PARP Inhibitors In Patients Research Articles

Combining next-generation hormonal therapy with PARP inhibition in metastatic castration-resistant prostate cancer

In a paradigm of precision oncology, elegant preclinical work showed that inhibition of poly(ADP-ribose) polymerase (PARP) proteins can exploit a deficiency of cancer cells to repair DNA double-strand breaks through homologous recombination repair (HRR), 1 Lord CJ Ashworth A PARP inhibitors: synthetic lethality in the clinic. Science. 2017; 355: 1152-1158 Crossref PubMed Scopus (1411) Google Scholar and the resulting synthetic lethality was first shown to be clinically effective in ovarian cancer carrying a germline deleterious mutation in BRCA1 or BRCA2, key HRR genes. 2 Banerjee S Moore KN Colombo N et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021; 22: 1721-1731 Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar For prostate cancer, the discovery of alterations in BRCA2 and other HRR-related genes in up to 20% of advanced disease 3 Robinson D Van Allen EM Wu YM et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161: 1215-1228 Summary Full Text Full Text PDF PubMed Scopus (2077) Google Scholar led to the development of several biomarker-driven trials of PARP inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) 4 Abida W Patnaik A Campbell D et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020; 38: 3763-3772 Crossref PubMed Scopus (309) Google Scholar , 5 de Bono JS Mehra N Scagliotti GV et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021; 22: 1250-1264 Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar , 6 Hussain M Mateo J Fizazi K et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020; 383: 2345-2357 Crossref PubMed Scopus (289) Google Scholar , 7 Smith MR Scher HI Sandhu S et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022; 23: 362-373 Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar and to the regulatory approval of rucaparib and olaparib as monotherapy for the treatment of mCRPC harbouring mutations in BRCA2 and other HRR genes. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trialTalazoparib 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. Full-Text PDF

Efficacy of PARP inhibitors in patients with metastatic castration resistant prostate carcinoma: A meta-analysis of phase III randomized controlled trials.

e17060 Background: PARP inhibitors effectively treat several solid tumors, regardless of the presence of BRCA mutations. Patients with castration-resistant metastatic prostate cancer become refractory to androgen deprivation therapy. PARP inhibitors were recently approved for use in prostate cancer, and have opened new avenues in prostate cancer treatment research. Methods: We systematically searched multiple databases using pre-specified search terms. We included only phase III RCTs comparing PARP inhibitors versus standard of care in patients with castration-resistant biopsy-proven metastatic prostate cancer. The outcomes studied were radiologically guided progression-free survival (PFS) and overall survival (OS). We used a random effects model via RevMan 5.4 software for statistical analysis. Results: 3 phase III RCTs met the inclusion criteria with a total of 1606 patients (PARP inhibitors = 867 patients, standard of care = 739 patients). Compared to the standard of care, PARP inhibitors showed significantly higher PFS [HR = 0.62( 95% CI, 0.49-0.78) P < 0.0001]. There was no statistically significant difference in OS [HR = 0.85( 95% CI, 0.69-0.1.04) P = 0.11] between the two groups. Conclusions: The use of PARP inhibitors in patients with castration-resistant metastatic prostate cancer is associated with improved progression-free survival. No significant difference was observed in overall survival between the two groups. There is a need to study the cost-benefit analysis of using PARP inhibitors as they do not show any improvement in overall survival. [Table: see text]

Systematic high-throughput combination drug screen to enhance poly (ADP-ribose) polymerase (PARP) inhibitor efficacy in ovarian cancer.

