"Foundation Medicine, Inc. today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for FoundationOne Liquid CDx to be used as a companion diagnostic for AKEEGA (niraparib and abiraterone acetate) from Janssen Biotech, Inc, a Johnson & Johnson company, the first and only FDA-approved dual-action tablet combining PARP inhibition and hormone therapy for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC)."

No abstract available

P1, N=23, Completed, Rhizen Pharmaceuticals SA | Active, not recruiting --> Completed

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.

P1, N=23, Active, not recruiting, Rhizen Pharmaceuticals SA | Trial primary completion date: Dec 2023 --> Mar 2024

Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

P1/2, N=39, Terminated, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | N=78 --> 39 | Trial completion date: Apr 2024 --> Jul 2023 | Recruiting --> Terminated | Trial primary completion date: Jan 2024 --> Jul 2023; The sponsor voluntarily terminated the study

P1/2, N=96, Not yet recruiting, Fujian Cancer Hospital

"Foundation Medicine Inc., today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for FoundationOne^® CDx to be used as a companion diagnostic for Janssen Biotech, Inc. (Janssen’s) AKEEGA™ (niraparib and abiraterone acetate Dual Action Tablet), which was approved by the FDA for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC)."

Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations.

These bispecific antibodies were effective in PDX models and showed promise in cell line models of NSCLC, where they delayed the development of acquired resistance to cetuximab and talazoparib. EGFR/Notch bispecific antibodies decrease the subpopulation of stem-like cells, reduce the frequency of tumour-initiating cells, and downregulate mesenchymal gene expression. These findings suggest that combining EGFR and Notch signalling blockade can potentially increase the response to PARP blockade.

In the therapeutic setting of BRCA+ breast cancer, treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, which keep cancer cells from repairing their damaged DNA and cause cell death, is remarkable. This review summarizes the evidence demonstrating the value of BRCA1/2 status as a diagnostic and prognostic tool and as a predictive biomarker in the personalized approach to hereditary BRCA + cancers.

P2, N=30, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

In the current investigation, we show that targeted inhibition of HR by stabilization of RAD51-RECQL5 complex by a pharmacological inhibitor of RECQL5 (4a; 1,3,4-oxadiazole derivative) in the presence of PARPi [talazoparib (BMN673)] leads to abolition of functional HR with uncontrolled activation of NHEJ repair...Moreover, functional inhibition of RECQL5 suppresses metastatic potential of breast cancer cells in response to PARPi. Together, we identified RECQL5 as a novel pharmacological target for expanding PARPi based treatment horizon for HR-proficient cancers.

The combination of a WEE1 inhibitor and PARP-1 inhibitor had enhanced efficacy and is proposed as a new therapeutic option for patients with MDS or AML. Our findings have clinical implications for a potential novel therapeutic strategy for MDS and AML patients.

TEAEs were generally manageable with no unexpected safety findings. (ClinicalTrials.gov: NCT04635631 [prospectively registered November 19, 2020]).

PARP inhibitors, such as Niraparib (Zejula), Rucaparib (Rubraca), and Talazoparib (Talzenna), target and block enzyme activity in different cancers, particularly those with impaired DNA repair pathways due to BRCA1 or BRCA2 mutations. Further, we will present results for relative binding free energies for the inhibitors in the wild type and the cancer-variant PARP1 using thermodynamic integration (TI) and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) methods. This presentation will describe the comparative results and discuss the observed effects of the individual inhibitors on the specific systems.

Two PARP inhibitors are approved by the US Food and Drug Administration for patients with germline BRCA-mutated advanced breast cancer (olaparib and talazoparib). This case illustrates the benefits of a multidisciplinary approach to managing patients with mBC and involving the patient in the decision-making process. This patient case is fictional and does not represent events or a response from an actual patient; this fictional case is for educational purposes only.

Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated.

P2, N=150, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Dec 2025

Olaparib and rucaparib PARPi have been approved for the treatment of mCRPC. Therefore, the underlying molecular mechanisms of TAL-induced cell death and its association with DNA damage response should be further analyzed.ConclusionOur findings suggest that TAL induces apoptosis in mCRPC cells, and thus TAL treatment as PARPi could be a promising therapeutic modality for treating mCRPC. However, the response of mCRPC cells to TAL was different due to probably different genetic profiles.

