Rubraca (rucaparib)

Our data provide a novel insight into the potential interactions of MYC and PVT1 with other genes. Moreover, we identified a new PARP inhibition mechanism down-regulating MYC, as well as the linear and circular PVT1 transcripts. Future work should expand on clinical studies to better understand the prognostic role of PVT1 in OC.

P2, N=1500, Recruiting, Bristol-Myers Squibb | N=800 --> 1500 | Trial completion date: Aug 2025 --> Aug 2029 | Trial primary completion date: Aug 2025 --> Aug 2029

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

P2, N=292, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Feb 2025 --> Sep 2024

P2, N=130, Suspended, Gustave Roussy, Cancer Campus, Grand Paris | N=1000 --> 130 | Trial primary completion date: Apr 2024 --> Dec 2024

The dysregulation of microRNAs and transcription factors adds complexity to ACC's molecular profile. Exploration of drug-gene interactions reveals promising therapeutic strategies, involving FDA-approved drugs such as amsacrine and rucaparib, providing avenues for personalized interventions.

P3, N=405, Active, not recruiting, pharmaand GmbH | Trial completion date: Mar 2024 --> Dec 2024

PARPi switch maintenance to consolidate a response to platinum-based therapy is recommended for earlier treatment lines to have the greatest impact on the chance of cure and length of survival. This article reviews the clinical utility of PARPis and how to integrate them into best practices.

P2, N=7, Terminated, University of Utah | Active, not recruiting --> Terminated; New standard of care for study participant population

This prospective phase II trial represents a critical step towards addressing the therapeutic gap in mCRPC patients harboring HRR pathway mutations, particularly in demographic regions with limited access to PARP inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally.

Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

P2, N=292, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Jun 2024 --> Feb 2025

PARPis are an effective therapeutic option for newly-diagnosed and recurrent ovarian cancer. Despite a minor increase in the frequency of serious adverse effects, they are generally well tolerated.

Based on the PROfound and TRITON3 trials, olaparib and rucaparib were respectively approved as monotherapy in pretreated patients with mCRPC and alterations in prespecified genes. The combinations of olaparib with abiraterone (PROpel) and niraparib with abiraterone (MAGNITUDE) were approved as first-line options in patients with mCRPC and alterations in BRCA1/2, whereas the combination of talazoparib with enzalutamide (TALAPRO-2) was approved in the same setting in patients with alterations in any of the HRR genes, which are found in around a quarter of patients with advanced prostate cancer...Future directions will include refining the treatment sequencing in patients with mCRPC in the clinic while taking into account the financial toxicity as well as the potential side effects encountered with these therapies and elucidating their mechanism of action in patients with non-altered HRR genes. Herein, we review the biological rationale behind using PARPis in mCRPC and the key aforementioned clinical trials that paved the way for these approvals.

These activities could be harnessed in the clinic or open new drug discovery opportunities. The study reported here highlights the importance of characterizing the activity of drug metabolites to comprehensively understand drug response in the clinic and exploit our current drug arsenal in precision medicine.

We found that XRN2-deficient lung and breast cancer cells display sensitivity to two clinically relevant PARP inhibitors, Rucaparib and Olaparib. Finally, the enhanced stress response instigated by compromised PARP1 catalytic function in XRN2-deficient cells activates caspase-3 to initiate cell death. Collectively, these findings provide mechanistic insights into the sensitivity of XRN2-deficient cancer cells to PARP inhibition and strengthen the underlying translational implications for targeted therapy.

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

The aim of the present systematic review and meta-analysis is to evaluate the efficacy and safety of approved (Olaparib, Rucaparib) and investigational (Talazoparib, Niraparib, Veliparib) PARPi in mCRPC patients. PARP inhibitors represent a viable option for mCRPC patients. Current evidence suggests an increased effectiveness in homologous recombination repair (HRR) gene mutation carriers, especially BRCA2.

Rucaparib demonstrated significant efficacy in improving PFS and ORR in ovarian cancer patients, particularly those having BRCA mutations. However, they should be closely monitored due to the greater risk of various adverse effects.

P1/2, N=25, Terminated, pharmaand GmbH | Phase classification: P1b/2 --> P1/2

To expand the benefit of PARPi to patients without detectable HRR alterations, multiple studies are addressing potential synergies between PARP inhibition (PARPi) and androgen receptor pathway inhibitors (ARSi), radiation, radioligand therapy, chemotherapy, or immunotherapy, and these strategies are also being evaluated in the hormone-sensitive setting. In this review, we summarize the development of PARPi in prostate cancer, the potential synergies, and combinations being investigated as well as the future directions of PARPi for the management of the disease.

In newly diagnosed BRCAm-OC patients, olaparib (HR: 0.33; 95% confidence interval [CI]: 0.25, 0.43) and other PARPis [niraparib (HR: 0.40; 95% CI: 0.29, 0.55), rucaparib (HR: 0.40; 95% CI: 0.21, 0.76) and veliparib (HR: 0.44; 95% CI: 0.28, 0.69)] had a statistically significant effect on PFS versus placebo. All PARPis showed significant benefit, with olaparib showing greater benefit in newly diagnosed and PSR OC women. CRD42021288932.

P3, N=190, Active, not recruiting, North Eastern German Society of Gynaecological Oncology

PAAD tumors with high HRD levels revealed significant T helper lymphocyte depletion, upregulated levels of cancer stem cells, and increased sensitivity to rucaparib, Olaparib, and veliparib. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were identified through the combination of WGCNA, LASSO analysis and a random forest algorithm. A novel HRD-related risk model that can predict clinical prognosis and immunotherapeutic response in PAAD patients was constructed.