5546 Background: PARP inhibitors currently offer the greatest benefit to patients with loss-of-function BRCA1 or 2 mutations or other causes of homologous recombination deficiency (HRD). We hypothesized that combination therapy, possibly by augmenting or inducing an HRD phenotype, would enhance the efficacy of PARP inhibition in epithelial ovarian cancer. Methods: We performed a high-throughput screen of an informer set containing FDA-approved drugs, clinical candidates, and small-molecule probes to identify synergistic partners with olaparib in representative HRD and non-HRD human epithelial ovarian cancer cells. Single agent activity was described by area under the curve of the Hafner growth rate index (AUC_GRI) and synergy was ranked by cumulative difference from Bliss (ΔBliss). Analysis of the drug screen was performed using algorithms developed by the Gulf Coast Consortia’s Combinatorial Drug Discovery Program at the Texas A&M Institute of Bioscience and Technology. MTT assays were then independently performed to verify and characterize synergy between CT7439, an agent selected following the drug screen, and olaparib. MTT data were analyzed using the SynergyFinder Plus web application. Results: In an initial single agent screen, we identified 62 compounds with a mean AUC_GRI <0.75, indicating inhibitory activity. Prioritizing more potent agents and those of mechanistic interest, we selected 40 hits to validate and advance to a combination screen. Diverse mechanisms of action were represented among the hits, including many small molecule inhibitors of various cell cycle pathways. Following a combination screen with olaparib, the compounds selected for final validation were: AZD 7762 (CHK1/2 inhibitor), dinaciclib (pan-CDK inhibitor), onalespib (HSP90 inhibitor), and SN-38 (topoisomerase 1 inhibitor). The ΔBliss for these agents are presented in the table. Due to mechanistic rationale and concern for overlapping toxicities among the other candidates, we focused further study on CDK inhibitors. In MTT assays, we identified robust synergy between olaparib and CT7439, a next-generation oral CDK12/13 inhibitor, with a mean Bliss synergy score of 1.31 and scores as high as 22.03 at certain concentrations in the non-HRD model OVCAR-5. These findings were recapitulated in the HRD cell lines OVCAR-4 (mean Bliss synergy score 1.56) and OVCAR-8 (mean Bliss synergy score 5.69). Results from an in vivo model will be presented as well. Conclusions: Pairing a PARP inhibitor and CDK inhibitor, a strategy identified by a high-throughput drug screen and known to impair homologous recombination, resulted in robust synergy in both HRD and non-HRD ovarian cancer models. Clinical translation of this combination may enhance the efficacy of PARP inhibitors in patients with ovarian cancer. [Table: see text]

Comparison of PARPi efficacy according to homologous recombination deficiency biomarkers in patients with ovarian cancer: a systematic review and meta-analysis.

Mutations in the BRCA1/2 (BRCA) genes are associated with response to poly(ADPribose) polymerase (PARP) inhibitors (PARPi). In addition, there are different homologous recombination deficiency (HRD) biomarkers available in clinical practice [e.g., genome-wide loss-of-heterozygosity (gLOH) and myChoice® score] that identify patients who can benefit from PARPi. Inconsistencies in biomarkers used in PARPi clinical trials make it challenging to identify clinically relevant predictive biomarkers. This study aims to compare clinically available HRD biomarkers in terms of benefits from PARPi. We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a Random Effects model. Patients were classified according to their HRD status: (I) BRCAm (patients with BRCA mutation of germline or somatic origin); (II) non-BRCA HRD [patients BRCA wild-type (wt) with another HRD biomarker-gLOH or myChoice®]; and (III) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice®+ with gLOH-high. Five studies (3,225 patients) analyzing PARPi in first line setting were included. Patients with BRCAmut had progression-free survival (PFS) with hazard ratio (HR) 0.33 [95% confidence interval (CI): 0.30-0.43]; patients with non-BRCA HRD had a PFS HR 0.49 (95% CI: 0.37-0.65), and patients with HRP had a PFS HR 0.78 (95% CI: 0.58-1.03). Eight studies (5,529 patients) with PARPi including first line and recurrence settings were included. BRCAmut had PFS HR 0.37 (95% CI: 0.30-0.48), BRCAwt & HRD 0.45 (95% CI: 0.37-0.55) and HRP 0.70 (95% CI: 0.57-0.85). Patients with BRCAwt & myChoice® ?42 had PFS HR 0.43 (95% CI: 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95% CI: 0.28-0.62). Patients with HRD derived significantly more benefit from PARPi when compared to patients with HRP. The benefit of PARPi in patients with HRP tumors was limited. Careful cost-effectiveness analysis, and alternative therapies or clinical trial enrollment should strongly be considered for patients with HRP tumors. Among patients with BRCAwt, a similar benefit was found in patients with gLOH-high and those myChoice®+. The clinical development of further HRD biomarkers (e.g., Sig3) may help identify more patients who benefit from PARPi.

Phase II study of niraparib in patients with advanced melanoma with genetic homologous recombination (HR) mutation/alteration.

