scholarly journals The Development of Rucaparib/Rubraca®: A Story of the Synergy Between Science and Serendipity

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 564 ◽  
Author(s):  
Nicola J Curtin
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Current Position ◽  
Current Application ◽  
Physical Effort ◽  
Final Development ◽  
History Of ◽  
Accelerated Approval ◽  
The Relationship

The poly(ADP-ribose) polymerase (PARP) inhibitor, Rubraca®, was given its first accelerated approval for BRCA-mutated ovarian cancer by the FDA at the end of 2016, and further approval by the FDA, EMA and NICE followed. Scientists at Newcastle University initiated the early stages, and several collaborations with scientists in academia and the pharmaceutical industry enabled its final development to the approval stage. Although originally considered as a chemo- or radiosensitiser, its current application is as a single agent exploiting tumour-specific defects in DNA repair. As well as involving intellectual and physical effort, there have been a series of fortuitous occurrences and coincidences of timing that ensured its success. This review describes the history of the relationship between science and serendipity that brought us to the current position.

scholarly journals Long-Term Follow-Up of a Female Patient Treated with Olaparib—Hope for a Long Life without Relapse?

2021 ◽  
Vol 18 (7) ◽  
pp. 3430
Author(s):  
Mateusz Kozłowski ◽  
Katarzyna Nowak ◽  
Aneta Cymbaluk-Płoska
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitor ◽  
Brca1 Gene ◽  
High Specificity ◽  
Reproductive Organs ◽  
Platinum Based Chemotherapy ◽  
Long Term Follow Up ◽  
History Of ◽  
Advanced Stages

Ovarian cancer is one of the most common cancers of the reproductive organs. As there are no symptoms in the early stages, it is mainly detected in the advanced stages. Even then, the symptoms are non-specific and include, for example, abdominal pain, early satiety, or changes in bowel habits. Both biochemical marker levels and imaging studies are used in the initial diagnosis. However, it should be emphasized that they are not characterized by high specificity. Treatment is multistage, and usually first-line debulking surgery is used followed by platinum-based chemotherapy. Here we present a clinical case of a 56-year-old female, a carrier of a mutation in the BRCA1 gene, with a history of breast cancer and with recurrent epithelial ovarian cancer. The patient was qualified for treatment with a PARP inhibitor and is currently undergoing treatment with olaparib. In the patient’s follow up of 50 months to date, there has been no recurrence of cancer. Few side effects have been observed, and the most serious one that can be effectively treated is anemia. On the basis of the described case, the authors concluded that olaparib treatment is effective, relatively safe, and does not significantly affect daily functioning.

scholarly journals Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: ROSiA Single-Arm Phase 3B Study

2016 ◽  
Vol 27 (1) ◽  
pp. 50-58 ◽  
Author(s):  
Amit M. Oza ◽  
Frédéric Selle ◽  
Irina Davidenko ◽  
Jacob Korach ◽  
Cesar Mendiola ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Single Agent ◽  
Clinical Signs ◽  
Progression Free Survival ◽  
Gynecology And Obstetrics ◽  
Common Grade ◽  
History Of ◽  
Grade 3

ObjectiveThe aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer.Patients and MethodsIn this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator’s choice of 175 mg/m2 q3w or 80 mg/m2 weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety.ResultsBetween December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1–50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7–27.6 months).ConclusionExtended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.

A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6003-6003 ◽  
Author(s):  
Joyce F. Liu ◽  
Mark F. Brady ◽  
Ursula A. Matulonis ◽  
Austin Miller ◽  
Elise C. Kohn ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Primary Endpoint ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Phase Iii ◽  
High Grade ◽  
Primary Analysis ◽  
Open Label ◽  
Platinum Based Chemotherapy

