Niraparib in ovarian cancer: results to date and clinical potential

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

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Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review

Diagnostics ◽

10.3390/diagnostics9030087 ◽

2019 ◽

Vol 9 (3) ◽

pp. 87 ◽

Cited By ~ 24

Author(s):

Stergios Boussios ◽

Peeter Karihtala ◽

Michele Moschetta ◽

Afroditi Karathanasi ◽

Agne Sadauskaite ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Synthetic Lethality ◽

Excision Repair ◽

Parp Inhibitor ◽

Advanced Ovarian Cancer ◽

Pegylated Liposomal Doxorubicin ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Biologic Agent

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

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PARP inhibitors in the treatment of metastatic breast cancer patients with germline BRCA1/2 mutations. Experience of treatment with talazoparib in clinical practice

Medical Council ◽

10.21518/2079-701x-2020-9-57-61 ◽

2020 ◽

pp. 57-61

Author(s):

M. A. Frolova ◽

E. V. Glazkova ◽

M. B. Stenina

Keyword(s):

Breast Cancer ◽

Homologous Recombination ◽

Base Excision Repair ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Synthetic Lethality ◽

Excision Repair ◽

Parp Inhibitors ◽

Phase Iii ◽

Base Excision

Germline BRCA1/2 mutations account for about 10% of all breast cancer. BRCA1/2 proteins are involved in homologous recombination - DNA double-strand break repair mechanism. Poly-(ADP ribose) polymerases (PARP) are required to repair DNA single-strand breaks through base excision repair. PARP inhibitors represent a modern option of treatment of metastatic HER2 negative breast cancer with germline BRCA1/2 mutations. Mechanism of action of PARP inhibitors is based on the concept of synthetic lethality under conditions of BRCA dysfunction, when both DNA repair mechanisms, homologous recombination and base excision repair, are impaired. This leads to the apoptosis of cancer cells. Currently two PARP inhibitors are registered in Russia for the treatment of BRCA-associated metastatic HER2 negative breast cancer – olaparib and talazoparib. Efficacy of PARP inhibitors olaparib and talazoparib versus standard chemotherapy has been studied in very similarly designed phase III trials OlympiAD и EMBRACA. Benefit in the progression free survival, acceptable toxicity profile and positive impact on quality of life support inclusion of PARP inhibitors in treatment schemes of metastatic BRCAassociated breast cancer. Very important is the role of PARP inhibitors in treatment of very aggressive triple negative breast cancer with limited number of effective therapy options. We represent here a clinical case of treatment of metastatic triple negative breast cancer with talazoparib in 4th line of therapy.

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FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Cancers ◽

10.3390/cancers13081866 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1866

Author(s):

Katia A. Mesquita ◽

Reem Ali ◽

Rachel Doherty ◽

Michael S. Toss ◽

Islam Miligy ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

High Throughput Screening ◽

Nuclear Translocation ◽

Synthetic Lethality ◽

Excision Repair ◽

Progression Free Survival ◽

Ovarian Cancer Cells ◽

Physical Interaction ◽

Base Excision

FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy.

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First-line PARP inhibitors in ovarian cancer: summary of an ESMO Open - Cancer Horizons round-table discussion

ESMO Open ◽

10.1136/esmoopen-2020-001110 ◽

2020 ◽

Vol 5 (6) ◽

pp. e001110

Author(s):

Susana Banerjee ◽

Antonio Gonzalez-Martin ◽

Philipp Harter ◽

Domenica Lorusso ◽

Kathleen N Moore ◽

...

Keyword(s):

Ovarian Cancer ◽

Maintenance Therapy ◽

Parp Inhibitor ◽

Advanced Ovarian Cancer ◽

Round Table ◽

Parp Inhibitors ◽

Phase Iii ◽

European Medicines Agency ◽

First Line ◽

Phase Iii Trials

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer.