TPS9596 Background: There are a limited number of therapeutic options available for metastatic melanoma patients progressing on the checkpoint inhibitor(s) and BRAF-targeting drugs. PARP inhibitors have been approved in the setting of BRCA1/2 germline mutations, and have demonstrated activity in the setting of HR deficiency in other cancers. Documentation of PARP inhibitors in melanoma would have clear clinical impact. We have previously shown that 21-34% of metastatic melanomas harbor at least 1 molecular aberration in the HR pathway, considered pathogenic, and likely leading to HR deficiency. Previously, we demonstrated dramatic regression of tumors harboring HR mutation(s) with PARP inhibitor treatment in a PDX model. These findings provide a strong rationale to evaluate the clinical efficacy of a PARP inhibitor in patients with advanced melanoma with HR deficiency. Methods: This is a single arm, open-label, multi-center phase II trial. The primary objective of the study is: To evaluate the clinical efficacy of niraparib in advanced melanoma patients with HR deficiency. The secondary objectives is to evaluate PFS, OS, and safety profile of niraparib. The key eligibility criteria: Advanced melanoma patients with mutation in any of the following: ARID1A/B, ARID2, ATM, ATR, ATRX, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCD2, MRN11A, RAD50, RAD51, RAD54B, PALB2 (requires a genetic analysis result performed at any CLIA-certified laboratory) disease progression on PD1-antibody therapy and if BRAF mutant, BRAF/MEK inhibitors ≥ 18 years of age; ECOG PS ≤ 1; prior systemic cytotoxic therapy ≤1 regimen; no limit on number of prior immunotherapy or targeted therapy regimens. No symptomatic brain metastasis; active brain lesions ≥6 mm size, or requiring steroid treatment Patients will be treated with oral niraparib once daily (28-day cycle); the dose will be 300 mg (if weight ≥77 kg and platelet counts of ≥150,000 µL); otherwise 200 mg RECIST 1.1 will be used to evaluate clinical response every 8 weeks. Adverse events will be recorded according to CTCAE version 4.03. The primary study endpoint is overall response rate. Simon’s optimal 2-stage design is proposed. With significance level of5% and 80% power, our null hypothesis that the true response rate is 0.10 will be tested against a one-sided alternative: H0: p ≤ 10%, a response rate of no real interest VS H1: p ≥ 30%, a response rate that would be of considerable interest 10 patients will be analyzed for a response evaluation in the first stage of the study, and 19 in the second stage, for a total of 29 patients. If the response rate is 10% (1/10) or less at the end of the first stage, further accrual will be terminated. With 2 or more responses in the first stage, accrual will continue to a total of 29 patients for this cohort. The null hypothesis will be rejected if ≥6 responses are observed in a cohort of 29 subjects. Clinical trial information: NCT03925350 .

Maintenance therapy with a poly(ADP-ribose) polymerase inhibitor (PARP) in patients with newly diagnosed ovarian cancer: A systematic review and meta-analysis.

e17587 Background: PARP inhibitors (PARPi) have been approved for maintenance therapy in newly diagnosed ovarian cancer patients with or without homologous recombination deficiency (HRD). In this meta-analysis, the latest clinical data to assess the efficacy and safety of this approach across different subgroups were synthesized. Methods: PubMed, Scopus, and Cochrane databases were searched for randomized controlled trials that compared maintenance PARPi with placebo in newly diagnosed ovarian cancer. The outcomes of interest included progression-free survival (PFS) according to HRD status, overall survival (OS), second PFS (PFS2), and time-to-first subsequent treatment (TFST). Heterogeneity was examined with I2 statistics. A random-effects model was used for outcomes with high heterogeneity. Results: A total of 6 Randomized clinical trials with 3609 patients were included, of whom 2348 (65%) received maintenance PARPi. PFS was significantly longer for HRD-positive patients receiving PARPi [Hazard ratio (HR) 0.44, 95% Confidence interval (CI) 0.37 – 0.52 p<0.001] and for HRD-negative patients [HR 0.71, 95% CI 0.54 – 0.92 p=0.009]. Maintenance PARPi was associated with improved OS in HRD-positive patients [HR 0.59, CI 0.47 -0.73, p<0.001] but not in unselected patients. PFS2 in the HRD-positive population was reported in three trials, and it favored the use of PARPi [HR 0.57, CI 0.43 – 0.76, p<0.001]. Adverse events ≥grade 3 were more common in patients on maintenance PARPi (p<0.001). The occurrence of myelodysplastic syndrome was numerically but not significantly higher in the PARPi group. Conclusions: Maintenance with PARPi in patients with newly diagnosed ovarian cancer significantly prolongs PFS regardless of HRD status. Moreover, PARPi maintenance improves OS and PFS2 in patients with BRCA and/or HRD-positive tumors compared to placebo. [Table: see text]

