Rubraca (rucaparib)

PARPi are active against PCa with HRR mutations, especially in those with germline or somatic BRCA1/2 mutations.  There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease.

P1/2, N=13, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | N=26 --> 13 | Trial completion date: Oct 2023 --> Apr 2024 | Recruiting --> Terminated | Trial primary completion date: Oct 2023 --> Apr 2024; Treatment availability issue: The manufacturer of AsiDNA™ decided to cease production to develop an improved version, and the contract ensuring access to this molecule has expired.

P2, N=20, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

While the exact mechanisms determining the nature of the PARPis and AZD8797 interaction remain to be uncovered, our data indicate that, in a subset of models, selected PARPis strongly synergize with the inhibition of CX3CR1, suggesting a potential therapeutic opportunity.

UWB-OlaJR exhibits varying sensitivity to PARPis, showing cross-resistance to veliparib and talazoparib, and sensitivity with increased cytotoxicity to niraparib and rucaparib. Moreover, S1 nuclease fiber assay shows that niraparib and rucaparib induce greater DNA single-strand gaps than other PARPis, leading to increased DNA damage and cell death. Our study provides novel insights into differential PARPi sensitivity in olaparib-resistant BRCA-mutant OvCa, which requires further investigation of inter-agent differences in large prospective studies.

P3, N=42, Completed, North Eastern German Society of Gynaecological Oncology | Active, not recruiting --> Completed | N=190 --> 42 | Trial completion date: Jan 2025 --> Jul 2024

Our findings reveal that both PARPi olaparib and rucaparib sensitize A549 cells to 12C-ion exposure, with olaparib exhibiting superior sensitization. Thus we are the first to demonstrate that olaparib sensitizes NSCLC cells to carbon ion by interfering with HR and NHEJ pathway. These insights underscore the promising therapeutic potential of combining PARP inhibition with carbon ion exposure for effective NSCLC management.

When combined with adjuvant breast/chest wall radiotherapy, the MTD of rucaparib was 300 mg daily, corresponding to one-fourth of the approved monotherapy dose. The majority of DLTs seen were skin desquamation events (6/8 DLTs). We conclude that rucaparib is a very potent radiosensitizer, possibly leading to improved LRR, but poorer cosmesis in BCT patients.

The 100-gene expression signature identified in this study may serve as a valuable predictive biomarker for PARP inhibitor sensitivity in gastric cancer.

The FDA recently approved olaparib and rucaparib for treating mCRPC patients with HRR gene alterations. Ongoing trials are investigating combination therapies involving PARP inhibitors combined with radiation, chemotherapy, immunotherapy, and androgen receptor signaling inhibitors (ARSIs) to improve the effectiveness of PARP inhibitors and broaden the range of patients who can benefit from the treatment. This review provides an overview of the development of PARP inhibitors in prostate cancer and analyzes the mechanisms underlying their resistance.

P2, N=73, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Oct 2026 --> Jan 2027 | Trial primary completion date: Oct 2024 --> Jan 2025

Molecular docking studies identified rucaparib as a potential drug targeting ZBP1. Our research findings suggest that targeting ZBP1 could represent a novel therapeutic approach to inhibit the progression of ccRCC.

P2, N=79, Active, not recruiting, University of Colorado, Denver | Trial completion date: Sep 2024 --> Dec 2024

P2, N=33, Completed, Zhonglin Hao | Active, not recruiting --> Completed

P2, N=12, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Completed | N=30 --> 12

PARP inhibitors, such as olaparib, niraparib, or rucaparib, provide considerable benefits regarding progression-free survival expansion and overall outcomes improvement in first-line maintenance and recurrent settings. Ongoing clinical trials and future potential for personalized therapy approaches using PARP inhibitors for advanced ovarian cancer are also highlighted. However, despite these drugs' phenomenal ability to revolutionize treatment protocols for such cancer types, several challenges remain: toxicity management, cost, and development of resistance will require more research to optimize their use or broaden patient populations who can benefit from them.

PARP inhibitors, such as Olaparib, Rucaparib, Niraparib, and Talazoparib have been approved in a number of cancers including BRCA 1/BRCA2 associated malignancies although there are many difficulties as therapeutical resistance. It emphasizes that isoxazole-based PARP inhibitors compounds could be novel anti-cancer drugs. Through this review, we hope to grow a curiosity in additional explorations of isoxazole-based PARP inhibitors and their applications in the trends of novel insights towards precision cancer therapy.

P1, N=20, Completed, University of Arizona | Active, not recruiting --> Completed

P1/2, N=25, Active, not recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Jul 2027 --> Jan 2028 | Trial primary completion date: Jul 2024 --> Jan 2025

In PC, sensitivity to PARPi is dependent on the specific type and zygosity of the CDK12 mutation. PARPi monotherapy may have some activity in PC patients with biallelic inactivating CDK12 alterations.

Currently, four PARPi including Olaparib, Rucaparib, Niraparib, and Talazoparib have been developed and greatly improved clinical outcomes in cancer patients. However, accumulating evidences suggest that required or de novo resistance emerged. In this review, we discuss the molecular mechanisms leading to PARPi resistances and review the potential strategies to overcome PARPi resistance.

P2, N=494, Active, not recruiting, Royal Marsden NHS Foundation Trust | Recruiting --> Active, not recruiting | N=924 --> 494

The findings underscore the need for meticulous monitoring and dose adjustments to optimize therapeutic outcomes and mitigate the increased risks associated with adverse events. International Prospective Register of Systematic Review Identifier: CRD42023459646.

P2, N=64, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jul 2024 --> Jan 2025

P2, N=73, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jul 2026 --> Oct 2026 | Trial primary completion date: Jul 2024 --> Oct 2024

We propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. Combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic.

