Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): Updated analyses

Abida, Wassim; Campbell, David; Patnaik, Akash; Sautois, Brieuc; Shapiro, Jeremy; Vogelzang, Nicholas J.; Bryce, Alan H.; McDermott, Ray; Ricci, Francesco; Rowe, Julie; Zhang, J.; Simmons, Andrew; Despain, Darrin; Dowson, Melanie; Golsorkhi, Tony; Chowdhury, Simon

doi:10.1093/annonc/mdz248.003

Cited by 79 publications

(76 citation statements)

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“…Preliminary results of the phase II study TRITON2 demonstrated high ORR (43.9%) with durable response over 24 weeks for the majority of mCRPC patients carrying BRCA mutations. However, only poor response could be achieved for patients with other mutations than BRCA [19]. Similar interim results were presented for the GALAHAD phase II study with highest ORR (41%) and rPFS of 8.2 months for BRCA mutated CRPC patients treated with the PARPi niraparib [20].…”

Section: Introductionsupporting

confidence: 65%

Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

Marhold

Topakian

2020

memo

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SummaryHomologous repair deficiency is a clinically relevant molecular aberration in prostate cancer. The goal of this short review is to summarize the study landscape of treatments targeting these aberrations through discussion of the most relevant clinical trials. Due to its shortness, this review does not claim to be exhaustive and a major focus is being laid on PARP inhibitors in clinical development for prostate cancer.

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Section: Introductionsupporting

confidence: 65%

Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

Marhold

Topakian

2020

memo

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“…Although PARP inhibitor treatment has demonstrated radiographic and PSA responses in patients with BRCA alterations (4)(5)(6)(7)(8), the data presented here offer compelling evidence that response to PARP inhibitors is limited in men with mCRPC harboring an ATM, CDK12, or CHEK2 alteration. These data provide an optimistic outlook for treatment of prostate cancer with other DDR gene alterations, such as PALB2.…”

Section: Other Ddr Gene Cohortmentioning

confidence: 86%

“…Confirmed radiographic and prostate-specific antigen (PSA) responses were observed in 25 (43.9%) of 57 and 51 (52.0%) of 98 patients with a deleterious BRCA alteration, respectively, in the phase 2 TRITON2 study (CO-338-052; NCT02952534) evaluating the PARP inhibitor rucaparib in men who progressed on an androgen receptor (AR)directed therapy and chemotherapy (4). Olaparib and niraparib also have reported activity in patients with BRCA-mutant mCRPC (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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

Abida

Campbell

Patnaik

et al. 2020

Clinical Cancer Research

310

261

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Association for Cancer Research. D. Campbell has nothing to disclose. A. 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; and has received research funding from Clovis Oncology, Bristol-Myers Squibb, and GlaxoSmithKline. J. Shapiro has served in a consulting or advisory role for Amgen, Astellas, Ipsen, Merck, and Roche and received financial support for travel from Amgen and Merck. B. Sautois has served a consulting or advisory role for Clovis Oncology, Astellas, Janssen, and Sanofi and received financial support for travel and/or accommodation from Janssen. N.J. Vogelzang has served in a consulting or advisory role for Clovis Oncology,

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“…The phase II trial TRITON2 (NCT02952534) is testing rucaparib 600 mg twice daily in CRPC patients with a germline or somatic alteration in BRCA1/2 or HR deficiency who progressed on ≥1 lines of AR-targeted therapy and 1 line of chemotherapy. 45 According to the preliminary results presented at ESMO, 48% and 45% of BRCA carriers had a PSA response and radiological response, respectively. Now the continuation trial, the phase III TRITON3, will be evaluating rucaparib efficacy compared to physician's choice of abiraterone, enzalutamide, or docetaxel.…”

Section: Parp Inhibition In Prostate Cancermentioning

confidence: 99%

Update on PARP inhibitor therapy for solid tumors

Bayraktar¹,

Glück²,

Darling³

2019

JCPCR

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Abbreviations: SSB, single-strand break; HR, homologous recombination; NHEJ, non-homologous end joining; PARPi, PARP inhibitors; PFS, progression-free survival; CT, care chemotherapy; CI, confidence interval; TNBC, triple-negative breast cancer; FDA, food and drug administration; G-CSF, granulocyte colony stimulating factors (SSB), mismatch repair (MMR), and double-strand break (DSB). 1 Polyadenosine diphosphate [ADP] ribose polymerase-1 (PARP1) and -2 (PARP2) enzymes 2 are responsible for repair of most of the SSB. After they detect the defective site, they bind to the DNA damage site and recruit a set proteins to repair the break. 3,4 When those proteins are recruited to the damaged site, the PARP-DNA interaction becomes unstable so that DNA repair can proceed. 5 If the SSB are not repaired, they are converted to DSB. 6 In that situation, another repair mechanism called homologous recombination (HR) will play a role. This mechanism is well represented in PARP1 knockout mice that SSB could not be repaired, but HR repair and non-homologous end joining (NHEJ) pathways were able to repair the formed DSB ( Figure 1). HR is slower than NHEJ, but it is more accurate. 7 J Cancer Prev Curr Res. 2019;10(4):98-107. 98 AbstractPoly (ADP-ribose) polymerases (PARPs) play an important role in DNA damage repair. They are primarily involved in base excision repair in single strand breaks. So far, the clinical trial results are very promising in breast and ovarian cancer with deleterious germline BRCA1 and BRCA2 mutations, and their use is expanding to include other solid tumors with homologous recombination (HR) repair defect. Studies suggest a correlation between tumor sensitivity to platinums and response to PARP inhibitors (PARPi) in women with ovarian cancer. The hypothesis is that by interfering with DNA repair, PARPi sensitize cells to DNA-damaging chemotherapies and radiation therapy. This article provides an overview of clinical trial results obtained with PARPi in the treatment of breast, ovarian, prostate, gastric, pancreatic, and lung cancers. In addition, we review resistance mechanisms to PARPi, toxicities of PARPi, and potential treatment combinations with PARPi.

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Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): Updated analyses

Cited by 79 publications

References 0 publications

Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

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

Update on PARP inhibitor therapy for solid tumors

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