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Poly-(ADP-ribose) polymerase inhibitors: paradigm shift in the first-line treatment of newly diagnosed advanced ovarian cancer

Pharmacogenomics ◽

10.2217/pgs-2019-0178 ◽

2020 ◽

Vol 21 (10) ◽

pp. 721-727

Author(s):

Fady Gh Haddad ◽

Elias Karam ◽

Elissar Moujaess ◽

Hampig Raphael Kourie

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Excision Repair ◽

Advanced Ovarian Cancer ◽

Progression Free Survival ◽

Parp Inhibitors ◽

First Line ◽

Free Survival ◽

Base Excision ◽

Breast Cancer Gene

Debulking surgery associated with chemotherapy represent the backbone of ovarian cancer therapy. Adding bevacizumab has improved survival. Recently, PARP inhibitors were added in the first line as maintenance treatment for the patients who achieve a complete or partial response. These drugs act by blocking the activity of the PARP enzyme responsible for base-excision repair, and have shown positive responses when used for tumors lacking homologous recombination. Olaparib, niraparib and veliparib were evaluated and showed an increase in the duration of progression-free survival: 22.1 months (hazard ratio [HR] = 0.59), 13.8 (HR = 0.62) and 23.5 (HR = 0.68) with olaparib, niraparib and veliparib, respectively. This review describes the benefit of PARP inhibitors as maintenance therapy and discusses the efficacy according to breast cancer gene and homologous recombination status.

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Poly adenosine diphosphate ribose polymerase inhibitors maintenance in patients with ovarian cancer: A systematic review and meta-analysis of randomized controlled trials.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17081 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17081-e17081

Author(s):

Thura WIN Htut ◽

Aung Tun ◽

Anita Sultan ◽

Sriman Swarup ◽

Myo Zaw ◽

...

Keyword(s):

Ovarian Cancer ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Adenosine Diphosphate ◽

Parp Inhibitors ◽

The Other ◽

Phase Iii ◽

Controlled Trials ◽

Randomized Controlled ◽

Platinum Based Chemotherapy

e17081 Background: Ovarian cancer is the deadliest of gynecologic cancers and many recur despite achieving a clinical response to initial platinum-based chemotherapy. The use of poly adenosine diphosphate ribose polymerase (PARP) inhibitors maintenance has shown to improve survival in ovarian cancer. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2019 were queried. Phase 3 randomized controlled trials (RCT) which employed PARP inhibitors maintenance in ovarian cancer were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to some heterogeneity among studies. Results: Four phase III RCTs with a total of 1792 patients were eligible. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. The randomization ratio was 2:1 in all studies. Participants were sensitive to platinum-based chemotherapy, as newly diagnosed in SOLO-1 trial and had been previously on two such regimens in the other trials, with an objective response. Almost all patients in the SOLO-2 and SOLO-1 trials had a gBRCA mutation, while there were patients with and without the said mutation in the other two studies. The pooled HR for PFS was statistically significant at 0.32 (95% CI: 0.27-0.38; P < 0.0001), including gBRCA cohort (HR, 0.28; 95% CI: 0.24-0.33; P < 0.0001) and non-gBRCA cohort (HR, 0.39; 95% CI: 0.32-0.48; P < 0.0001). Conclusions: Our meta-analysis demonstrated that the use of maintenance therapy with PARP inhibitors significantly improved PFS compared to placebo, regardless of the presence or absence of gBRCA mutation.

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Risk of secondary hematologic malignancies and tolerability in patients with ovarian cancer treated with PARP inhibitors: A systematic review and meta-analysis of four phase III randomized controlled trials.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e23056 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e23056-e23056

Author(s):

Kyaw Zin Thein ◽

Somedeb Ball ◽

Anita Sultan ◽

Sriman Swarup ◽

Myo Zaw ◽

...

Keyword(s):

