Overall survival using radium-223 (Ra223) in metastatic castrate-resistant prostate cancer (mCRPC) patients with and without DNA damage repair (DDR) defects.

Abstract

121 Background: Ra223 is a therapeutic option for mCRPC patients (pts) with symptomatic bone metastases. DDR-defective prostate cancers, specifically those with homologous recombination deficiency (HRD), accumulate irreparable DNA damage following genotoxic treatment. This study assessed presence or absence of DDR alterations in mCRPC pts treated with Ra223, investigating the effect on efficacy and overall survival (OS). Methods: All pts included were treated with Ra223 and had genomic results from a comprehensive next-generation sequencing panel of DDR genes that directly or indirectly led to HRD, from primary or metastatic tissue. Exclusion criteria were prior platinum-based chemotherapy or treatment with poly-ADP ribose polymerase inhibitors (PARPi). Pts were grouped by presence (DDR+) or absence (DDR-) of pathogenic somatic and/or germline aberrations in DDR genes. Primary endpoint was OS, and secondary endpoints were time to alkaline phosphatase (ALP) progression, time to next systemic therapy and biochemical responses; comparing DDR+ and DDR– groups. Results: 93 pts were included in this two-centre retrospective study. Median age was 68 years. 56% received prior chemotherapy. Baseline characteristics where comparable between DDR status subgroups. 28 (30%) pts had mutations in DDR genes, most frequently occurring in ATM (8.6%), BRCA2 (6.5%), and CDK12 (4.3%) genes. DDR+ pts showed prolonged OS (median 36.3 vs. 17.0 months; HR 2.29; 95% CI 1.21-4.32; P= 0.01). Median time to alkaline phosphatase progression was 6.9 months for DDR+ pts and 5.8 months for DDR- pts (HR 1.48; 95% CI 0.87-2.50; P =0.15), and median time to next systemic therapy was 8.9 months for DDR+ pts and 7.3 months for DDR- pts (HR 1.58; 95% CI 0.94-2.64; P =0.08). A higher proportion of DDR+ pts completed Ra223 therapy (79% vs 47%; P= 0.05). No differences in biochemical (prostate-specific antigen, ALP) responses were seen. Conclusions: Pts harboring deleterious DDR aberrations more commonly completed Ra223, and derived a greater OS benefit. These findings need prospective confirmation, but support combination of Ra223 with PARPi or ATR inhibitors in DDR-defective mCRPC pts.

Radionuclide Therapy in Prostate Cancer: From Standalone to Combination PSMA Theranostics

“…The first clinical evidence for combining agents that impair DNA repair and RNT comes from studies of 223 Ra-dichloride, an a-emitter. A retrospective analysis showed that the presence of defective DNR repair (somatic or germline) was associated with improved OS and a prolonged reduction in alkaline phosphatase (47). Synergy between an ATR inhibitor and 223 Ra has also been demonstrated (48).…”

Radium-223 voor gemetastaseerd castratieresistent prostaatcarcinoom: stand van zaken en toekomstperspectief

“…Een retrospectief Nederlands-Amerikaans onderzoek met 93 mCRPC-patiënten heeft laten zien dat patiënten met gendefecten in elementen van de DDR pathways (voornamelijk ATM, BRCA2, CDK12) die behandeld waren met Ra-223 een langere mediane OS hadden dan patiënten zonder zulke gendefecten (36,3 vs. 17,0 maanden; HR 2,29; p = 0,01) [27]. Ook op de eindpunten 'tijd tot ALP-progressie' en 'tijd tot volgende systemische behandeling' leken patiënten met DDR pathway-defecten in het voordeel.…”