Recently, poly-ADP-ribose polymerase (PARP) inhibition (by drugs such as Olaparib, Niraparib or Rucaparib) directed synthetic lethality approach in BRCA germline mutant or platinum sensitive disease has generated real hope for patients. However, in the more common platinum sensitive sporadic HGSOC, the clinical mechanisms of development of PARPi resistance remains to be defined. Here we provide a comprehensive review of the current status of PARPi and the mechanisms of resistance to therapy.

P1, N=31, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

•Next generation sequencing identified a BRCA 2 mutation in a patient with stage IVB neuroendocrine cancer of the cervix.•Treatment with rucaparib resulted in disease stabilization for 74 months.•The patient remains fully active working full time as a nurse and pursing a nurse practitioner degree.

P2 | "NSCLC harboring biallelic alterations in BRCA1/2 and/or HRDsig+ represent a potentially actionable subset of NSCLC responsive to PARP inhibition (NCT03845296)."

The addition of PARPi can markedly improve the potency of SSTR2-targeted PRRT in SCLC models in SSTR2 low-expressing tumors. Further evaluation in humans seems justified based on the results as novel treatment options for SCLC are urgently needed.

Se sugiere utilizar bevacizumab u olaparib más bevacizumab en pacientes con CEO estadios III/IV BRCA1/2 negativo o desconocido (HRD positivo) que recibieron quimioterapia basada en platino más bevacizumab y obtuvieron RC/RP...Para pacientes con CEO de alto grado avanzado o metastásico en recaída platino-sensibles se sugiere: • Quimioterapia combinada basada en platino: carboplatino/doxorrubicina liposomal o carboplatino/paclitaxel o carboplatino/ nab-paclitaxel o carboplatino/docetaxel o carboplatino/gemcitabina, por seis ciclos. Si no se tolera la terapia combinada, dar carboplatino o cisplatino solo. • Quimioterapia combinada: carboplatino/gemcitabina o carboplatino/paclitaxel o carboplatino/doxorubicina liposomal, más bevacizumab, seguida de bevacizumab como mantenimiento (hasta progresión o toxicidad)...El paclitaxel semanal o la doxorrubicina liposomal pegilada o el topotecan pueden ser administrados con o sin bevacizumab. • Existen otros agentes que se consideran potencialmente act ivos (capecitabina, ciclofosfamida, ifosfamida, irinotecán, oxaliplatino, pemetrexed, vinorelbina, ciclofosfamida), que se podrían recomendar para líneas posteriores. • Las pacientes con receptores hormonales positivos que no toleran o no tienen respuesta a los regímenes citotóxicos pueden recibir terapia hormonal con tamoxifeno u otros agentes, incluidos los inhibidores de la aromatasa (anastrozol y letrozol) o acetato de leuprolide o acetato de megestrol...El niraparib podría ser útil en pacientes BRCA 1/2 +/-/desconocido, al igual que el rucaparib, sin embargo, este último no tiene aún aprobación del ente regulador en Colombia. Conclusiones: se espera que las recomendaciones emitidas en este consenso contribuyan a mejorar la atención clínica, el impacto oncológico y la calidad de vida de estas mujeres.

In summary, pyridine-containing quinazoline-2,4(1 H,3 H)-dione is a novel PARP-targeting molecular scaffold for imaging probe development, and [68Ga]Ga-SMIC-2001 is a highly promising PET probe capable of imaging tumors with PARP overexpression.

CPNE1 could be a predictive biomarker and a potential target for biological therapy in STAD.

P3, N=1000, Active, not recruiting, pharmaand GmbH | Trial primary completion date: Dec 2024 --> May 2024

In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens.

Our data indicate that, rather than acting via abrogation of cell cycle checkpoints, ATR, CHK1 and WEE1 inhibitors cause an HRD phenotype and hence "induced synthetic lethality" with PARPi.

P2, N=79, Active, not recruiting, University of Colorado, Denver | N=138 --> 79

PARP inhibitors such as olaparib and talazoparib have demonstrated efficacy in patients with BRCA mutations, leading to FDA approvals for ovarian and breast cancers. Similarly, in the second case, rucaparib demonstrated effectiveness as a maintenance therapy subsequent to achieving a near-complete response to taxane and platinum-based treatment. These findings emphasize the promising role of rucaparib in managing metastatic breast cancer in patients with BRCA1/2 mutations, further contributing to the expanding armamentarium of targeted therapies in breast cancer care.

Rucaparib can induce clinical responses in a biomarker-selected metastatic prostate cancer population without concurrent ADT. However, the pre-specified efficacy threshold was not met, and enrolment was truncated. Although durable responses were observed in a subset of patients, further study of PARPi treatment without ADT in mHSPC is unlikely to change clinical practice.

At present, it has been found the following types of targets: gene mutation targets such as BRCA associated protein 1 (BAP1) and cyclin-dependent kinase 2A (CDKN2A); epigenetic targets such as lysine (K)-specific demethylase 4A (KDM4A) and lysine-specific demethylase 1 (LSD1), and signal protein targets such as glucose-regulated protein 78 (GRP78) and signal transducer and activator of transcription 3 (STAT3). So far, available clinical trials include phase II clinical trials of histone methyltransferase inhibitor Tazemetostat, poly (ADP-ribose) polymerase (PARP) inhibitor Rucaparib and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib, as well as phase I clinical trials of mesothelin-targeting chimeric antigen receptor T-cell immunotherapy (CAR-T) cell injection in the thoracic cavity and TEA domain family member (TEAD) inhibitor VT3989 and IK-930, and the results of these trials have showed certain clinical efficacy..

Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in BRCA-, PALB2-, and ATM-mutated cancers despite progression on previous platinum.