Neoadjuvant PARP inhibitors in patients with early HER2-negative breast cancer harboring BRCA 1/2 germline mutations: A systematic review and meta-analysis.

e12611 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of germline BRCA mutated (gBRCAm) breast cancer (BC) patients in the adjuvant and metastatic settings. Several studies have explored the role of PARPi in the neoadjuvant setting both with and without chemotherapy. Here, we explore the efficacy and safety of neoadjuvant PARPi in early HER2-negative BC patients. Methods: We searched PubMed, Scopus, and the Cochrane Library databases for randomized (RCT) and non-randomized clinical trials (non-RCT) that reported the proportion of patients with pathological complete response (pCR) after neoadjuvant PARPi and safety. Statistical analysis was performed using R software. Data were pooled using the random effects model. Results: Analysis included 3 RCTs and 4 non-RCTs, with 942 HER-2 negative breast cancer patients, 293 harboring a gBRCA 1/2 mutation. In a pooled analysis, gBRCAm carriers achieved a significantly higher rate of pCR than BRCA wild-type patients (56% versus 37%, p=0.04) with neoadjuvant PARPi. There was no difference in pCR when PARPi were combined with carboplatin (+/- chemotherapy) (40% versus 44%, p=0.69). Among RCTs (n=457) patients received PARPi in combination with either Paclitaxel plus Carboplatin (PCb) (85%) or with Paclitaxel alone (P) (15%). PARPi were associated with a higher pCR which approached, but did not meet statistical significance (51% vs 41%; Odds Ratio [OR]: 1.30, 95%CI 0.97 to 1.74, p=0.08). gBRCAm was associated with higher pCR compared to wild type in RCTs analysis (60% versus 48%; OR: 1.64, 95%CI 1.01 to 2.68, p=0.05). The most common adverse events (AEs) were cytopenias, nausea, fatigue, alopecia, and dizziness. Hematological toxicities were the most frequent serious AEs, including anemia (15%), neutropenia (22%), and thrombocytopenia (3%). The combination of PARPi and carboplatin was associated with higher hematological AEs (78% versus 46%; P=0.002). Conclusions: The addition of PARPi in the neoadjuvant setting improves pCR in early-stage HER2-negative breast cancer and germline BRCA 1/2 mutations, but not for unselected patients. Combination of PARPi with carboplatin does not improve pCR and leads to substantially worse toxicity. Further studies are warranted to identify the best neoadjuvant PARPi schema.[Table: see text]

Phenotypic differences related to homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) treated in routine care settings in the United States (US).

e17047 Background: Recent evidence suggests mutations in HRR genes predict clinical benefit from treatment with PARP inhibitors in patients (pts) with mCRPC. Little is known about the prevalence, clinical and prognostic phenotypes associated with HRR-mutated (HRRm) mCRPC pts receiving routine oncology care in the US. We assessed HRRm positivity rate and described difference in phenotypic factors between HRRm+ and HRRm- mCRPC patients receiving routine care in community oncology settings. Methods: In this retrospective cohort study, we identified biologically male pts with mCRPC, ≥18 years, who received HRRm testing and on systemic anti-cancer treatment from 5/1, 2020 – 3/31, 2022, from the Integra Connect database, an electronic medical record (EMR) and claims database of US cancer pts in community oncology. We defined 2 cohorts based on their HRRm status (defined by the presence of an alteration in at least 1 of the following genes: BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L). We described age and race (at diagnosis), cancer stage and Gleason score (at staging), and line of therapy (LOT), Eastern Cooperative Oncology Group (ECOG) performance status, prostate-specific antigen (PSA) values and microsatellite instability (MSI) status using values closest to mCRPC diagnosis. HRR tests were stratified by germline, ctDNA, and solid tumor. Results: The study cohort comprised 376 HRRm-tested pts: by ctDNA only – 29%, germline only – 16.2%, solid tissue only – 18.4% and > 2 testing types – 33.5%. 96 had HRRm+ mCRPC (25.5%). Median (IQR) age at diagnosis for both cohorts was 67 (43-89) years and there were no statistically significant differences in age, race, stage, Gleason score, PSA value, LOT or ECOG by HRRm status. HRRm+ rates by ctDNA, germline, and solid tissue testing were 26.6%, 13.1% and 21.7%, respectively. Of the 126 patients with > 2 testing types, HRRm+ rate was 30.9%. A higher, but not statistically significant, proportion of HRRm+ pts had Gleason scores 9-10 compared to HRRm- pts (54.8% vs 48.6%). Of HRRm- pts, 10.2% had MSI-H status compared to 6.5% in HRRm+ pts. Conclusions: In this real-world cohort of HRR gene-tested pts with mCRPC, we observed a 25.5% HRRm+ rate, which suggests the prevalence for HRR mutation is significant enough to warrant testing for all pts with mCRPC. Further research is needed to examine the impact of these findings on overall survival and other clinical outcomes.

