Efficacy of Radium-223 in Bone-Metastatic Castration-Resistant Prostate Cancer With and Without Homologous Repair Gene Defects

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TAKE-HOME MESSAGE

•Somatic tumor and germline DNA testing are becoming more meaningful in the management of patients with advanced prostate cancer. This study evaluated the potential impact of germline or somatic homologous recombination deficiency (HRD) mutations on radium-223 efficacy in metastatic castrate-resistant prostate cancer (mCRPC) with bone metastasis. A total 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 a single center between 2013 and 2018. The authors found 36% of radium-223 patients had an HRD mutation (BRCA2 was the most prevalent). HRD-positive patients showed greater alkaline phosphatase response and a trend toward longer overall survival (median, 36.9 vs 19.0 months) compared with HRD-negative patients.

•Based on these data, the authors suggest that patients who have inherited or acquired DNA repair gene mutations derive greater benefit from radium-223 compared with patients without these mutations.

– Gautam Jayram, MD

Advanced Prostate Cancer 

Written by Oliver Sartor MD

This is a small but important article that looks at the alpha-emitting bone-targeted radiopharmaceutical radium-223 in patients with or without homologous recombination repair deficiency mutations. The investigators found that individuals treated with radium who had a homologous recombination repair deficiency seemed to respond better, as measured by greater degrees of alkaline phosphatase response, longer time to alkaline phosphatase progression, and a trend toward longer survival.

It is limited by a relatively small sample size and they only had 10 men with homologous repair deficiency mutations. However, these data build upon previous publications, which suggest a similar increased efficacy in radium-treated patients with DNA repair mutations.

The implications are that DNA-damaging agents, in particular, alpha particles, may be preferentially effective in men with homologous recombination repair deficiencies and that in addition to PARP inhibitors and carboplatinum, the radiopharmaceuticals might be considered advantageous in this class of agents. There are case reports with PSMA targeted with tissue 177 that suggest similar findings and that’s probably more than enough, but that’s an interesting finding.

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.

European Association of Urology

Efficacy of Radium-223 in Bone-Metastatic Castration-Resistant Prostate Cancer With and Without Homologous Repair Gene Defects

Eur Urol 2019 Aug 01;76(2)170-176, P Isaacsson Velho, F Qazi, S Hassan, MA Carducci, SR Denmeade, MC Markowski, DL Thorek, TL DeWeese, DY Song, PT Tran, MA Eisenberger, ES Antonarakis

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.