6003 Background: Combination cediranib (C) and olaparib (O) improved progression-free survival (PFS) in patients (pts) with relapsed platinum (plat)-sensitive high-grade ovarian cancer (ovca) compared to O alone in a Phase 2 trial (NCT01116648). We conducted this randomized, open-label Phase 3 trial (NCT02446600) to assess whether combination C+O, or O alone, was superior to standard of care (SOC) plat-based therapy in relapsed plat-sensitive ovca. Methods: Eligible pts had recurrent plat-sensitive [ > 6-month plat-free interval (PFI)] high-grade serous or endometrioid, or BRCA-related, ovca. One prior non-plat therapy and unlimited prior plat-therapies were allowed; prior anti-angiogenics in the recurrent setting or prior PARP inhibitor were exclusions. Pts were randomized 1:1:1 to SOC (carboplatin/paclitaxel; carboplatin/gemcitabine; or carboplatin/liposomal doxorubicin), O (300mg twice daily), or C+O (C 30mg daily + O 200mg twice daily). Randomization was stratified by g BRCA status, PFI (6-12 vs > 12 months), and prior anti-angiogenic therapy. Target sample size was 549 pts; primary analysis occurred 2 years after the last pt enrolled. The primary endpoint was PFS. Type 1 error = 0.025 was controlled by a gatekeeping hierarchy that assessed C+O vs SOC, then O alone vs SOC, and finally C+O vs O. All maintenance therapy was prohibited. Results: Between 4FEB2016 and 13NOV2017, 565 pts enrolled (187 SOC, 189 O, 189 C+O), and 528 pts initiated treatment (166 SOC, 183 O, 179 C+O). 23.7% of patients had g BRCAmut. Median follow-up was 29.1 months. 53 pts on SOC initiated non-protocol therapy (predominantly PARP inhibitor maintenance) before disease progression. The hazard ratio (HR) for PFS was 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail) between C+O and SOC and 1.20 (95% CI 0.93-1.54) between O and SOC, with median PFS of 10.3, 8.2, and 10.4 months for SOC, O, and C+O, respectively. Response rates were 71.3% (SOC), 52.4% (O), and 69.4% (C+O). In gBRCA pts, HR for PFS was 0.55 (95% CI 0.73-1.30) for C+O vs SOC, and 0.63 (95% CI 0.37-1.07) for O vs SOC. In non-g BRCA pts, HR for these comparisons was 0.97 (95% CI 0.73-1.30) and 1.41 (1.07-1.86). No OS differences between arms were observed at 44% events. Pts receiving C+O (vs SOC) had more frequent Grade 3 or higher gastrointestinal (30.1% vs 8.4%), hypertension (31.7% vs 1.8%), and fatigue events (17.5% vs 1.8%). Conclusion: C+O demonstrated similar activity to SOC in relapsed plat-sensitive ovca but did not meet the primary endpoint of improved PFS. Clinical trial information: NCT02446600.

scholarly journals Rucaparib in ovarian cancer: an update on safety, efficacy and place in therapy

2018 ◽  
Vol 10 ◽  
pp. 175883591877848 ◽  
Author(s):  
Graziela Z. Dal Molin ◽  
Kohei Omatsu ◽  
Anil K. Sood ◽  
Robert L. Coleman
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Therapeutic Option ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Free Survival ◽  
Platinum Based Chemotherapy ◽  
Phase Ii And Iii

Rucaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor and potent inhibitor of PARP1, PARP2 and PARP3 enzymes. Phase II and III trials have documented that rucaparib has single-agent antitumor activity in patients with high-grade ovarian carcinoma, with both BRCA-mutated (germline and somatic) and with homologous recombination deficiency (HRD). Rucaparib as a maintenance treatment showed increased progression-free survival in patients with ovarian carcinoma who achieved a response to platinum-based chemotherapy, with an acceptable safety profile. The approval of this drug, along with the companion diagnostic FoundationFocus CDxBRCA test represents an important new therapeutic option in the treatment of ovarian cancer. This article reviews the mechanisms of action, safety, pharmacokinetics and pharmacodynamics and indications for use of rucaparib as well as future trials.

Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer.

1992 ◽  
Vol 10 (4) ◽  
pp. 520-528 ◽  
Author(s):  
D I Jodrell ◽  
M J Egorin ◽  
R M Canetta ◽  
P Langenberg ◽  
E P Goldbloom ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Response ◽  
Performance Status ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Area Under The Curve ◽  
Advanced Ovarian Cancer ◽  
High Dose ◽  
The Relationship ◽  
Carboplatin Auc

PURPOSE The study was undertaken to define the relationship between tumor response and carboplatin area under the curve (AUC) in patients with ovarian cancer; to study the relationship between carboplatin AUC and myelosuppression in the same population; to establish the true impact of carboplatin AUC, prior therapy, and pretreatment platelet and WBC counts on toxicity; and to define an optimal carboplatin exposure for treating patients with ovarian cancer. METHODS With the equation AUC = dose/(glomerular filtration rate [GFR]+25), carboplatin AUC (course 1) was calculated for 1,028 patients (450 previously untreated) who received single-agent carboplatin (40 to 1,000 mg/m2) for advanced ovarian cancer. GFR was measured (chromium-51-edathamil [51Cr-EDTA] or creatinine clearance) in all patients. RESULTS Regression analysis showed that carboplatin AUC, prior treatment, and Eastern Cooperative Oncology Group grade performance status (PS) are predictors of tumor response, thrombocytopenia, and leukopenia. Pretreatment platelet and WBC counts are additional predictors of thrombocytopenia and leukopenia, respectively. Although the likelihood of tumor response increased with increasing carboplatin AUC, this relationship was nonlinear. In all patient subsets, the likelihood of complete response (CR) or overall response did not increase significantly above a carboplatin AUC of 5 to 7 mg/mL x minutes. At any given carboplatin AUC, thrombocytopenia occurred more frequently than leukopenia, although both approached 100% as carboplatin AUC increased. Both thrombocytopenia and leukopenia were more frequent in pretreated than in untreated patients regardless of pretreatment count. At any carboplatin AUC, the influence of PS on likelihood of response and toxicity was profound. CONCLUSION Carboplatin dosing by AUC will lead to more predictable toxicity, and increasing carboplatin AUC above 5 to 7 mg/mL x minutes does not improve the likelihood of response but does increase myelotoxicity. Therefore, careful evaluation of high-dose carboplatin therapy in a prospective, randomized trial is needed before such treatment becomes accepted practice.