Recently, they have been shown to be responsive to treatment with poly ADP-ribose polymerase inhibitors, such as niraparib, olaparib, and rucaparib, used in combination with abiraterone acetate and prednisone or prednisolone, or as monotherapy...The top five treatment regimens for mCRPC were ADT monotherapy (19%), enzalutamide (ENZ; 14%), olaparib (OLA; 13%), abiraterone acetate (AA; 11%), and docetaxel (DOC; 10%), with 14% of patients receiving ≥1 medication... Among treated patients with BRCA+ mCRPC, ADT monotherapy, ENZ, OLA, AA, and DOC were most commonly used. The majority of ADT monotherapy patients died, while a substantial proportion of patients initiating 1L therapy died or initiated a clinical trial drug and did not advance to 2L, suggesting unmet need for more effective 1L treatment for patients with BRCA+ mCRPC.

The currently approved PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, fuzuloparib, and pamiparib. The present review introduces the necessity for research on the development of selective PARP-1 inhibitors from the perspective of structural and functional mechanisms of PARP-1 inhibition. A review of recently reported selective PARP-1 inhibitors provides the foundation for exploring novel strategies for designing selective PARP-1 inhibitors from the perspective of structure-activity relationships combined with computer simulations.

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

Here we report the four year progression-free survival rate of maintenance rucaparib in patients with BRCA or PALB2 related pancreatic cancer. Our data suggest that a select portion of this patient population achieves highly durable clinical remissions. This finding is further highlighted by two patients who have discontinued rucaparib for adverse events one and two years ago, respectively, and have not had biochemical or imaging evidence of progression to date.

P2, N=73, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2024 --> Mar 2025 | Trial primary completion date: Mar 2023 --> Mar 2024

P3, N=61, Active, not recruiting, Alliance for Clinical Trials in Oncology | Suspended --> Active, not recruiting | N=1002 --> 61

P1/2, N=18, Active, not recruiting, Academic and Community Cancer Research United | Phase classification: P2 --> P1/2 | Trial primary completion date: Jan 2020 --> Feb 2024

Mechanisms of sensitization and resistance have been only partially elucidated. In our review, we summarize the current clinical evidence regarding PARPis in mPCa and the future directions of these targeted agents.

In mCRPC, PARPis increase the risk of hematological toxicity compared with other treatments, both as single agents or combined with ARTA (high-quality evidence). Clinicians should be aware of this risk and the correct management, especially with the expected increased PARPis use in mCRPC.

P2, N=138, Active, not recruiting, University of Colorado, Denver | Trial primary completion date: May 2024 --> Oct 2023

Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.

By reanalysing published data on olaparib, talazoparib, rucaparib and niraparib, we provide a concise overview of responses by molecular subgroup...Olaparib-abiraterone, niraparib-abiraterone, and talazoparib-enzalutamide all prolonged progression-free survival compared to an ARSI alone in HRRm patients...The rate of grade ≥3 adverse events for the combination regimens is 10-30% higher when compared to an ARSI alone. Given the limited efficacy in unselected patients, these PARPi-ARSI combinations may be best reserved for selected patients.

Patients were treated with a variety of PARPi including Olaparib (n=48), Talazoparib (n=33), Rucaparib (n = 13) and Niraparib (n = 6.) Of the 418 patients, 45 individuals harbored an HRD germline mutation...The percentage of Trp53 R172H cells in the blood was measured by flow cytometry at baseline (6 weeks after transplantation) and after treatment with vehicle alone, Talazoparib or Olaparib daily, or cisplatin weekly, for 4 weeks...Indeed, our data suggest the opposite, with the fitness advantage of DDR gene-mutated HSPCs lost in cells with a heterozygous Brca1-mutations. These data suggest that PARPi therapy may have less of an impact on leukemia risk compared to carboplatin and in fact may show synergistic effects with HRD in blocking the competitive advantage of DDR CH during genotoxic stress.

GDSC database analysis identified 53 drugs with remarkable differences between the groups, including A.443654 and AG.014699. Our study highlights the significant association of five prognosis-related genes (MTHFD2, CDKN2A, TPM2, MPZ, and DNMT1) with HNSC. These findings provide further evidence of the crucial role of GMRGs in HNSC.

Currently, four agents, namely olaparib, rucaparib, niraparib, and talazoparib, have obtained approval in the United States and Europe. Additionally, this review briefly covers veliparib, a PARP inhibitor under development, and two recently approved PARP inhibitors in China, fuzuloparib and pamiparib. Although significant progress has been made in understanding PARP inhibitors, there are several unanswered questions that remain, necessitating further research across a broader spectrum of cancer types within this evolving class of anticancer agents.

A total of 21 patients received different types of PARPi (olaparib, n=12; niraparib, n=7; rucaparib, n=1; and talazoparib, n=1) for a median of 27 months. Twelve patients had germline BRCA mutation, two had somatic BRCA mutation, and one had loss of heterozygosity. MRD was only detected in one patient, who experienced recurrence 3 months after ctDNA evaluation.

P2, N=49, Completed, University of Oklahoma | Active, not recruiting --> Completed

The purpose of this study was to evaluate optimal dosing, safety and efficacy of olaparib or rucaparib maintenance plus minus bevacizumab in germline BRCA mutations or HRD-positive AOC patients. The most common ≥ grade III AEs (CTCAE V.5) were anemia (24%), thrombocytopenia (7%), fatigue (22%), diarrhea (2%) and transamnitis (5%). Conclusions We found that lower doses of PARPi were equally efficacious with good tolerance in comparison with standard dose and can be offered as first-line maintenance therapy in AOC patients with germline BRCA mutation or HRD positive in a resource-limited setting.