Pedro Isaacsson Velho1, Fahad Qazi2, Sayeedul Hassan3, Michael A Carducci4, Samuel R Denmeade4, Mark C Markowski1, Daniel L Thorek5, Theodore L DeWeese6, Daniel Y Song6, Phuoc T Tran6, Mario A Eisenberger4, Emmanuel S Antonarakis7. 1. Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA. 2. MedStar Health, Baltimore, MD, USA. 3. Sinai Hospital of Baltimore, Baltimore, MD, USA. 4. Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA; Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA. 5. Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA; Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA. 6. Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA; Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, USA. 7. Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA; Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA. Electronic address: eantona1@jhmi.edu.
Abstract
BACKGROUND: Pathogenic mutations in genes mediating homologous recombination (HR) DNA repair are present in 20-30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment. OBJECTIVE: To evaluate the potential impact of germline or somatic HR-deficiency (HRD) mutations on radium-223 efficacy in mCRPC with bone metastasis. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective single-institution study. Medical records of 190 mCRPC patients for whom germline and/or somatic DNA sequencing data were available were reviewed. Of these patients, 28 had received standard-of-care radium-223 at Johns Hopkins between February 2013 and February 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Alkaline phosphatase (ALP) responses and time-to-ALP-progression were the coprimary endpoints. Prostate-specific antigen (PSA) responses, overall survival (OS), and time to next systemic therapy were also evaluated. RESULTS AND LIMITATIONS: Of the 28 patients included, 10 men (35.7%) had a germline/somatic HRD mutation (three in BRCA2, and one each in ATM, ATR, CHEK2, FANCG, FANCI, FANCL, and PALB2) and 18 (64.3%) did not. Men with HRD mutations (HRD+) had numerically lower ages (66 vs 73yr, p=0.25), more soft-tissue metastases (50% vs 38%, p=0.43), and higher baseline ALP levels (130 vs 108 U/l, p=0.84). Compared with HRD(-) men, HRD(+) patients showed greater ALP responses (80% vs 39%, p=0.04), longer time to ALP progression (median10.4 vs 5.8mo, hazard ratio [HR] 6.4, p=0.005), and a trend toward longer OS (median 36.9 vs 19.0mo, HR 3.3, p=0.11). PSA responses (0% vs 0%, p>0.99) and time to next systemic therapy (HR 1.5, p=0.39) were similar between the two groups. Results are limited by the retrospective nature of the analysis and the small sample size. CONCLUSIONS: In this exploratory study, bone-metastatic CRPC patients with inactivating HRD mutations demonstrated significantly improved ALP responses and time to ALP progression. These results should motivate prospective validation of the "synthetic lethality" hypothesis between HRD mutations and radium-223 activity. PATIENT SUMMARY: In this report, we retrospectively examined outcomes to metastatic prostate cancer in patients with and without DNA repair mutations who received radium-223, a therapy that kills cancer cells by causing direct DNA damage. Our study suggested that patients who have inherited or acquired DNA repair gene mutations derived greater benefit from radium-223 when compared with patients without these mutations. We concluded that radium-223 might have an important role in this setting; however, prospective studies are needed to confirm whether DNA repair mutations truly make radium-223 work better or not.
BACKGROUND: Pathogenic mutations in genes mediating homologous recombination (HR) DNA repair are present in 20-30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment. OBJECTIVE: To evaluate the potential impact of germline or somatic HR-deficiency (HRD) mutations on radium-223 efficacy in mCRPC with bone metastasis. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective single-institution study. Medical records of 190 mCRPC patients for whom germline and/or somatic DNA sequencing data were available were reviewed. Of these patients, 28 had received standard-of-care radium-223 at Johns Hopkins between February 2013 and February 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Alkaline phosphatase (ALP) responses and time-to-ALP-progression were the coprimary endpoints. Prostate-specific antigen (PSA) responses, overall survival (OS), and time to next systemic therapy were also evaluated. RESULTS AND LIMITATIONS: Of the 28 patients included, 10 men (35.7%) had a germline/somatic HRD mutation (three in BRCA2, and one each in ATM, ATR, CHEK2, FANCG, FANCI, FANCL, and PALB2) and 18 (64.3%) did not. Men with HRD mutations (HRD+) had numerically lower ages (66 vs 73yr, p=0.25), more soft-tissue metastases (50% vs 38%, p=0.43), and higher baseline ALP levels (130 vs 108 U/l, p=0.84). Compared with HRD(-) men, HRD(+) patients showed greater ALP responses (80% vs 39%, p=0.04), longer time to ALP progression (median10.4 vs 5.8mo, hazard ratio [HR] 6.4, p=0.005), and a trend toward longer OS (median 36.9 vs 19.0mo, HR 3.3, p=0.11). PSA responses (0% vs 0%, p>0.99) and time to next systemic therapy (HR 1.5, p=0.39) were similar between the two groups. Results are limited by the retrospective nature of the analysis and the small sample size. CONCLUSIONS: In this exploratory study, bone-metastatic CRPC patients with inactivating HRD mutations demonstrated significantly improved ALP responses and time to ALP progression. These results should motivate prospective validation of the "synthetic lethality" hypothesis between HRD mutations and radium-223 activity. PATIENT SUMMARY: In this report, we retrospectively examined outcomes to metastatic prostate cancer in patients with and without DNA repair mutations who received radium-223, a therapy that kills cancer cells by causing direct DNA damage. Our study suggested that patients who have inherited or acquired DNA repair gene mutations derived greater benefit from radium-223 when compared with patients without these mutations. We concluded that radium-223 might have an important role in this setting; however, prospective studies are needed to confirm whether DNA repair mutations truly make radium-223 work better or not.