In addition we performed whole Exome sequencing, RNA sequencing as well as metabolomic analysis to investigate the underlying resistance mechanism.Results and DiscussionsThe PARPi resistant cells derived from the treatment regime with olaparib are also cross-resistant to other approved PARPis such as niraparib, talazoparib and rucparib. In contrast, treating the cells with DNA-damage inducing agents (oxaliplatin & methyl methane sulfonate) resulted in the same drug efficiency seen in the sensitive cells...These results suggest a so far unknown, PARPi resistance mechanism characterized by a metabolic switch and affecting the cell cycle of PARPi-resistant cells but is independent of the DNA-repair capacity of the cells. ConclusionIn this study, we could identify, a so far, unknown PARPi-specific resistance mechanism, which seems to be independent of DNA-repair capacity of the cells.

P3; Recruiting --> Active, not recruiting

P1/2, N=44, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2024 --> Jul 2027 | Trial primary completion date: Jul 2024 --> Jul 2027

P1, N=23, Active, not recruiting, Rhizen Pharmaceuticals SA | Recruiting --> Active, not recruiting | N=60 --> 23 | Trial completion date: Aug 2023 --> Feb 2024 | Trial primary completion date: May 2023 --> Dec 2023

Olaparib and talazoparib are PARP inhibitors that have been approved for the management of HER2-negative breast cancer in patients with germline BRCA1/2 mutations. This review article highlights the clinical efficacy of PARP inhibitors in patients with HER2-negative breast cancer in early and advanced settings.

"Foundation Medicine, Inc., today announced that the company and its collaborators will present 21 abstracts demonstrating the value of high-quality tumor profiling tests to inform cancer care at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting from June 2-6 in Chicago."

To explore treatments to overcome resistance, in vitro studies with TLZ sensitive and resistant ascites-derived murine cell lines were carried out and demonstrated that ATR inhibitor and PI3K inhibitor could be used in combination with the InCeT-TLZ to overcome acquired PARPi resistance. Compared to intraperitoneal PARPi injection, the InCeT-TLZ better inhibits tumor growth, delays the ascites formation, and prolongs the overall survival of treated mice, which could be a promising therapy option that benefits thousands of women diagnosed with ovarian cancer.

P2, N=30, Not yet recruiting, M.D. Anderson Cancer Center

No abstract available

No abstract available

One BRCA1 mutated clone showed indeed significantly increased survival after treatment with mitomycin C and the PARP1 inhibitor talazoparib, which both cause damages mainly repaired by HR, compared to the parental cell line. We revealed that this resistance is likely associated with (I) more efficient DNA repair, shown by high RAD51 foci formation (p ≤ 0.05) (II) avoidance of DNA replication stress, indicated by efficient replication fork restart after IR (p ≤ 0.001) and low rates of stalled replication forks after hydroxyurea treatment (p ≤ 0.01) (III) differences in the activation of immune signaling in response to DNA damage, shown by cytosolic DNA after IR, micronuclei formation and IRF3 translocation...Conclusion Our results indicate that radiochemoresistance may be linked to DNA repair, replication stress and immune signaling in the analyzed cell lines. Targeting at least two of these pathways at the same time may offer a new therapeutic approach to treat tumors that have been shown to be therapy resistant before.

P3, N=1125, Active, not recruiting, Pfizer | Trial primary completion date: May 2024 --> Oct 2022

P1, N=20, Recruiting, Roswell Park Cancer Institute | Trial completion date: Oct 2024 --> Oct 2025

We identified an effective ferroptosis-related prognostic model based on single-cell sequencing. The potential prediction model is devoted to exploring clinical therapeutic targets for NSCLC.

P2; Active, not recruiting --> Completed | Trial completion date: Oct 2024 --> Mar 2023

Overall, talazoparib clinical outcomes in this real-world population are consistent with findings from EMBRACA.

The present study therefore examined the effects of the poly‑ADP‑ribose polymerase (PARP) and WEE1‑like protein kinase (WEE1) inhibitors, BMN673 and MK‑1775, respectively, alone or in combination on four MB cell lines...These data suggest that MK‑1775 alone may be of interest for all MB cell lines, and that the combination of PARP/WEE1 inhibitors may provide possible therapeutic opportunities for the therapy of SHH MBs. Their use warrants further investigations in the future.

P1, N=20, Recruiting, Roswell Park Cancer Institute | Phase classification: P1/2 --> P1

Molecular dynamics simulations were conducted for these complexes for 200 ns to examine their structural stability and dynamic behaviour and further compared with the complex of talazoparib (TALA), an FDA-approved PARPi...This research offers critical information about PARPi, which could potentially be incorporated into the treatment of TNBC. Moreover, these findings were validated by comparing them with an FDA-approved PARPi.

P1, N=12, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2023 --> Jun 2024