.; Mehra, Niven

doi:10.1016/j.ejca.2020.05.001

Cited by 43 publications

(43 citation statements)

References 21 publications

(24 reference statements)

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“…Recent studies have shown an OS benefit in patients with mCRPC that have genetic aberrations associated with homologous recombination deficiency (HRD) receiving radium‐223. As we did not have this data, we were unable to control for the presence or absence of HRD in our cohorts or its potential impact on our results 32,33 . Finally, data collection was dependent upon the completeness of the information contained in each chart and reported on the electronic case report form.…”

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Clinical outcomes, management, and treatment patterns in patients with metastatic castration‐resistant prostate cancer treated with radium‐223 in community compared to academic settings

Sartor

Appukkuttan

Weiss³

et al. 2021

The Prostate

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Background:The most common site of disease in metastatic castration-resistant prostate cancer (mCRPC) is the bone. The ALSYMPCA study demonstrated that radium-223 significantly improved overall survival (OS) in mCRPC patients with symptomatic bone metastases and without visceral metastases. However, administration requires a multidisciplinary approach and an infrastructure that supports coordination of care, which may differ by practice site. We aimed to evaluate practice patterns and treatment outcomes in patients with mCRPC treated at a community practice (CP) compared with those treated at an academic center (AC). Methods: This retrospective review included 200 adult mCRPC patients receiving radium-223 between January 2014 and June 2017. The primary endpoint, OS, was estimated from the date of radium-223 initiation. Secondary outcomes included a comparison of baseline characteristics, reasons for initiation and discontinuation of radium-223, and treatment sequencing. A subset analysis of OS based on the number of radium-223 doses and on sequencing of radium-223 either before or after chemotherapy was also conducted.Results: Most patients were treated at a CP (57%). Patients treated at CP sites were significantly older (74.9 vs. 71.9 years; p = .031) and had more comorbidities (Klabunde score 1.1 vs. 0.7; p = .020) than those in an AC but initiated treatment within a shorter period of time from diagnosis of mCRPC (1.3 vs. 1.9 years; p < .001) and received a greater mean number of radium-223 doses (5.4 vs. 4.8; p = .001). There were no observed differences in OS between CPs versus ACs (21.6 vs. 20.7 months; p = .306).Overall, patients who received 5-6 doses versus 1-4 doses of radium-223 had a longer median OS (23.3 vs. 6.4 months; p < .001). The most common reason for discontinuation in patients who did not complete treatment was disease progression. Overall, 43% of patients received radium-223 monotherapy and 57% concurrently with other agents.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Discussionmentioning

confidence: 95%

“…As we did not have this data, we were unable to control for the presence or absence of HRD in our cohorts or its potential impact on our results. 32,33 Finally, data collection was dependent upon the completeness of the information contained in each chart and reported on the electronic case report form.…”

Section: Limitationsmentioning

confidence: 99%

Clinical outcomes, management, and treatment patterns in patients with metastatic castration‐resistant prostate cancer treated with radium‐223 in community compared to academic settings

Sartor

Appukkuttan

Weiss³

et al. 2021

The Prostate

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“…(2019) [ 95 ] 190 BRCA2, ATM, CHEK2, ATR, FANCI, FANCL and PALB2) Increased response to radium-223 Van et al. (2020) [ 96 ] 93 DNA repair defects (BRCA2, ATM, CDK12) Increased response to radium-223 CTC, circulating tumor cell; mCRPC, metastatic castration–resistant PCa; PCa, prostate cancer; PSA, prostate-specific antigen; PSCA, prostate stem cell antigen. …”

Section: Genomic Evaluation For Mcrpcmentioning

confidence: 99%

“…It selectively targets the bone microenvironment and emits high-energy alpha particles that cause double-strand DNA breaks [ 91 , 93 ], which exert potent localized cytotoxic effects [ 94 ]. Patients harboring aberrations in DNA repair genes experience a greater benefit from radium-223, relative to patients without these mutations [ 95 , 96 ].…”

Section: Genomic Evaluation For Mcrpcmentioning

confidence: 99%

Clinical implications of genomic evaluations for prostate cancer risk stratification, screening, and treatment: a narrative review

Chung

Morgan

Hong

2020

Prostate International

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New classification systems based on molecular features have been introduced to improve precision medicine for prostate cancer (PCa). This review covers the increasing risk of PCa and the differences in response to targeted therapy that are related to specific gene variations. We believe that genomic evaluations will be useful for guiding PCa risk stratification, screening, and treatment. We searched the PubMed and MEDLINE databases for articles related to genomic testing for PCa that were published in 2020 or earlier. There is increasing evidence that germline mutations in DNA repair genes, such as BRCA1/2 or ATM , are closely related to the development and aggressiveness of PCa. Targeted prostate-specific antigen screening based on the presence of germline alterations in DNA repair genes is recommend to achieve an early diagnosis of PCa. In cases of localized PCa, even if it has a favorable risk classification, patients under active surveillance with these gene alterations are likely to develop aggressive PCa. Thus, active treatment may be preferable to active surveillance for these patients. In cases of metastatic castration–resistant PCa, BRCA1/2 and DNA mismatch repair genes may be useful biomarkers for predicting the response to androgen receptor–targeting agents, poly (ADP-ribose) polymerase inhibitors, platinum chemotherapy, prostate-specific membrane antigen–targeted therapy, immunotherapy, and radium-223. Genomic evaluations may allow for risk stratification of patients with PCa based on their molecular features, which may help guide precision medicine for treating PCa.

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“…The mutation rates of BRCA1/2 (15% combined), ATR (9%) and ATM (7%) in PCa patients are significantly higher in lethal compared with localized disease and are associated with earlier age at death and shorter PSMA-RLT proteomics/phosphoproteomics 5 5 survival time (5,7). While recent clinical data have associated mutations in DDR genes with response (8) or resistance (9) to alpha-particle therapy, the roles of DDR/RSR and TP53 pathways in modulating responses to RLT in PCa have not been investigated systematically.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer

et al. 2020

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Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA-RLT.Experimental Design: Therapeutic efficacy of PSMA-RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53-knockout tumor-bearing Nod scid gamma mice. Two days post-RLT, the (phospho)proteome was analyzed by mass spectrometry.Results: PSMA-RLT significantly improved disease control in a dose-dependent manner.(Phospho)proteomic datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, PI3K/AKT, and MYC signaling. C4-2 TP53-knockout tumors were less sensitive to PSMA-RLT than parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusions:We identified signaling alterations that may mediate resistance to PSMA-RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients.

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Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer

Cited by 43 publications

References 21 publications

Clinical outcomes, management, and treatment patterns in patients with metastatic castration‐resistant prostate cancer treated with radium‐223 in community compared to academic settings

Clinical outcomes, management, and treatment patterns in patients with metastatic castration‐resistant prostate cancer treated with radium‐223 in community compared to academic settings

Clinical implications of genomic evaluations for prostate cancer risk stratification, screening, and treatment: a narrative review

Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer

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