Elsevier

European Urology

Volume 76, Issue 2, August 2019, Pages 170-176
European Urology

Platinum Priority – Prostate Cancer
Editorial by Oliver Sartor on pp. 177–178 of this issue
Efficacy of Radium-223 in Bone-metastatic Castration-resistant Prostate Cancer with and Without Homologous Repair Gene Defects

https://doi.org/10.1016/j.eururo.2018.09.040Get rights and content

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 73 yr, 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 5.8 mo, hazard ratio [HR] 6.4, p = 0.005), and a trend toward longer OS (median 36.9 vs 19.0 mo, 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.

Introduction

Prostate cancer (PCa) is a heterogeneous disease at the clinical, pathological, and molecular levels. Based on genetic abnormalities, especially in genes that control mechanisms of DNA repair, new attempts to classify the different molecular subgroups of this disease have been made [1]. In recent years, the critical importance of DNA repair defects, especially in the homologous recombination (HR) pathway as well as the mismatch repair pathway, has been demonstrated in both germline and somatic lineages, and has prognostic and therapeutic implications [1], [2]. The genes responsible for the HR pathway, particularly BRCA1, BRCA2, CHEK2, ATM, RAD51D, and PALB2, play a crucial role in repairing double-strand (ds) DNA breaks [3]. Defects in some of these genes have been associated with an increased risk of PCa development and disease aggressiveness [4], [5].

Germline mutations in DNA repair genes are present in 8–12% of metastatic PCa [1], [2], whereas the previously estimated prevalence was 4–5% in localized disease [6], [7]. In addition, somatic aberrations in genes responsible for DNA repair are seen in 20–30% of PCa patients [1]. Different studies have confirmed that together both germline and somatic HR-deficiency (HRD) pathogenic mutations are seen in up to one-third of patients with metastatic castration-resistant prostate cancer (mCRPC) [1], [8], strengthening not only the high prevalence of these mutations but also their role as prognostic [9], [10], [11], [12] and predictive biomarkers [8], [13].

Radium-223 is an alpha-particle–emitting bone-targeted therapy that demonstrated consistent improvement in pain [14], [15] and overall survival (OS) in patients with mCRPC harboring bone disease [16]. Alpha particles emitted at the site of disease have high linear energy transfer, resulting in the deposition of energy in the immediate vicinity of the radionuclide's decay. This highly localized radiotherapy selectively targets the bone microenvironment and metastatic tumor cells, causing unrepairable dsDNA breaks [17], resulting in potent but locally restricted cytotoxic effects [18]. By the mechanism of “synthetic lethality”, tumors with defects in mechanisms of DNA repair are theoretically more susceptible to therapies that cause DNA damage, such as dsDNA breaks [19], [20]. Therefore, the present study hypothesized that patients who harbor germline and/or somatic HRD mutations may have a greater clinical benefit from radium-223, due to dsDNA breaks going unrepaired because of an underlying HRD mutation in the tumor cells [21]. To this end, we performed a retrospective study to test this biological hypothesis.

Section snippets

Patients and methods

Patients with mCRPC who received radium-223 over a 5-yr period (between February 2013 and February 2018) and who were being seen at the Johns Hopkins Hospital formed the study population. These consecutive patients were offered somatic and/or germline genomic panel testing for clinical purposes, using different commercially available (Foundation One, Personal Genome Diagnostics, Color Genomics, Invitae) and in-house next-generation DNA sequencing platforms. This was an unselected patient

Baseline genomic and clinical characteristics

Between February 15, 2013 and February 15, 2018, a total of 190 mCRPC patients agreed to undergo clinical-grade somatic and/or germline genetic testing using the next-generation DNA sequencing platforms listed above. All germline testing was performed from saliva. Somatic testing involved a mix of primary tumor testing as well as from metastatic biopsies. Of these 190 mCRPC cases, 28 patients had received radium-223 at some point during their treatment course, forming our study population. No

Discussion

The findings of our hypothesis-generating study support the theoretical rationale that tumors harboring HRD mutations may be more sensitive to therapies that cause direct damage to DNA, such as radium-223. In the pivotal phase III ALSYMPCA study [16], which compared radium-223 versus placebo plus best supportive care, ALP response rates (≥30% declines from baseline) were found in 47% versus 3% of patients (p < 0.001). In our study, the overall ALP response rate in the unselected population

Conclusions

Our preliminary findings suggest that bone-predominant mCRPC patients with germline and/or somatic mutations in HR-pathway genes may be associated with clinical benefit from radium-223 (in terms of ALP responses, normalization of ALP, and the time to ALP progression) as well as potential prolongation of survival. The retrospective nature of our study and the limitations inherent to that design suggest that these provocative findings should be considered as hypothesis generating only at this

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