PARADIGM-2: Two parallel phase I studies of olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, with treatment stratified by MGMT status

Fulton, Ben; Short, Susan; James, Allan; Nowicki, Stefan; McBain, Catherine; Jefferies, Sarah; Kelly, Caroline; Stobo, Jon; Morris, Anna; Williamson, Aoife; Chalmers, Anthony J.

doi:10.1016/j.ctro.2017.11.003

Cited by 51 publications

(44 citation statements)

References 21 publications

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“…The 6-month PFS was 45% in 13 evaluable patients, providing supporting evidence to proceed to late-phase trial testing of olaparib in combination with radiotherapy AE temozolomide for newly diagnosed GBM (PARADIGM-2; ref. 47). In contrast to olaparib, niraparib was shown to effectively penetrate the BBB in preclinical models and have a significant antitumor effect in germline BRCA2-mutant intracranial xenografts at clinically relevant doses (48).…”

Section: Clinical Studiesmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

271

206

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A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness."

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Section: Clinical Studiesmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

271

206

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“…The PARP inhibitor Olaparib is therefore undergoing clinical trial evaluation in combination with anti-PD1 mAbs to assess clinical efficacy [ 31 , 37 ]. Enhancing the effects of RT-induced DNA damage through DDR inhibitors is a logical approach to improving tumour response and is currently being extensively investigated; the addition of an ICI such as anti-PD1 to overcome tumour-induced immunosuppression is an exciting prospective approach [ 38 ].…”

Section: The Effects Of Rt On the Induction Of Systemic Immunitymentioning

confidence: 99%

Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations

et al. 2020

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Radiotherapy (RT) is a highly effective anti-cancer therapy delivered to around 50–60% of patients. It is part of therapy for around 40% of cancer patients who are cured of their disease. Until recently, the focus of this anti-tumour efficacy has been on the direct tumour cytotoxicity and RT-induced DNA damage. Recently, the immunomodulatory effects of RT on the tumour microenvironment have increasingly been recognized. There is now intense interest in potentially using RT to induce an anti-tumour immune response, which has led to rethinking into how the efficacy of RT could be further enhanced. Following the breakthrough of immune check point inhibitors (ICIs), a new era of immuno-oncology (IO) agents has emerged and established immunotherapy as a routine part of cancer treatment. Despite ICI improving outcomes in many cancer types, overall durable responses occur in only a minority of patients. The immunostimulatory effects of RT make combinations with ICI attractive to potentially amplify anti-tumour immunity resulting in increased tumour responses and improved outcomes. In contrast, tumours with profoundly immunosuppressive tumour microenvironments, dominated by myeloid-derived cell populations, remain a greater clinical challenge and RT may potentially further enhance the immunosuppression. To harness the full potential of RT and IO agent combinations, further insights are required to enhance our understanding of the role these immunosuppressive myeloid populations play, how RT influences these populations and how they may be therapeutically manipulated in combination with RT to improve outcomes further. These are exciting times with increasing numbers of IO targets being discovered and IO agents undergoing clinical evaluation. Multidisciplinary research collaborations will be required to establish the optimal parameters for delivering RT (target volume, dose and fractionation) in combination with IO agents, including scheduling to achieve maximal therapeutic efficacy.

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“…It is noteworthy that both analyses on ovarian carcinoma and nonovarian carcinomas showed similarly favorable PFS6 and PFS12 in the HRD group only in the context of monotherapy but not in combination therapy. The strategy of combination therapy is developed based on the definition of “contextual synthetic lethality” by inducing HRD or downregulating HR DNA repair through the addition of other agents, such as cytotoxic chemotherapy, radiotherapy or targeted inhibitors . This strategy offers a new insight that may help increase the benefit of PARPis even in the absence of HRD.…”

Section: Discussionmentioning

confidence: 99%

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

Feng

Sundaram

et al. 2019

Intl Journal of Cancer

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PARP inhibitors (PARPis) have remarkable antitumor activity in BRCA mutant ovarian carcinoma. Emerging evidence has shown that responses to PARPis are not limited to BRCA mutant tumors, but could expand to other homologous recombination deficiency (HRD) carcinomas. However, relatively little is known about the efficacy of PARPis in patients with HRD when compared to non‐HRD carriers. In this systematic review, 13 clinical trials were included and analyzed for the treatment effect of PARPis on progression free survival (PFS) and overall survival (OS) for HRD (BRCA mutant HRD, n = 697; BRCA wild‐type HRD, n = 478) vs. non‐HRD (n = 1,417) patients. Pooled analyses of the effect of PARPis in both ovarian and nonovarian carcinoma groups showed significantly higher PFS rates at 6 months and 12 months (PFS6 and PFS12) in the HRD subgroup, as compared to the non‐HRD subgroup. Within the HRD subgroup, the BRCA‐mutant population achieved significantly higher PFS6 (OR: 2.29, 95% CI: 1.03–5.08) and PFS12 (OR: 1.95, 95% CI: 1.26–3.01) when compared to BRCA wild‐type patients. Furthermore, within BRCA wild‐type carcinomas, mutations in other HRD‐related genes also led to increased PFS6 (OR: 1.72, 95% CI: 1.27–2.43) and PFS12 (OR: 1.85, 95% CI: 1.31–2.62), as compared to non‐HRD counterparts. Therefore, patients with HRD carcinomas exhibited pronounced PFS advantages upon treatment with PARPis, as compared to non‐HRD carcinomas. In addition to BRCA mutations, other non‐BRCA HRD‐related aberrations may serve as novel biomarkers for the prediction of PARPi efficacy.

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PARADIGM-2: Two parallel phase I studies of olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, with treatment stratified by MGMT status

Cited by 51 publications

References 21 publications

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

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