Clinical efficacy of PARP inhibitors in breast cancer

BRCA1 and BRCA2 are key tumor suppressor genes that are essential for the homologous recombination DNA repair pathway. Loss of function mutations in these genes result in hereditary breast and ovarian cancer syndromes, which comprise approximately 5% of cases. BRCA1/2 mutations are associated with younger age of diagnosis and increased risk of recurrences. The concept of synthetic lethality led to the development of PARP inhibitors which cause cell cytotoxicity via the inhibition of PARP1, a key DNA repair protein, in cells with germline BRCA1/2 mutations. Although still poorly understood, the most well-acknowledged proposed mechanisms of action of PARP1 inhibition include the inhibition of single strand break repair, PARP trapping, and the upregulation of non-homologous end joining. 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.

Abstract P4-01-08: Efficacy of PARP Inhibitors in Patients With BRCA1/2-related Breast Cancer with Prior Platinum Exposure: A Systematic Review and Meta-Analysis

Abstract Background: Approximately 5% of breast cancer patients carry a deleterious germline BRCA1/2 mutation, which leads malignant cells to be deficient in the repair of DNA double-strand breaks via homologous recombination. The poly(adenosine diphosphate–ribose) polymerase (PARP) enzymes are important on DNA single-strand break repair and PARP inhibitors (PARPi) cause an accumulation of unresolved DNA damage in tumors with BRCA1/2 mutations, resulting in cell death. However, because platinum salts also ultimately cause double-strand DNA breaks and may have overlapping mechanisms of resistance with PARPi, the efficacy of PARPi in patients with prior platinum therapy is unknown. We sought to evaluate the efficacy of PARPi in patients with BRCA1/2-related breast cancer and previous platinum exposure. Methods: We performed a systematic review and meta-analysis of studies that evaluated the efficacy of PARPi in patients with advanced or metastatic breast cancer and germline BRCA1/2 mutations. Two independent investigators identified double-blind, randomized controlled trials (RCTs) that included the subgroup of previous exposure to platinum. PubMed, Embase, and Cochrane databases were searched for papers up to June 26, 2022. Data extraction from published reports and quality assessment were performed under Cochrane recommendations. Hazard ratios (HRs) with a 95% confidence interval (CI) were pooled, and a p-value of < 0.05 was considered statistically significant. The software Review Manager 5.3 was selected for conducting the statistical analysis. The primary endpoint of interest was progression-free survival (PFS). Results: Out of 2069 database results (487 on PubMed; 1376 on Embase; and 206 on Cochrane), 42 studies were selected for full review, and 4 RCTs, with a total of 249 patients, were included in the final investigation. The PARPi included were Olaparib, Talazoparib, Niraparib, and Veliparib. Pooled analysis showed that PARPi improved PFS in breast cancer patients with prior treatment with platinum-based therapy compared to the control group [HR = 0.72; 95% CI, 0.53-0.97; p = 0.03]. In comparison, the population without previous platinum exposure had a similar but slightly greater benefit from PARPi [HR = 0.68; 95% CI, 0.52-0.89; p = 0.005]. A subgroup analysis containing only the three randomized trials with PARPi monotherapy confirmed the central tendency favoring PARPi over physicians’ choice of single-agent chemotherapy in patients with prior platinum-therapy; however, because of small numbers and wide confidence interval it was not statistically significant [HR = 0.72; 95% CI, 0.51-1.01; p = 0.06]. Conclusions: Our findings suggest that PARPi are associated with longer PFS in patients with advanced breast cancer and previous exposure to platinum therapy, decreasing the concerns about cross-resistance between the drug classes. Nonetheless, more extensive studies are still necessary to investigate the efficacy of PARPi in patients with prior platinum exposure and truly platinum-resistant disease. Progression-free survival of included studies Citation Format: Alice D. Marinho, Beatriz Mella S. Pessoa, Gabriela R. Brandao, Caroliny H. Da Silva, Pedro A. Reis, Ana Carolina M. Comini, Felipe Batalini. Efficacy of PARP Inhibitors in Patients With BRCA1/2-related Breast Cancer with Prior Platinum Exposure: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-08.

