Synthetic Lethal Targeting of CDK12-Deficient Prostate Cancer with PARP Inhibitors.

Purpose: The cyclin-dependent kinase (CDK), CDK12, is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer characterized predominantly by frameshift, loss-of-function mutations in CDK12. This subtype exhibits aggressive clinical features.

Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study.

Background: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration.

Objective: To present the final data from TRITON2.

Design, Setting, And Participants: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy.

Rucaparib or Physician's Choice in Metastatic Prostate Cancer.

Background: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious alteration. Data are needed to confirm and expand on the findings of the phase 2 study.

Methods: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a , , or alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI).

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

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.

What Plasma Can Tell Us When Tissue Cannot: A Case Report of Genomic Testing in mCRPC and Clinical Response to Treatment With the PARP Inhibitor Rucaparib.

Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was approved in the United States based on the phase 2 TRITON2 study of patients with or (BRCA)-mutated metastatic castration-resistant prostate cancer (mCRPC). Although genomic screening is recommended as part of a comprehensive assessment of prostate cancer prognosis and treatment options, the best way to select patients with mCRPC for treatment with a PARP inhibitor depends on individual clinical circumstances. For example, assessment of tumor tissue may not always be feasible.

Nivolumab plus rucaparib for metastatic castration-resistant prostate cancer: results from the phase 2 CheckMate 9KD trial.

Background: CheckMate 9KD (NCT03338790) is a non-randomized, multicohort, phase 2 trial of nivolumab plus other anticancer treatments for metastatic castration-resistant prostate cancer (mCRPC). We report results from cohorts A1 and A2 of CheckMate 9KD, specifically evaluating nivolumab plus rucaparib.

Methods: CheckMate 9KD enrolled adult patients with histologically confirmed mCRPC, ongoing androgen deprivation therapy, and an Eastern Cooperative Oncology Group performance status of 0-1.

A Case Study of Clinical Response to Rucaparib in a Patient with Metastatic Castration-Resistant Prostate Cancer and a .

PARP inhibitors, such as rucaparib, have been well characterized in metastatic castration-resistant prostate cancer (mCRPC) associated with BRCA alterations, and the clinical activity of these agents has also been evaluated in patients with mCRPC associated with alterations in other non-BRCA DNA damage repair (DDR) genes, including . There is likely a differential sensitivity to PARP inhibition based on the specific DDR gene altered, but research in this area is limited because of the low frequency of alterations in these genes. Here, we describe a mCRPC patient with a truncating rearrangement of who had a radiographic and PSA response when treated with the PARP inhibitor rucaparib within the TRITON2 trial.

Rucaparib in patients presenting a metastatic breast cancer with homologous recombination deficiency, without germline BRCA1/2 mutation.

Background: Breast cancer may present genomic alterations leading to homologous recombination deficiency (HRD). PARP inhibitors have proven their efficacy in patients with HER2-negative (HER2-) metastatic breast cancer (mBC) harbouring germline (g) BRCA1/2 mutations in 3 phases III trials. The single-arm phase II RUBY trial included 42 patients, 40 of whom received at least one dose of rucaparib.

Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study.

Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic or (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2.

Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms.

Purpose: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations (GA) that inform clinical care.

Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a or Gene Alteration.

Purpose: or () alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study.

Methods: We enrolled patients who progressed after one to two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC.

Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study.

Purpose: Genomic alterations in DNA damage repair (DDR) genes other than may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non- DDR gene alterations.

Patients And Methods: TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC.

Genomic loss of heterozygosity and survival in the REAL3 trial.

Background: Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy.

Methods: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay.

Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?

PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments.