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. 2023 Mar;83(3):200-209.
doi: 10.1016/j.eururo.2022.09.010. Epub 2022 Oct 13.

Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib

Andrea Loehr  1 , Arif Hussain  2 , Akash Patnaik  3 , Alan H Bryce  4 , Daniel Castellano  5 , Albert Font  6 , Jeremy Shapiro  7 , Jingsong Zhang  8 , Brieuc Sautois  9 , Nicholas J Vogelzang  10 , Gurkamal Chatta  11 , Kevin Courtney  12 , Andrea Harzstark  13 , Francesco Ricci  14 , Darrin Despain  15 , Simon Watkins  16 , Charmin King  17 , Minh Nguyen  1 , Andrew D Simmons  1 , Simon Chowdhury  18 , Wassim Abida  19
Affiliations

Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib

Andrea Loehr et al. Eur Urol. 2023 Mar.

Abstract

Background: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown.

Objective: To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib.

Design, setting, and participants: Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS).

Outcome measurements and statistical analysis: The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib.

Results and limitations: No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively).

Conclusions: These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance.

Patient summary: Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.

Keywords: Acquired resistance; BRCA reversion mutations; Circulating tumor DNA; Metastatic castration-resistant prostate cancer; Next-generation sequencing; Poly(adenosine diphosphate-ribose) polymerase inhibitor.

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Conflict of interest statement

Financial disclosures: Wassim Abida certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr. Loehr reported being employed by Clovis Oncology and may own stock or have stock options in that company. Dr. Hussain served as consultant for AstraZeneca, Bayer, Bristol Myers Squibb, and Merck; has been on advisory boards for AstraZeneca, and Aveo; and received support for sponsored clinical trials from Clovis Oncology, Bayer, Calithera, Constellation, Roche, Pfizer, and Sotio. Dr. Patnaik has served in a consulting or advisory role for Exelixis, Janssen, and Jounce Therapeutics; has received honoraria from Clovis Oncology, Merck, Prime Inc., and Roche; has received research funding from Clovis Oncology, Bristol Myers Squibb, GlaxoSmithKline, and Progenics; and has received clinical trial support from AstraZeneca and Laekna. Dr. Bryce has received grants or contracts from AstraZeneca, Gilead, and Janssen; has received consulting fees from Bayer and Merck; and has received honoraria from Elsevier, Fallon Medica, Grand Rounds in Urology, Horizon CME, MJH Life Sciences, PRIME Education, and Research to Practice; and is a named inventor on patent application no. 15/735,289. Dr. Castellano has consulting and advisory roles for Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Lilly, MSD Oncology, Novartis, Pfizer, Pierre-Fabre, Roche, and Sanofi; received research funding from Janssen; and received travel support from AstraZeneca, Bristol Myers Squibb, Roche, and Pfizer. Dr. Font has consulting and advisory roles for Astellas, Eusa, Janssen, and Sanofi; and has received research funding from AstraZeneca. Dr. Shapiro has no disclosures or conflicts. Dr. Zhang has received consulting fees from AstraZeneca, Bayer, Dendreon, Myoant Sciences, and Pfizer; and received speaker fees from AstraZeneca, Dendreon, and Sanofi. Dr. Sautois has served in a consulting or advisory role for Clovis Oncology, Astellas, Bristol Myers Squibb Belgium, and Janssen; and has received honoraria from Janssen and Merck Sharp & Dohme. Dr. Vogelzang has served as a consultant for Clovis Oncology and AstraZeneca on advisory boards and speakers’ bureaus. Dr. Chatta has received grants or contracts from Astex Pharmaceuticals and the National Comprehensive Cancer Network. Dr. Courtney has received research funding from Astellas Pharma, and has received past honoraria from Exelixis, Janssen, and Sanofi. Dr. Harzstark has no disclosures or conflicts. Dr. Ricci has no disclosures or conflicts. Mr. Despain reported being employed by Clovis Oncology and may own stock or have stock options in that company. Dr. Watkins reported being employed by Clovis Oncology and may own stock or have stock options in that company. Ms. King reported being employed by Clovis Oncology and may own stock or have stock options in that company. Ms. Nguyen reported being employed by Clovis Oncology and may own stock or have stock options in that company. Dr. Simmons reported being employed by Clovis Oncology and may own stock or have stock options in that company. Dr. Chowdhury has served as consultant to Clovis Oncology, AstraZeneca, Athenex, Bayer, Beigene, Janssen Oncology, and Novartis on advisory boards and on speakers’ bureaus; has received honoraria from Beigene, Huma, Janssen, Remedy Bio, and Telix; owns stock of Curve.Life, Huma, Remedy Bio; and has received research funding from Clovis Oncology. Dr. Abida has received honoraria from Aptitude Health, AstraZeneca/MedImmune, Clinical Education Alliance, Daiichi Sanyko, OncLive/MJH Life Sciences, Janssen, ORIC Pharmaceuticals, Roche, and Medscape; and has received research funding from Clovis Oncology, AstraZeneca, Epizyme, ORIC Pharmaceuticals, and Zenith Epigenetics.

Figures

Fig. 1 –
Fig. 1 –
Summary of patients included in the analysis of reversion mutations in postprogression plasma samples. Alterations with unknown mechanisms of reversion were homozygous deletions and rearrangements. BRCA+ = BRCA1 or BRCA2 mutated; mCRPC = metastatic castration-resistant prostate cancer; NGS = next-generation sequencing; Pts = patients; TRITON2 = Trial of Rucaparib in Prostate Indications 2.
Fig. 2 –
Fig. 2 –
Summary of BRCA reversion mutation incidence. (A) Number of reversion mutations detected per patient. (B) Frequency of patients who developed BRCA reversion mutations within intervals of increasing treatment duration. BRCA indicates BRCA1 or BRCA2.
Fig. 3 –
Fig. 3 –
Association between detectable reversion mutations and patient clinical outcomes. (A) Time on treatment. (B) Duration of PSA response. PSA = prostate-specific antigen.
Fig. 4 –
Fig. 4 –
Genomics and course of clinical disease in a patient with BRCA+ mCRPC who progressed with multiple subclonal BRCA2 reversion mutations. (A) An overview of all reversion mutation clones detected over time. (B) Dynamics of emergent BRCA2 reversion mutations, radiographic response, and PSA levels. CR = complete response; ctDNA = circulating tumor DNA; mCRPC = metastatic castration-resistant prostate cancer; PD = progressive disease; PR = partial response; PSA = prostate-specific antigen.
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