Authors: Sten Nilsson; Roy H Larsen; Sophie D Fosså; Lise Balteskard; Kari W Borch; Jan-Erik Westlin; Gro Salberg; Oyvind S Bruland Journal: Clin Cancer Res Date: 2005-06-15 Impact factor: 12.531
Authors: Peter Hoskin; Oliver Sartor; Joe M O'Sullivan; Dag Clement Johannessen; Svein I Helle; John Logue; David Bottomley; Sten Nilsson; Nicholas J Vogelzang; Fang Fang; Mona Wahba; Anne-Kirsti Aksnes; Christopher Parker Journal: Lancet Oncol Date: 2014-10-17 Impact factor: 41.316
Authors: Guru Sonpavde; Gregory R Pond; William R Berry; Ronald de Wit; Andrew J Armstrong; Mario A Eisenberger; Ian F Tannock Journal: Urol Oncol Date: 2010-10-02 Impact factor: 3.498
Authors: C Parker; S Nilsson; D Heinrich; S I Helle; J M O'Sullivan; S D Fosså; A Chodacki; P Wiechno; J Logue; M Seke; A Widmark; D C Johannessen; P Hoskin; D Bottomley; N D James; A Solberg; I Syndikus; J Kliment; S Wedel; S Boehmer; M Dall'Oglio; L Franzén; R Coleman; N J Vogelzang; C G O'Bryan-Tear; K Staudacher; J Garcia-Vargas; M Shan; Ø S Bruland; O Sartor Journal: N Engl J Med Date: 2013-07-18 Impact factor: 91.245
Authors: D Leongamornlert; N Mahmud; M Tymrakiewicz; E Saunders; T Dadaev; E Castro; C Goh; K Govindasami; M Guy; L O'Brien; E Sawyer; A Hall; R Wilkinson; D Easton; D Goldgar; R Eeles; Z Kote-Jarai Journal: Br J Cancer Date: 2012-05-08 Impact factor: 7.640
Authors: Z Kote-Jarai; D Leongamornlert; E Saunders; M Tymrakiewicz; E Castro; N Mahmud; M Guy; S Edwards; L O'Brien; E Sawyer; A Hall; R Wilkinson; T Dadaev; C Goh; D Easton; D Goldgar; R Eeles Journal: Br J Cancer Date: 2011-09-27 Impact factor: 7.640
Authors: Elena Castro; Chee Goh; David Olmos; Ed Saunders; Daniel Leongamornlert; Malgorzata Tymrakiewicz; Nadiya Mahmud; Tokhir Dadaev; Koveela Govindasami; Michelle Guy; Emma Sawyer; Rosemary Wilkinson; Audrey Ardern-Jones; Steve Ellis; Debra Frost; Susan Peock; D Gareth Evans; Marc Tischkowitz; Trevor Cole; Rosemarie Davidson; Diana Eccles; Carole Brewer; Fiona Douglas; Mary E Porteous; Alan Donaldson; Huw Dorkins; Louise Izatt; Jackie Cook; Shirley Hodgson; M John Kennedy; Lucy E Side; Jacqueline Eason; Alex Murray; Antonis C Antoniou; Douglas F Easton; Zsofia Kote-Jarai; Rosalind Eeles Journal: J Clin Oncol Date: 2013-04-08 Impact factor: 44.544
Authors: Sten Nilsson; Lars Franzén; Christopher Parker; Christopher Tyrrell; René Blom; Jan Tennvall; Bo Lennernäs; Ulf Petersson; Dag C Johannessen; Michael Sokal; Katharine Pigott; Jeffrey Yachnin; Michael Garkavij; Peter Strang; Johan Harmenberg; Bjørg Bolstad; Oyvind S Bruland Journal: Lancet Oncol Date: 2007-07 Impact factor: 41.316
Authors: Eleonora Dondossola; Stefano Casarin; Claudia Paindelli; Elena M De-Juan-Pardo; Dietmar W Hutmacher; Christopher J Logothetis; Peter Friedl Journal: J Natl Cancer Inst Date: 2019-10-01 Impact factor: 13.506
Authors: Michael J Morris; Eva Corey; Theresa A Guise; James L Gulley; William Kevin Kelly; David I Quinn; Arne Scholz; George Sgouros Journal: Nat Rev Urol Date: 2019-11-11 Impact factor: 14.432
Authors: Emmanuel S Antonarakis; Tamara L Lotan; Harsimar Kaur; Daniela C Salles; Sanjana Murali; Jessica L Hicks; Minh Nguyen; Colin C Pritchard; Angelo M De Marzo; Jerry S Lanchbury; Bruce J Trock; William B Isaacs; Kirsten M Timms Journal: Clin Cancer Res Date: 2020-07-21 Impact factor: 12.531
Authors: Bastiaan M Privé; Peter H J Slootbeek; Babette I Laarhuis; Samhita Pamidimarri Naga; Maarten J van der Doelen; Ludwike W M van Kalmthout; Bart de Keizer; Samer Ezziddin; Clemens Kratochwil; Alfred Morgenstern; Frank Bruchertseifer; Marjolijn J L Ligtenberg; J Alfred Witjes; Inge M van Oort; Martin Gotthardt; Sandra Heskamp; Marcel J R Janssen; Winald R Gerritsen; James Nagarajah; Niven Mehra Journal: Prostate Cancer Prostatic Dis Date: 2021-07-12 Impact factor: 5.554