Ovarian Cancer ◽

Synthetic Lethality ◽

Meta Analysis ◽

Group Versus ◽

Hematologic Malignancies ◽

Parp Inhibitors ◽

Phase Iii ◽

Control Group ◽

Study Group ◽

Significant Drop

e23056 Background: Poly adenosine diphosphate ribose polymerase (PARP) inhibitors have shown to improve survival in ovarian cancer (OC) through synthetic lethality with potentiation of double-strand breaks in tumor cells. Yet, there are concerns of secondary hematologic malignancies (SHM) and notable adverse events (AE) leading to treatment discontinuation (TD), interruption (TI), or dose reduction (DR). Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2019 were queried. Phase 3 RCTs utilizing PARP inhibitors maintenance in OC were eligible. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: A total of 1792 patients from four phase III RCTs were included. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. Almost all patients in the SOLO-2 & -1 trials had a gBRCA mutation, while there were patients with and without the said mutation in the other two studies. The SHM incidence was 1.25% in PARP inhibitors group vs 0.83% in control group (RR, 1.15; 95% CI: 0.41–3.22, p = 0.79). TI due to AE was 59.71% in study group versus 11.39% in control arm (RR, 4.94; 95% CI: 2.44 – 9.96, P < 0.001). DR was reported in 47.73% in PARP inhibitors arm versus 6.86% in control group (RR, 7.73; 95% CI: 4.17 – 14.31, P < 0.001). TD rate was 10.97% higher in study group compared to control arm (RR, 6.63; 95% CI: 3.55 – 11.31, P < 0.001). Conclusions: The risk of SHM was not significantly increased in PARP inhibitors group. However, patients on PAPR inhibitors arm experienced significant drop outs due to AE, despite showing significant improvement in PFS in studies. Proper supportive care may enhance compliance.

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Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6002 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6002-6002 ◽

Cited By ~ 21

Author(s):

Andres Poveda ◽

Anne Floquet ◽

Jonathan A. Ledermann ◽

Rebecca Asher ◽

Richard T. Penson ◽

...

Keyword(s):

Ovarian Cancer ◽

Brca Mutation ◽

Parp Inhibitor ◽

Phase Iii ◽

Tolerability Profile ◽

Platinum Sensitive ◽

Platinum Based Chemotherapy ◽

Long Term Treatment

6002 Background: SOLO2 (ENGOT ov-21; NCT01874353) showed that maintenance therapy with the PARP inhibitor olaparib in pts with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (BRCAm) led to a statistically significant improvement in median progression-free survival (PFS) of 13.6 months vs placebo (hazard ratio [HR] 0.30). Time to second progression or death significantly improved (Pujade-Lauraine et al Lancet Oncol 2017) and a quality-adjusted PFS benefit was seen (Friedlander et al Lancet Oncol 2018) with maintenance olaparib vs placebo. We report the preplanned final OS analysis for SOLO2. Methods: Pts with PSROC and a BRCAm who had received ≥2 lines of treatment and were in response to their most recent platinum-based chemotherapy received maintenance olaparib (300 mg bid tablets) or placebo. Pts were stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6–12 months vs >12 months). OS was a secondary endpoint. The only preplanned OS sensitivity analysis was an OS analysis in the Myriad germline BRCAm subset (Myriad BRAC Analysis test). Results: At final data cut-off (Feb 3, 2020), median follow-up was 65 months in both treatment arms. A long-term treatment benefit was seen with olaparib vs placebo with an OS HR of 0.74 (95% confidence interval [CI] 0.54–1.00) in the full analysis set (FAS; unadjusted for crossover; 38.4% of placebo pts crossed over to a PARP inhibitor) (Table). At 5 years: by Kaplan-Meier estimates, 28.3% of pts in the olaparib arm vs 12.8% of pts in the placebo arm were alive and had still not received subsequent treatment; 42.1% of olaparib pts vs 33.2% of placebo pts were alive. The long-term tolerability profile of olaparib was generally consistent with that reported previously. Conclusions: In the final analysis of SOLO2, maintenance olaparib provided an unprecedented improvement of 12.9 months in median OS vs placebo. This is the first study with olaparib tablets, and the first since Study 19 (NCT00753545), to provide long-term follow-up and final OS data in pts with PSROC and a BRCAm. Clinical trial information: NCT01874353. [Table: see text]

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Real-world clinical practice: Toxicities of maintenance PARP inhibitors in recurrent ovarian cancer—The Royal Marsden experience.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18770 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18770-e18770

Author(s):

Zohra Ali ◽

Laura Appadu ◽

Ellen Kitetere ◽

Julian Wampfler ◽

Dorothy Yang ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Practice ◽

Maintenance Therapy ◽

Real World ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Routine Clinical Practice ◽

