Annals of Pharmacotherapy

Effect of PARP Inhibitors as Maintenance Treatment on Restricted Mean Survival Time in Platinum-Sensitive Recurrent Ovarian Cancer: A Systematic Review and Meta-analysis

Background Earlier trials on the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in platinum-sensitive relapsed ovarian cancer used the hazard ratio (HR) as an efficacy parameter. Objective The present meta-analysis was focused on improving the robustness and clinical interpretability of the efficacy evaluation of PARP inhibitors using the restricted mean survival time (RMST). Methods A search for relevant studies published up to July 31, 2020, was performed in electronic databases to identify eligible trials comparing PARP inhibitors with placebo. The difference in RMST was used as a PARP inhibitor efficacy parameter. Combined differences in RMST with 95% CIs across studies were calculated using a random-effects model. Results Four trials (6 articles) were assessed, including 1079 patients treated with PARP inhibitors and 598 with placebo. The combined RMST differences for up to 360 days (PARP inhibitors minus placebo: point estimate and 95% CI) among all patients and the patients of subgroups with BRCA mutations, homologous recombination-deficient (HRD) carcinoma, and BRCA wild-type carcinoma were 87 days (95% CI = 71, 102), 112 days (95% CI = 96, 129), 99 days (95% CI = 80, 119), and 69 days (95% CI = 47, 92), respectively. The combined RMST differences for up to 660 and 720 days were also larger among patients with BRCA mutations than among those with HRD carcinoma. Conclusion and Relevance Based on using the RMST difference as an alternative measure to the HR, this meta-analysis suggests that PARP inhibitors are the most effective for patients with BRCA mutations, followed by patients with HRD carcinoma.

A Review of Tisotumab Vedotin-tftv in Recurrent or Metastatic Cervical Cancer

Objective: To evaluate the safety and efficacy of tisotumab vedotin-tftv (TV), a first-in-class vectorized anti-tissue factor (TF) antibody-drug conjugate (ADC), for the treatment of recurrent or metastatic cervical cancer. Data Sources: A literature search of ClinicalTrials.gov, Embase, and PubMed was conducted using the terms tisotumab vedotin AND cervical cancer from inception to June 30, 2022. Study Selection and Data Extraction: All applicable publications, package inserts, meeting abstracts, and clinical trials involving TV in the treatment of cervical cancer were reviewed. Data Synthesis: TV is a fully human TF-specific monoclonal antibody conjugated to monomethyl auristatin E, which serves as a highly potent cytotoxic payload. In the pivotal phase II InnovaTV 204 clinical trial, TV demonstrated an objective response rate of 24% (95% confidence interval [CI], 16%-33%). The mean duration of response was 8.3 months. Common toxicities included abdominal pain, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, dry eye, epistaxis, nausea/vomiting, and peripheral neuropathy. Unique and/or serious adverse events warranting careful monitoring include ocular complications, hemorrhaging, peripheral neuropathies, fetal-embryo toxicity, pneumonitis, and immunogenicity. Relevance to Patient Care and Clinical Practice: Recurrent or metastatic cervical cancer remains a high-risk disease with limited treatment options. Using ADCs to target tumors with aberrant expression of TF appears to be a viable treatment strategy. Conclusions: TV is the first Food and Drug Administration–approved TF-directed ADC. With a manageable safety profile and promising anticancer activity, TV warrants consideration as a novel targeted agent for the treatment of recurrent or metastatic cervical cancer. Further studies are required to determine the optimal place in therapy for TV.

Niraparib for the Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Objective: To review the efficacy and safety of niraparib for the treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (OC, FTC, and PPC). Data Sources: A literature search via MEDLINE through PubMed from August 2013 to January 2020 was performed using the key terms niraparib, PARP inhibitors, ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. Study Selection and Data Extraction: Completed and ongoing trials were identified through a review of the website trial registry https://www.clinicaltrials.gov . Data Synthesis: In a phase III, double-blind clinical trial, progression-free survival improved in patients treated with niraparib compared with placebo as maintenance treatment for patients with platinum-sensitive, recurrent OC: 21 versus 5.5 months in the germline breast cancer susceptibility gene ( gBRCA) cohort (hazard ratio [HR] = 0.27; 95% CI = 0.17 to 0.41; P < 0.001) and 9.3 versus 3.9 months in the overall nongermline breast cancer susceptibility gene (non- gBRCA) cohort (HR = 0.45; 95% CI = 0.34 to 0.61; P < 0.001). Adverse events included thrombocytopenia and anemia. Relevance to Patient Care and Clinical Practice: Poly (ADP-ribose) polymerase (PARP) inhibitors have gained a place in the therapeutic management of OC, FTC, and PPC because of their ability to suppress growth of homologous recombination deficiency–positive tumors, including those with BRCA1/2 mutations. Niraparib inhibits the DNA repair mechanism vital to the survival of cancer cells, poly-ADP ribose polymerase. Conclusions: PARP inhibitors can be used as a single agent for maintenance therapy for platinum-sensitive recurrent disease in patients with partial or complete response following 2 or more rounds of platinum-based therapy.

