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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)

Date

30 Sep 2019

Session

Poster Display session 3

Presenters

Elena Castro

Citation

Annals of Oncology (2019) 30 (suppl_5): v325-v355. 10.1093/annonc/mdz248

Authors

E. Castro1, R. Lozano Mejorada2, M. Saez3, U.F.F. De Giorgi4, I. Aragón5, N. Romero Laorden6, G.A. De Velasco Oria de Rueda7, L. Magraner2, M.I. Pacheco2, J. Puente8, A. González del Alba9, P. Borrega Garcia10, V. Conteduca11, J.C. Villa Guzman12, E. Fernandez Parra13, A. Rodriguez-Vida14, A. Medina Colmenero15, R. Morales Barrera16, D. Lorente17, D. Olmos Hidalgo18

Author affiliations

  • 1 Prostate Cancer Clinical Research Unit, Instituto de Investigación Biomédica de Málaga (IBIMA) and Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, 29010 - Malaga/ES
  • 2 Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 - Madrid/ES
  • 3 Medical Oncology, Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, Málaga/ES
  • 4 Medical Oncology Department, Istituto Tumori della Romagna I.R.S.T., 47014 - Meldola/IT
  • 5 Prostate Cancer Clinical Research Unit, Instituto de Investigación Biomédica de Málaga (IBIMA) and Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, Malaga/ES
  • 6 Medical Oncology, Hospital Universitario de La Princesa, 28006 - Madrid/ES
  • 7 Medical Oncology, University Hospital 12 De Octubre, 28041 - Madrid/ES
  • 8 Medical Oncology, Hospital Clinico Universitario San Carlos, 28040 - Madrid/ES
  • 9 Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, 28222 - Madrid/ES
  • 10 Medical Oncology, Hospital San Pedro De Alcantara, 10003 - Caceres/ES
  • 11 Oncology, Istituto Tumori della Romagna I.R.S.T., 47014 - Meldola/IT
  • 12 Medical Oncology, Hospital General Ciudad Real, 13005 - Ciudad Real/ES
  • 13 Medical Oncology, Hospital Universitario Virgen de Valme, 41014 - Sevilla/ES
  • 14 Medical Oncology, Hospital del Mar, 08003 - Barcelona/ES
  • 15 Medical Oncology, Fundacion Centro Oncologico de Galicia, 15009 - A Coruna/ES
  • 16 Medical Oncology Dept., Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 17 Medical Oncology, Hospital Provincial de Castellón, 12002 - Castellón/ES
  • 18 Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid and Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, 28029 - Madrid/ES
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Background

Ra223 is a bone-seeking a-emitter targeted therapy that induces double-strand DNA breaks (DSBs). The HR pathway is used to accurately repair DSBs and a significant proportion of mCRPC patients harbor pathogenic germline HR mutations (gHR+). We hypothesize that gHR+ patients, with an impaired ability to repair DSBs, are more likely to respond to Ra223 than gHR- patients.

Methods

This is an exploratory preplanned analysis of the PRORADIUM study (NCT02925702). PRORADIUM is a prospective observational biomarkers study of mCRPC patients treated with standard-of-care Ra223. Participants were screened for germline mutation in DNA damage and response genes using a multigene panel (Castro et al. J Clin Oncol 2019). Alkaline Phosphatase (ALP) response at 12 weeks was the primary endpoint. PSA response at 12 weeks, overall survival (OS) from Ra223 and clinical and/or radiographic progression free survival (PFS) were also analyzed.

Results

161 out of 168 patients enrolled in PRORADIUM with available germline testing results were included. A pathogenic gHR mutation was identified in 14 (8.7%) patients (5 BRCA2, 4 ATM, 1 BRCA1, 1 BRCA1+CHEK2, 1 BRIP1, 1 NBN, 1 BLM). Median age was 74 years (range 46-90). Performance status ECOG 1 was recorded in 91% pts. Median number of prior therapy lines for mCRPC was 2 (range 1-4) including at least one taxane in 63% patients. 54% of patients received 5 or 6 cycles of Ra223. After a median follow-up of 20 months, a > 30% decline in ALP at 12 weeks was observed in 75% of gHR+ patients compared to 43% of gHR- (p = 0.036). No differences in PSA >50% decline at 12 weeks (14% vs 8%, p = 0.437) or in PFS (4.5 vs 5.0 months, p = 0.670) were observed by gHR status. A trend towards more prolonged OS from Ra223 was observed in gHR + (median 14.4 vs 10.6 months, p = 0.066).

Conclusions

In our study, germline HR mutations were associated with improved ALP responses, suggesting a greater benefit from Ra223 in gHR+ patients.

Clinical trial identification

NCT02925702.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bayer.

Disclosure

E. Castro: Honoraria (self), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Roche; Honoraria (self): Pfizer. R. Lozano Mejorada: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Janssen. M. Saez: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: EUSA pharma. U.F.F. De Giorgi: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer. N. Romero Laorden: Advisory / Consultancy: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Astellas; Honoraria (self): Sanofi; Honoraria (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self): PharmaMar. G.A. De Velasco Oria de Rueda: Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Ipsen; Honoraria (self): Astellas; Honoraria (self): Bristol-Myers-Squibb; Honoraria (self): Bayer; Honoraria (self): Roche. J. Puente: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers-Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Clovis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: Sanofi; Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Kiowa; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer. A. González del Alba: Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy: Janssen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eusa Pharma; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers-Squibb; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD. P. Borrega Garcia: Advisory / Consultancy: Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi. V. Conteduca: Honoraria (self), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Bayer. A. Rodriguez-Vida: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (self): Takeda. A. Medina Colmenero: Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Janssen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Novartis; Advisory / Consultancy: Sanofi. R. Morales Barrera: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Johnson and Johnson; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Clovis; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Astellas. D. Lorente: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Travel / Accommodation / Expenses: Celgene. D. Olmos Hidalgo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Clovis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Tokai; Research grant / Funding (institution): Pfizer. All other authors have declared no conflicts of interest.

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