51P Efficacy of PARP inhibitors in patients with advanced high grade serous ovarian cancer according to BRCA domain mutations

51P Efficacy of PARP inhibitors in patients with advanced high grade serous ovarian cancer according to BRCA domain mutations

Dose Adjustment of Poly (ADP‑Ribose) Polymerase Inhibitors in Patients with Hepatic or Renal Impairment.

Poly (ADP-ribose) polymerase (PARP) inhibitors are small-molecule inhibitors of PARP enzymes (including PARP1, PARP2, and PARP3) that exhibit activity against tumor cells with defects in DNA repair. In recent years, five PARP inhibitors, olaparib, niraparib, rucaparib, talazoparib and veliparib, have been developed for the treatment of solid tumors, particularly in patients with breast-related cancer antigen (BRCA) 1/2 mutations, or those without a functional homologous recombination repair pathway. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. The five PARP inhibitors are eliminated primarily via the liver and kidneys, hepatic or renal impairment may significantly affect their pharmacokinetics (PK). Therefore, it is important to know the effects of hepatic or renal impairment on the PK and safety of PARP inhibitors. In this review, we characterize and summarize the effects of hepatic and renal function on the PK of PARP inhibitors and provide specific recommendations for clinicians when prescribing PARP inhibitors in patients with hepatic or renal impairment.

The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors.

Primary malignant central nervous (CNS) tumors are a devastating group of diseases with urgent need for improved treatment options. Surgery, radiation, and cytotoxic chemotherapy remain the primary standard treatment modalities, with molecularly targeted therapies having proven efficacy in only small subsets of cases. Poly(ADP-ribose) polymerase (PARP) inhibitors, which have had immense success in the treatment of extracranial cancers with homologous recombination deficiency (HRD), are emerging as a potential targeted treatment for various CNS tumors. Although few primary CNS tumors display canonical BRCA gene defects, preclinical evidence suggests that PARP inhibitors may benefit certain CNS tumors with functional HRD or elevated replication stress. In addition, other preclinical studies indicate that PARP inhibitors may synergize with standard therapies used for CNS tumors including radiation and alkylating agents and may prevent or overcome drug resistance. Thus far, initial clinical trials with early-generation PARP inhibitors, typically as monotherapy or in the absence of selective biomarkers, have shown limited efficacy. However, the scientific rationale remains promising, and many clinical trials are ongoing, including investigations of more CNS penetrant or more potent inhibitors and of combination therapy with immune checkpoint inhibitors. Early phase trials are also critically focusing on determining active drug CNS penetration and identifying biomarkers of therapy response. In this review, we will discuss the preclinical evidence supporting use of PARP inhibitors in primary CNS tumors and clinical trial results to date, highlighting ongoing trials and future directions in the field that may yield important findings and potentially impact the treatment of these devastating malignancies in the coming years.

Efficacy and safety of PARP inhibitors in elderly patients with advanced ovarian cancer: a systematic review and meta-analysis

BackgroundPoly-(ADP-ribose)-polymerase (PARP) inhibitors have shown to be effective as maintenance treatment in patients with advanced ovarian cancer. Although most ovarian cancers develop after age 65, older patients are often under-represented...

Corrected Allele Frequency of BRCA1/2 Mutations Is an Independent Prognostic Factor for Treatment Response to PARP-Inhibitors in Ovarian Cancer Patients.