Real-World Efficacy and Safety of PARP Inhibitors in Recurrent Ovarian Cancer Patients With Somatic BRCA and Other Homologous Recombination Gene Mutations

Background: Real-world data regarding the use of poly (ADP-ribose) polymerase (PARP) inhibitors in recurrent ovarian cancer patients with non-BRCA homologous recombination (HR) mutations or somatic BRCA mutations are lacking. Objective: The purpose of our study is to evaluate the response rate, duration of treatment, time to progression (TTP), and toxicities of olaparib, niraparib, and rucaparib in somatic BRCAm and non-BRCA HR-mutated patients. Methods: This was a retrospective study using the electronic medical record to identify patients across our health system who were initiated on a PARP inhibitor for ovarian cancer between December 2014 and December 2019. Patients were screened for the presence of a somatic BRCA1/2 mutation or a mutation in non-BRCA HR genes. Data were collected via chart review. Results: For the efficacy analysis, 8 patients had somatic BRCA mutations and 12 patients had HR mutations. The overall response rate (ORR) was 50% for BRCA-mutated (BRCAm) patients and 9.1% for non-BRCA HR-mutated (non-BRCA HRm) patients. 72.7% of patients with non-BRCA HR mutations had stable disease. The duration of therapy ranged from 2 to 66 months. The median TTP was 9.5 months. Overall, 66.7% of patients in the entire cohort started on a reduced dose of PARP inhibitor. Dose reductions due to AEs were observed in 52.4% of patients, while AEs requiring treatment interruption occurred in 61.9%. Conclusion and Relevance: We found that PARP inhibitors provided stable disease in a high proportion of recurrent ovarian cancer patients who had pathogenic HR mutations, with toxicities comparable to major trials. Patients with non-BRCA HR and somatic BRCA mutations could benefit from PARP inhibitors.

A Randomized Controlled Trial Plus a Systematic Review and Meta-Analysis of Published Studies Evaluating a Conventional Prophylactic Regimen of Oral Dexamethasone vs Short-Course Intravenous Dexamethasone in Preventing Paclitaxel-Associated Hypersensitivity Reactions in Patients With Gynecologic Malignancies

Background: Hypersensitivity reactions (HSRs) are often encountered in patients receiving paclitaxel infusions. The conventional method, comprising dexamethasone 20 mg (Dex20) taken 12 and 6 hours before paclitaxel plus histamine (H)1 and H2-antagonists administered 30 minutes before paclitaxel, is an effective but cumbersome method in reducing HSRs in gynecologic oncology patients. Objective: Determine the effectiveness of a simplified premedication method (short-course) comprising Dex20 and H1 and H2 antagonists administered 30 minutes before paclitaxel vs the conventional method in preventing HSRs. Methods: The effectiveness of the short-course vs the conventional method was investigated via a Randomized Controlled Trial (RCT) and a Systematic Review and Meta-analysis by searching PubMed, EMBASE, and the Cochrane Library from inception to December 4, 2024. Primary outcomes were any-grade and grade ≥3 HSRs. Differences in effectiveness were presented as risk difference (RD) using the Mantel–Haenszel estimation and expressed with 95% confidence intervals (CIs). P -values <0.05 were considered statistically significant. The Cochrane Handbook for Systematic Reviews and Newcastle-Ottawa Score determined the quality of RCTs and observational studies. Results: Three RCTs and 2 observational studies totaling 905 patients were analyzed. The short-course method showed a significantly higher incidence of any-grade HSRs than the conventional method (RD = 7%, 95% confidence interval [CI] = 0.3% to 12.8%, P = 0.04). Although in favor of the conventional method, there was no significant difference in grade ≥3 HSRs (RD = 2%, 95% CI = −0.4% to 4.8%, P = 0.09). Subgroup analyses of RCTs showed no significant differences in any-grade HSRs (RD = 6%, 95% CI = 0.3% to 12.8%, P = 0.39) or grade ≥3 HSRs (RD = 1%, 95% CI = −1.1% to 2.4%, P = 0.48). Conclusion and relevance: The conventional method is favored over the short-course in preventing paclitaxel-associated HSRs. The short-course method is a plausible alternative for patients unable to comply with the conventional method’s requirements. Included studies were either observational studies prone to bias and inconclusive inferences or RCTs, which may not be statistically powerful enough to produce reliable results. Larger sample size prospective studies are needed to authenticate findings.