Impact of germline mutations in homologous recombination (HR) genes on the response to Radium-223 for metastatic castration resistant prostate cancer (mCRPC)

Castro, Elena; Mejorada, R. Lozano; Sáez, María Isabel Corbí; Giorgi, U.F.F. De; Aragón, Isabel M.; Laorden, N. Romero; Rueda, G.A. De Velasco Oria de; Montesinos-Magraner, Lluïsa; Pacheco, M.I.; Puente, Javier; Alba, Aránzazu Gonzalez del; García, P. Borrega; Conteduca, Vincenza; Guzmán, José Carlos Villa; Parra, Eva Fernandez; Rodríguez‐Vida, Alejo; Medina-Colmenero, A.; Barrera, Rafael; Lorente, David; Hidalgo, Daniel

doi:10.1093/annonc/mdz248.033

Cited by 11 publications

(10 citation statements)

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“…In the study of Isaacsson Velho et al [11] a trend towards an OS benefit was seen in the DDRþ group (median OS Z 36.9 versus 19.0 months; HR Z 3.3; P Z 0.11), which is in line with the OS benefit seen in our study. The recently presented interim analysis of the enrolling prospective PRORADIUM study (NCT02925702) also showed a trend towards prolonged OS in patients with germline homologous recombination mutations (median OS Z 14.4 versus 10.6 months, P Z 0.066) [15].…”

Section: Discussionmentioning

confidence: 94%

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

Doelen¹,

Velho

Slootbeek³

et al. 2020

European Journal of Cancer

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Radium-223 is a targeted alpha radiation therapy for metastatic castration-resistant prostate cancer. DNA damage repair (DDR) defective prostate cancers, specifically genetic aberrations leading to homologous recombination deficiency (HRD), accumulate irreparable DNA damage following genotoxic treatment. This retrospective study assessed DDR mutation status in patients treated with radium-223, investigating their association with efficacy and overall survival (OS). Patients and methods: Included patients were treated with radium-223 and had results from primary or metastatic tumour tissue of a comprehensive next-generation sequencing panel of DDR genes, including canonical HRD genes. Patients were grouped by presence (DDRþ) or absence (DDRÀ) of pathogenic somatic or germline aberrations in DDR genes. We evaluated OS, time to ALP progression (TAP), time to initiation of subsequent systemic therapy (TST) and biochemical responses between DDR groups.

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Section: Discussionmentioning

confidence: 94%

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

Doelen¹,

Velho

Slootbeek³

et al. 2020

European Journal of Cancer

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“…A significantly greater decline in alkaline phosphatase at 12 weeks was observed in HRR gene mutation carriers than in non-carriers (75% vs. 43%, p=0.036). OS was longer in HRR gene mutation carriers than in non-carriers, although the difference did not reach statistical significance (median 14.4 months vs. 10.6 months, p=0.066) (50). Taken together, not only PARP inhibitors, but also platinum, taxanes, and radium-223 may be promising treatment options for DNA repairdeficient prostate cancer.…”

Section: Are Parp Inhibitors Going To Dramatically Change the Treatment Landscape Of Mcrpc?mentioning

confidence: 89%

Treatment of Metastatic Castration-resistant Prostate Cancer: Are PARP Inhibitors Shifting the Paradigm?

et al. 2021

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Remarkable developments in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been achieved over the past decade. Although targeting the novel androgen receptor axis and using chemotherapeutic agents have improved survival, mCRPC is still a lethal disease. A better molecular characterization of cancer resulted in the determination of the important role of homologous recombination repair (HRR) genes in cancer development, and poly (ADP-ribose) polymerase (PARP) is one of the most attractive therapeutic targets. Recent clinical studies have demonstrated that PARP inhibitors significantly improve oncological outcomes in patients with mCRPC harboring BRCA mutations, and PARP inhibitors are becoming a standard of care for these patients. However, not only PARP inhibitors, but also chemotherapeutic agents such as platinum agents, taxanes, and radium-223 are active in HRR gene mutation carriers, and platinum sensitivity may predict the efficacy of PARP inhibitors for mCRPC. The combination of PARP inhibitors with other anti-cancer agents may overcome resistance mechanisms against PARP inhibitors and lead to survival benefits. Appropriate treatment sequences and combinations may change the therapeutic landscape of DNA repair deficient mCRPC.

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“…An early report on four patients with mutations in various HR associated genes demonstrated excellent serum ALP declines, and a case report on a single patient with mutated BRCA2 suggested an exceptionally long response to Ra-223 treatment [66,68]. Data from a small exploratory study in mCRPC patients treated with Ra-223 suggested that patients with HR associated gene mutations had favorable ALP responses and prolonged time to ALP progression in comparison to patients without these mutations, while a more favorable OS could not be confirmed [69]. However, two other studies showed that patients with HRD received more cycles of Ra-223 and had a significantly longer OS than patients without these defects [65,67].…”

Section: Molecular Markersmentioning

confidence: 97%

“…Multiple studies have explored the efficacy of Ra-223 in patients with HRD and mCRPC (Table 1) [65][66][67][68][69]. An early report on four patients with mutations in various HR associated genes demonstrated excellent serum ALP declines, and a case report on a single patient with mutated BRCA2 suggested an exceptionally long response to Ra-223 treatment [66,68].…”

Section: Molecular Markersmentioning

confidence: 99%

Radium-223 Treatment of Patients with Metastatic Castration Resistant Prostate Cancer: Biomarkers for Stratification and Response Evaluation

Zande

Oyen

Zwart

et al. 2021

Cancers

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Radium-223 dichloride ([223Ra]RaCl2; Ra-223) is a targeted alpha-emitting radiopharmaceutical which results in an overall survival and health related quality of life (HRQoL) benefit in symptomatic patients with metastatic castration resistant prostate cancer (mCRPC) and predominantly bone metastasis. Although effective, options to select patients who will derive treatment benefit and to monitor and predict treatment outcomes are limited. PSA response and radiographic evaluation are commonly used in mCRPC treatment assessment but are not informative in Ra-223 treated patients. Consequently, there is a clear need for predictive and prognostic tools. In this review, we discuss the physiology of bone metastases and the mechanism of action and efficacy of Ra-223 treatment, as well as offering an outline of current innovative prognostic and predictive biomarkers.

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Impact of germline mutations in homologous recombination (HR) genes on the response to Radium-223 for metastatic castration resistant prostate cancer (mCRPC)

Cited by 11 publications

References 0 publications

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

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

Treatment of Metastatic Castration-resistant Prostate Cancer: Are PARP Inhibitors Shifting the Paradigm?

Radium-223 Treatment of Patients with Metastatic Castration Resistant Prostate Cancer: Biomarkers for Stratification and Response Evaluation

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