Phase Iii ◽

Low Grade ◽

Starting Dose

e18770 Background: Maintenance therapy with PARP inhibitors (PARPi) in recurrent high grade ovarian cancer is standard of care for patients who have responded to second or subsequent lines of platinum-based chemotherapy. The increased access to PARP inhibitors (Olaparib, Niraparib and Rucaparib) has provided the opportunity to explore the real-world toxicities in routine clinical practice, toxicity management and the consequent impact on maintenance therapy outcomes. Methods: Patients with relapsed ovarian cancer that received maintenance PARP inhibitor therapy in routine clinical practice between April 2015 and April 2020 were identified. Electronic patient records were reviewed retrospectively to retrieve details of any reported toxicities (occurring at any time during therapy) and their management. Data was entered into and analysed in a Microsoft Excel spreadsheet. Results: 99 patients who received second or subsequent line maintenance PARPi therapy were included (median age 63.6 years). 36% had a germline BRCA1/2 mutation, 6% had a somatic BRCA1/2 mutation and 58% were BRCA wild-type. 69% received 2nd line maintenance therapy; 22% and 9% received a maintenance PARP inhibitor following 3rd or 4+ line therapy respectively. 56% had not received previous maintenance therapy; 43% had received Bevacizumab. 48% patients commenced maintenance therapy at full dose. 13% of patients experienced no toxicities. 60% of patients experienced G1-2 toxicities, with 42% experiencing >2 episodes; most common toxicities were fatigue, nausea/vomiting and thrombocytopenia. 26% of patients experienced >G3 toxicity, with 9% experiencing >2 episodes, 4% of which were recurring toxicities; most common toxicities were hypertension, neutropenia and anaemia. 64% of patients developed toxicity within the first cycle of treatment; 39% had a dose interruption, 56% of which were < 2 weeks duration. 59% patients required a dose reduction from their starting dose due to toxicities. There was no significant difference in median PFS between patients who had been dose reduced compared to those who received full starting dose (p > 0.05). Conclusions: In keeping with phase III clinical trials, our real-world experience is that most PARPi toxicities are low grade and occur early in treatment. Toxicities can be effectively managed with brief dose interruptions and dose reductions, without adverse impact on survival outcomes.

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Clinical Benefit With PARP Inhibitor for Pathogenic Germline FANCA-mutated Relapsed Epithelial Ovarian Cancer: a Case Report

10.21203/rs.3.rs-551734/v1 ◽

2021 ◽

Author(s):

Bing Qian ◽

Jin Lu ◽

Wenshu Leng ◽

Zhengqing Yan ◽

Shiqing Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Benefit ◽

Parp Inhibitor ◽

Susceptibility Gene ◽

Radical Resection ◽

Parp Inhibitors ◽

Fanconi Anaemia ◽

Platinum Based Chemotherapy ◽

Patient Consent ◽

Recombination Pathway

Abstract Background: PARP inhibitors have been approved as targeted therapy for BRCA-deficient metastatic ovarian cancer (OC). Fanconi anemia complementation group A (FANCA) is one of Fanconi anaemia-related genes and a susceptibility gene to breast and OC. However, whether germline FANCA-mutated relapsed epithelial OC could achieve clinical benefit from the treatment of PARP inhibitor is still unclear. Case presentation: A 49-year-old female patient was diagnosed with epithelial OC and underwent resection and first-line of platinum-based chemotherapy in 2016. After first recurrence, she underwent radical resection and received second-line of platinum-based chemotherapy in 2018. After the second relapse in July 2019, the patient underwent radical resection and the corresponding tumor tissue DNA suffered next generation sequencing (NGS) analysis revealed a germline FANCA mutation. Subsequently, the third-line treatment of liposomal doxorubicin hydrochloride plus lobaplatin was administrated for five cycles with patient consent and then oral niraparib (200 mg daily) was administered for maintenance treatment. During the follow-up, no evidence of tumor recurrence was observed. Currently, the PFS already exceeded 21 months and the treatment is still going on. Conclusions: This case highlighted that OC patients harboring with pathogenic gene alterations in homologous recombination pathway might achieved clinical benefit from PARP inhibitors, which should be confirmed in further studies.

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