scholarly journals PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

2017 ◽  
Vol 9 (4) ◽  
pp. 253-267 ◽  
Author(s):  
Tarra Evans ◽  
Ursula Matulonis
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Biologic Agent ◽  
Ovarian Cancer Cells ◽  
Antiangiogenic Agents ◽  
Brca Mutations

Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP inhibitors have been identified. As single agents, PARP inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present. PARP inhibitors have also been combined with chemotherapy, however, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations has hampered development of these combinations. Contrariwise, PARP inhibitor and biologic agent combinations, specifically antiangiogenic agents, appear well tolerated and show promising activity in both BRCA mutated ( BRCAm) and BRCA wild-type ( BRCAwt) cancers. Currently, multiple clinical trials are underway examining the antitumor activity of PARP inhibitor combination therapy.

scholarly journals Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Renata Colombo Bonadio ◽  
Maria del Pilar Estevez-Diz
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Current Knowledge ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Treatment Resistance ◽  
Parp Inhibitors ◽  
Wild Type ◽  
Inhibitor Activity ◽  
Secondary Resistance

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors’ efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

The relationship of the scleractinian corals to the rugose corals

Paleobiology ◽  
1980 ◽  
Vol 6 (02) ◽  
pp. 146-160 ◽  
Author(s):  
William A. Oliver
Keyword(s):  
Critical Points ◽  
Scleractinian Corals ◽  
Convincing Evidence ◽  
Early Triassic ◽  
Rugose Corals ◽  
History Of ◽  
The Subject ◽  
Relationship Of ◽  
The Relationship ◽  
Biologic Factors

The Mesozoic-Cenozoic coral Order Scleractinia has been suggested to have originated or evolved (1) by direct descent from the Paleozoic Order Rugosa or (2) by the development of a skeleton in members of one of the anemone groups that probably have existed throughout Phanerozoic time. In spite of much work on the subject, advocates of the direct descent hypothesis have failed to find convincing evidence of this relationship. Critical points are:(1) Rugosan septal insertion is serial; Scleractinian insertion is cyclic; no intermediate stages have been demonstrated. Apparent intermediates are Scleractinia having bilateral cyclic insertion or teratological Rugosa.(2) There is convincing evidence that the skeletons of many Rugosa were calcitic and none are known to be or to have been aragonitic. In contrast, the skeletons of all living Scleractinia are aragonitic and there is evidence that fossil Scleractinia were aragonitic also. The mineralogic difference is almost certainly due to intrinsic biologic factors.(3) No early Triassic corals of either group are known. This fact is not compelling (by itself) but is important in connection with points 1 and 2, because, given direct descent, both changes took place during this only stage in the history of the two groups in which there are no known corals.

Investigating the Relationship Between Self-Esteem and Stigma Among Young Adults With History of Suicide Attempts

Crisis ◽  
2016 ◽  
Vol 37 (4) ◽  
pp. 265-270 ◽  
Author(s):  
Meshan Lehmann ◽  
Matthew R. Hilimire ◽  
Lawrence H. Yang ◽  
Bruce G. Link ◽  
Jordan E. DeVylder
Keyword(s):  
Young Adults ◽  
Suicide Attempts ◽  
Self Esteem ◽  
High Risk Population ◽  
High Functioning ◽  
People With Mental Illness ◽  
History Of ◽  
The Individual ◽  
The Impact ◽  
The Relationship

Abstract. Background: Self-esteem is a major contributor to risk for repeated suicide attempts. Prior research has shown that awareness of stigma is associated with reduced self-esteem among people with mental illness. No prior studies have examined the association between self-esteem and stereotype awareness among individuals with past suicide attempts. Aims: To understand the relationship between stereotype awareness and self-esteem among young adults who have and have not attempted suicide. Method: Computerized surveys were administered to college students (N = 637). Linear regression analyses were used to test associations between self-esteem and stereotype awareness, attempt history, and their interaction. Results: There was a significant stereotype awareness by attempt interaction (β = –.74, p = .006) in the regression analysis. The interaction was explained by a stronger negative association between stereotype awareness and self-esteem among individuals with past suicide attempts (β = –.50, p = .013) compared with those without attempts (β = –.09, p = .037). Conclusion: Stigma is associated with lower self-esteem within this high-functioning sample of young adults with histories of suicide attempts. Alleviating the impact of stigma at the individual (clinical) or community (public health) levels may improve self-esteem among this high-risk population, which could potentially influence subsequent suicide risk.

Sign in / Sign up

Export Citation Format

Share Document