Preliminary results from TRITON2: A phase II study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations

Abida, Wassim; Bryce, Alan H.; Vogelzang, Nicholas J.; Amato, Robert J.; Percent, Ivor; Shapiro, Julia; McDermott, Ray; Hussain, Arif; Patnaik, Akash; Petrylak, Daniel P.; Ryan, Charles J.; Stanton, T.; Zhang, J.; Simmons, Andrew; Despain, Darrin; Collins, Marnie; Golsorskhi, T.; Scher, Howard I.; Chowdhury, Simon

doi:10.1093/annonc/mdy284.002

Cited by 53 publications

(70 citation statements)

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“…Our results suggest that men with mCRPC harboring ATM mutations may not respond to PARP inhibitors as well as those with BRCA1/2 mutations. A similar pattern was recently observed in the preliminary results of the TRITON2 study (Trial of Rucaparib in Prostate Indications 2) investigating rucaparib, in which none of the 18 patients with ATM mutations demonstrated a PSA 50 response, compared to 51% (23/45) of those with BRCA1/2 mutations [12]. This is seemingly in contrast to the TOPARP-A study (Phase II Trial of Olaparib in Patients with Advanced Castration Resistant Prostate Cancer -Part A), in which four of six patients (67%) with ATM mutations responded to olaparib, although only two of the six patients achieved a PSA 50 response at 12 wk, with the other two only achieving a decrease in circulating tumor cells [5].…”

Section: Discussionsupporting

confidence: 84%

Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations

et al. 2019

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Background: Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown. Objective: To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations. Design, setting, and participants: This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA. Outcome measurements and statistical analysis: The proportion of patients achieving a !50% decline in prostate-specific antigen (PSA 50 response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test. Results and limitations: The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA 50 responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p = 0.002). Patients with BRCA1/2 mutations had median PFS of 12.3 mo versus 2.4 mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05-0.57; p = 0.004). Limitations include the retrospective design and relatively small sample size. Conclusions: Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations. Patient summary: Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.

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Section: Discussionsupporting

confidence: 84%

Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations

et al. 2019

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“…All eight patients with BRCA1/2 alterations responded to olaparib, many with durable responses for over 1 year, but mutations in genes such as ATM, PALB2, or FANCA were also observed in some responding patients. Similar data have been reported in a preliminary analysis of a phase II trial of rucaparib [47]. Based on these studies, registration trials of different PARPi in prostate cancer are now ongoing, although with different strategies when it comes to defining the putative predictive biomarker suite.…”

Section: Expanding the Indications For Parpi To Other Tumour Types Wisupporting

confidence: 67%

A decade of clinical development of PARP inhibitors in perspective

Mateo

Lord

Serra³

et al. 2019

Annals of Oncology

513

428

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Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/ BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.

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“…32 Recently, the phase II TRITON2 study in patients with mCRPC associated with an identified HRR gene alteration reported an ORR of 44% for rucaparib in patients with a BRCA mutation, and two of eight patients with either BRIP1 or FANCA mutations also responded, leading to an ORR of 25% in these patients. 33 Thus, for many of these indications, identifying suitable patients with impaired DDR systems seems key to improving treatment outcomes.…”

Section: The Future Role Of Parp Inhibition In Clinical Practicementioning

confidence: 99%

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

Gourley

Balmañà

Ledermann

et al. 2019

JCO

168

133

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The DNA damage response (DDR) pathway coordinates the identification, signaling, and repair of DNA damage caused by endogenous or exogenous factors and regulates cell-cycle progression with DNA repair to minimize DNA damage being permanently passed through cell division. Severe DNA damage that cannot be repaired may trigger apoptosis; as such, the DDR pathway is of crucial importance as a cancer target. Poly (ADP-ribose) polymerase (PARP) is the best-known element of the DDR, and several PARP inhibitors have been licensed. However, there are approximately 450 proteins involved in DDR, and a number of these other targets are being investigated in the laboratory and clinic. We review the most recent evidence for the clinical effect of PARP inhibition in breast and ovarian cancer and explore expansion into the first-line setting and into other tumor types. We critique the evidence for patient selection techniques and summarize what is known about mechanisms of PARP inhibitor resistance. We then discuss what is known about the preclinical rationale for targeting other members of the DDR pathway and the associated tumor cell genetics that may confer sensitivity to these agents. Examples include DNA damage sensors (MLH1), damage signaling molecules (ataxia-telangiectasia mutated; ataxia-telangiectasia mutated–related and Rad3-related; CHK1/2; DNA-dependent protein kinase, catalytic subunit; WEE1; CDC7), or effector proteins for repair (POLQ [also referred to as POLθ], RAD51, poly [ADP-ribose] glycohydrolase). Early-phase clinical trials targeting some of these molecules, either as a single agent or in combination, are discussed. Finally, we outline the challenges that must be addressed to maximize the therapeutic opportunity that targeting DDR provides.

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Preliminary results from TRITON2: A phase II study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations

Cited by 53 publications

References 0 publications

Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations

Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations

A decade of clinical development of PARP inhibitors in perspective

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

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