PARP inhibitors (PARPi) have increased treatment options in ovarian cancer, particularly in patients with BRCA1/2 mutations, although there are still marked differences in the duration of patients’ response to this targeted therapy. BRCA testing is routinely performed in tumor tissue of ovarian cancer patients. The resulting molecular pathological findings include the genetic nomenclature of the mutation, the frequency of the mutated allele (variant allele frequency, VAF), and the tumor cell content. VAF measures the percentage of mutated alleles from the total alleles in the cells of the examined tissue. The aim of this study was to investigate the significance of VAF on the therapeutic response to PARPis in ovarian cancer patients. Epithelial ovarian cancer patients harboring BRCA1/2 tumor mutations, who underwent germline testing and received PARPi therapy at the Medical University of Vienna (n = 41) were included in the study. Corrected VAF (cVAF) was calculated based on VAF, tumor cell content, and germline mutation. Patients were divided into two groups based on their cVAF. Median PFS under PARPi in patients with low cVAF was 13.0 months (IQR [10.3-not reached]) and was not reached in the high cVAF group. High cVAF was significantly associated with longer PFS in the multivariate analysis (HR = 0.07; 95% CI [0.01–0.63]; p = 0.017). In conclusion, high cVAF was associated with a significantly better response to PARPi in this study population.

Shared decision making in frontline maintenance therapy for ovarian cancer: A qualitative assessment (590)

Shared decision making in frontline maintenance therapy for ovarian cancer: A qualitative assessment (590)

Experience with olaparib in a patient with luminal HER2-positive metastatic breast cancer

Hereditary breast cancer (BC) accounts for about 5-10% of cases. BRCA-associated tumors have been identified as a separate group of malignant neoplasms with distinctive clinical manifestations and specific treatment features. Understanding of biological mechanisms leading to cancer in BRCA1/2 mutation carriers and discovery of potential molecular targets, such as poly (ADP-ribose) polymerase (PARP), involved in base excision repair mechanisms, led to the development of a new class of targeted drugs belonging to the PARP inhibitors group. PARP inhibition leads to the preservation of single-stranded DNA breaks, the arrest of the replication fork, and the realization of the “synthetic lethality” phenomenon due to the inability to repair double-stranded DNA breaks by homologous recombination in cells with mutations in the BRCA1/2 genes. Two randomized trials OlympiAD and EMBRACA evaluated and proved the effectiveness of PARP inhibitors in patients with metastatic BRCA-mutated HER2-negative breast cancer in comparison with standard chemotherapy. At the same time, data on the potential use of PARP inhibitors for the treatment of BRCA-mutated HER2-positive breast cancer patients are extremely limited. This article presents a clinical example of the use of olaparib in a patient with BRCA-mutated HER2-positive metastatic breast cancer.

BRCA reversion mutations mediated by microhomology-mediated end joining (MMEJ) as a mechanism of resistance to PARP inhibitors in ovarian and breast cancer.

