P2, N=40, Active, not recruiting, Do-Youn Oh | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=74, Active, not recruiting, Seoul National University Hospital | Trial primary completion date: Dec 2023 --> Dec 2024

The primary end point is an investigator-assessed objective response rate in each cohort. Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).

P2, N=36, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Initiation date: Mar 2024 --> Sep 2024

However, optimal identification of high-risk patients who may derive benefit from this genomically-directed therapy is debated. In this study, we sought to characterize the real-world proportion of gBRCA1/2 PV carriers eligible for adjuvant olaparib according to the OlympiA criteria, and to compare clinicopathologic characteristics and outcomes between eligible and ineligible patients.

We show that TRIM33 knockdown sensitizes MM cells to the PARP inhibitor Olaparib, and this is synergistic with the standard of care therapy bortezomib, even in co-culture with bone marrow stromal cells (BMSCs). These findings suggest that TRIM33 loss contributes to the pathogenesis of high-risk MM and that this may be therapeutically exploited through the use of PARP inhibitors.

Upregulation of intracellular NAD+ levels by the addition of nicotinamide also induced resistance to olaparib and talazoparib in C1 cells. Taken together, our findings suggest that upregulation of intracellular NAD+ is one of the factors underlying the acquisition of PARP inhibitor resistance.

P1, N=44, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

P2, N=298, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2023 --> Dec 2024

P2, N=20, Not yet recruiting, Ibrahim Halil Sahin

We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.

In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.

The HR activity of xenograft tumor tissues quantitatively correlated with the effect of olaparib. Our data suggest that ASHRA could be a useful assay for diagnosing HBOC and predicting the efficacy of PARP inhibitors.

P2, N=122, Active, not recruiting, National Cancer Institute (NCI) | Terminated --> Active, not recruiting | Trial completion date: Jun 2022 --> Apr 2025

Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR. For PD-L1 and BRCA mutation-positive tumors, atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option. Neutropenia, diarrhea, and fatigue are frequently occurring serious adverse events.

P1/2, N=135, Recruiting, GlaxoSmithKline | Trial completion date: Nov 2025 --> Nov 2029 | Trial primary completion date: Jun 2025 --> Dec 2027

P1, N=102, Completed, CSPC Ouyi Pharmaceutical Co., Ltd.

Remarkably, Polθi binding to the Polθ-pol:DNA/DNA closed complex traps the polymerase on DNA for more than forty minutes which elucidates the inhibitory mechanism of action. These data reveal a unique small-molecule DNA polymerase:DNA trapping mechanism that induces synthetic lethality in HR-deficient cells and potentiates the activity of PARPi.

From several possibilities, we chose two conjugates that could be administered intravenously every 2 weeks and maintain TLZ within its known therapeutic window. We describe situations where the PEG∼TLZ conjugates would find utility in humans and suggest how the intravenously administered long-acting prodrugs could in fact be more effective than daily oral administration of free TLZ.

Olaparib is not a cost-effective maintenance treatment option. Companion diagnostics are an equally important cost driver as the drug itself.

Inflammation-related blood data, such as neutrophil count, obtained at the initial pre-treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.

Olaparib plus abiraterone has a manageable and predictable safety profile.

Regardless of BRCA1/2 status, PARPi in neoadjuvant therapy, can improve the pCR rate of HER2-negative breast cancer, especially in HR-positive patients. Thus, we should have performed larger randomized trials and provided a stronger evidence-based basis.

P1/2, N=54, Not yet recruiting, German Cancer Research Center | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Jun 2027 --> Jun 2028

P2, N=8, Active, not recruiting, John Diaz | Recruiting --> Active, not recruiting | N=48 --> 8

P1/2, N=13, Active, not recruiting, Brown University | Trial completion date: May 2024 --> Jan 2027 | Trial primary completion date: Jan 2024 --> Jan 2027

Two CDK-inhibitors (CDKi), the broad range dinaciclib and the CDK12-specific SR-4835, strongly reduced the expression of key HR genes and impaired HR functionality, as illustrated by BRCA1 and RAD51 nuclear foci obliteration. However, no olaparib response improvement was observed in vivo with SR-4835. These data support that the implementation of CDK-inhibitors could be effective to sensitize TNBC to olaparib as well as possibly to cisplatin or gemcitabine.

P1, N=18, Suspended, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P2, N=123, Active, not recruiting, National Cancer Institute (NCI)

P3, N=733, Active, not recruiting, Tesaro, Inc. | Trial completion date: Mar 2024 --> Sep 2024

P2, N=25, Active, not recruiting, National Cancer Institute (NCI) | N=60 --> 25 | Trial completion date: Jun 2023 --> Dec 2024

Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.

Following the approval of olaparib for the treatment of BRCA1/2 mutated, castration-resistant prostate cancer, further targeted therapeutic approaches are currently under development. In our review article, we provide an overview of current molecular testing in prostate cancer and discuss possible consequences.

P1/2, N=75, Recruiting, Massachusetts General Hospital | Phase classification: P1b/2 --> P1/2 | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2025

P1/2, N=122, Active, not recruiting, AtlasMedx, Incorporated | Recruiting --> Active, not recruiting

BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i)...Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.

P3, N=174, Active, not recruiting, The Netherlands Cancer Institute | Trial completion date: Dec 2029 --> Dec 2033 | Trial primary completion date: Apr 2024 --> Oct 2024

Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients.

P2, N=122, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Inadequate accrual rate

P3, N=5, Terminated, Jiangsu HengRui Medicine Co., Ltd. | N=136 --> 5 | Recruiting --> Terminated; Sponsor R & D Strategy Adjustment

P1, N=25, Recruiting, Roswell Park Cancer Institute | Active, not recruiting --> Recruiting

In vivo analysis results revealed that 4F-DDC inhibited the growth of HCC-1937-derived tumor xenografts, possibly via the induction of DNA damage and activation of the cGAS-STING pathway. In summary, the current study provides a new perspective on the antitumor mechanism of PARP inhibitors and showcases the therapeutic potential of 4F-DDC in the treatment of breast cancer.