5559 Background: PARP inhibitors exploit synthetic lethality in tumor cells with deficiency in homologous recombination repair (HRR). In line with this, most reported mechanisms of PARP inhibitor resistance restore HRR. Of multiple resistance mechanisms reported preclinically, reversion mutations in BRCA genes are the only confirmed mechanism of resistance to both platinum and PARP inhibitors in patients (pts) to date (Lin K et al. Cancer Discov 2019), with most studies focusing on ovarian cancer. MMEJ is an alternative DNA damage repair pathway, in which DNA polymerase θ (POLθ) has a key role; MMEJ has been suggested to play a role in BRCA reversion mutations (Tobalina L et al. Ann Oncol 2021). Methods: Targeted circulating tumor DNA (ctDNA) sequencing analyzed over 500 plasma samples collected at baseline and at progression to therapy in pts with ovarian or breast cancer and a mutation in BRCA1 and/or BRCA2 (BRCAm) who were treated with olaparib or chemotherapy in one of three Phase II/III clinical studies (LIGHT NCT02983799, SOLO3 NCT02282020, OlympiAD NCT02000622). Only pts with an original pathogenic BRCAm detected in ctDNA were evaluable. BRCA reversion mutations were identified using internal computational framework; DNA sequences surrounding BRCA reversion sites were analyzed for MMEJ signatures. Results: At baseline, in pooled data across treatment arms and across all available samples, BRCA reversion mutations were detected in 4/114 (3.5%) and 6/133 (4.5%) of breast and ovarian cancer pts, respectively, which may have developed on prior platinum therapy. At progression, BRCA reversion mutations were detected in 34/79 (43%) breast cancer pts and in 26/101 (26%) ovarian cancer pts who received olaparib, with at least 2/79 and 4/101 reversions already present at baseline, respectively. At progression, in the chemotherapy arm, BRCA reversion mutations were detected in 3/34 (9%) breast cancer pts and 1/29 (3%) ovarian cancer pts, with 2/34 and 0/29 reversions present at baseline, respectively. Reversion mutations varied in allelic frequency and were either present as single or multiple reversions, suggesting multiple events within the tumor were driving resistance. The location and type of reversion mutations reflected the functional importance of BRCA protein domains. A large proportion of BRCA reversion mutations (47/69 [68%] that were evaluable) were mediated by the MMEJ pathway based on the presence of MMEJ signatures around BRCA reversion sites. Conclusions: We detected BRCA reversion mutations in at least ̃40% of breast and ̃20% of ovarian cancer pts following treatment with olaparib. A large proportion of these reversion mutations are likely to have been mediated by MMEJ repair, suggesting that POLθ inhibitors in combination with platinum or PARP inhibitors might prevent or delay emergence of PARP inhibitor resistance. Clinical trial information: NCT02983799, NCT02282020, NCT02000622.

PARP inhibitors – a new direction in the treatment of breast and ovarian cancer

Ovarian cancer, like breast cancer, may either develop spontaneously or as a result of a family history. BRCA1 and BRCA2 mutations significantly increase the risk of both cancers at all ages. It is estimated that 3–5% of women are BRCA mutation carriers. BRCA1 mutation carriers have a 65% risk of breast cancer and 39% risk of ovarian cancer. These risks are lower among BRCA2 mutation carriers, i.e. 45% and 11% for breast and ovarian cancer, respectively. In breast and ovarian cancer with BRCA mutations, blocking the function of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2, causes an accumulation of DNA damage that ultimately leads to cancer cell death. Based on this mechanism, PARP inhibitors have been used in the treatment of hereditary neoplasms, in which the proper functioning of DNA damage repair systems is disturbed. In clinical trials to date, PARP inhibitors significantly extended the progression-free survival in patients with confirmed BRCA mutations. Similar results have been obtained for patients without confirmed genetic background. Currently, PARP inhibitors are increasingly approved for use in the treatment of ovarian and breast cancer. From May 2021, the Ministry of Health has reimbursed maintenance therapy with PARP inhibitors in patients with known BRCA mutation status.

Associations with response to Poly(ADP-ribose) Polymerase (PARP) inhibitors in patients with metastatic breast cancer

PARP inhibitors (PARPi) have modest antitumor activity in patients with advanced breast cancer and mutation in BRCA. It is unclear whether some subgroups derive greater benefit from treatment. MEDLINE and EMBASE were searched from inception to March 2021 to identify trials of PARPi in patients with metastatic breast cancer. Objective response rate (ORR) and clinical benefit rate (CBR) to PARPi were extracted and pooled in a meta-analysis using the Mantel Haenszel random effects model. Meta-regression explored the influence of patient and tumor characteristics on ORR and CBR. For randomized trials, hazard ratio comparing PARPi to control therapy were pooled using inverse variance and random effects. Analysis included 43 studies comprising 2409 patients. Among these, 1798 (75%) patients had BRCA mutations and 1146 (48%) were triple negative. In 10 studies (28%; n = 680 patients), the PARPi was given in combination with platinum-based chemotherapy. Weighted mean ORR was 45%; 64% when combined with platinum vs 37% with PARPi monotherapy (p < 0.001). Previous platinum-based chemotherapy was associated with lower ORR (p = 0.02). Compared to standard chemotherapy, progression-free survival was improved (HR 0.64, p < 0.001), but there was no difference in overall survival (HR 0.87, p = 0.06). There were no differences in ORR or CBR between BRCA1 and BRCA2 mutations. PARPi are more active in combination with platinum than as monotherapy, with lower response if given as monotherapy after platinum exposure. Significant improvements in ORR translated to modest improvement in progression-free, but not overall survival. There was no association between ORR and BRCA mutations.