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Beyond https://adprun.net/, other PARPi that have been tested or are currently being tested in clinical trials for EOC include veliparib, niraparib, rucaparib, talazoparib and iniparib. Secondary mutations that restore BRCA1 and BRCA2 also predict platinum and PARPi resistance in the clinical setting. It seems that approximately 45 % of recurrent platinum-resistant BRCA1/2-mutated EOCs have secondary somatic mutations. It is now well established that gBRCAm EOC have a relatively distinct clinical behavior characterised by an earlier age at diagnosis, improved survival, visceral distribution of disease, higher response rates to platinum and certain non-platinum chemotherapy agents and sensitivity to PARPi [85–87]. Coleman et al. evaluated the use of single agent veliparib in relapsed EOC in a phase II trial.
- It is clear that if the indication for PARPi is to expand into a BRCA-wild type population, robust tests with a high probability of determining HRD status are needed [89–92].
- A total of 830 lesions were reviewed during this study, of which 193 (23.3%) were shown to demonstrate RDR on restaging assessments during PARP inhibitor treatment when compared to baseline imaging; new lesions occurring while on treatment compared to baseline were also included in this study.
- Prior malignancies that have been surgically resected and show no evidence of disease are acceptable.
Radiographic evaluations to assess the extent of disease were conducted every 9 weeks after day 1 of cycle 1 during study treatment and/or at any time when progression of disease was suspected. After 1 year of radiographic assessments, patients had imaging performed every 12 weeks until disease progression. If a patient discontinued treatment for a reason other than disease progression, death, withdrawal of consent, or loss to follow-up, scans and cancer antigen-125 testing continued at the specified intervals. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Sixty-two patients with ovarian carcinoma were enrolled in this open-label, single-arm phases 1 and 2 study.
Cancer Res.
No new safety signals were observed with the combination treatment of niraparib and pembrolizumab compared with the safety profiles of either drug as monotherapy. Fourteen patients in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, years]). The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. Only patients who received PARP inhibitors at biologically active monotherapy doses and who were assessed for response to therapy in these phase I clinical trials were entered into this study.
The first patient was noted to have pancytopenia during week 2, which was treated with filgrastim and was ongoing at the time of the patient’s death from PD during week 7. The second patient had a history of grade 2 anemia at baseline, which changed to grade 3 anemia following lymphodepletion and resolved to grade 2 on week 4. However, from week 5 until week 11 of the interventional phase, the patient had intermittent grade 3 anemia possibly related to the patient’s prior lymphodepletion and subsequent comorbidities. The third patient was noted to have pancytopenia on week 3, thought to be related to lymphodepletion and ADP-A2M10.
Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer
Fifty-nine patients with ovarian carcinoma discontinued treatment because of radiologic disease progression in 41, clinical disease progression in 8, an adverse event in 5, patient request in 4, and a move out of the country in 1 . The primary objectives of phase 1 were to establish the RP2D and dosing schedule of the niraparib and pembrolizumab combination and to evaluate DLTs during the first cycle of treatment. The primary objective of phase 2 was to estimate the clinical activity of combination treatment with niraparib and pembrolizumab in terms of objective response rate (ORR; the best of complete or partial responses) assessed by the investigators using RECIST 1.1. Secondary end points included duration of response, disease control rate , and progression-free survival, all by RECIST 1.1, and overall survival. Correlation of tumor BRCA mutation status and HRD status with other immune-related biomarkers and with efficacy outcomes were exploratory end points. RECIST 1.1 remains the standard criteria for antitumor response assessment in clinical trials.
- Therefore, the approval of olaparib in the maintenance setting in Europe and metastatic setting in the US for patients with deleterious BRCAm in EOC is just the tip of the iceberg for the utilization for this class of agents.
- After 4–6 cycles of combination treatment, patients in the experimental arm continued olaparib monotherapy 400 mg twice daily until disease progression or toxicity.
- Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis.
- The emergence of the DNA repair pathway as a rational target in various cancers led to the development of the PARP inhibitors .
- This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future.
- Furthermore, patients with BRCA1 mutation cancers had worse TTP and OS compared to those with BRCA2 mutation cancers, and our data suggest that this could potentially be related to an increased incidence of RDR.
- To date, the safety profile of afami-cel has been favorable, with mainly low-grade cytokine release syndrome and tolerable/reversible hematologic toxicities.
Patients in whom no germline BRCA1/2 testing was performed were classified as “BRCA1/2 status unknown”. Detailed family history of any known cancer was recorded for all patients, as well as a past history of other primary tumors. For the purposes of this study, patients were classified into two categories as either germline BRCA1/2 mutation carriers, or germline BRCA1/2 wildtype/unknown . Germline BRCA testing should be offered to all patients with ovarian cancer, regardless of age and family history, and additional biological and clinical investigations are strongly warranted to identify patients with this subset of tumors. The clinical relevance of the observations was assessed in a clinical trial published in 2011, which demonstrated efficacy of olaparib in a series of patients with sporadic, BRCA wild-type EOC, albeit at a slightly lower level (24 %) and confined mainly to patients with platinum-sensitive disease .
Trial design
In cell lines, secondary somatic mutations in BRCA1- or BRCA2-mutant cancer cells can restore protein expression, reconstitute HR, and confer resistance to PARPi and platinum. The first demonstration of clinically meaningful activity of a PARPi in EOC patients without a gBRCAm was provided by Gelmon et al. in a phase II study which included patients with HGS/undifferentiated OC with unknown BRCA status or BRCA-negative treated with olaparib. Olaparib has been evaluated, vs placebo, as maintenance therapy in patients with recurrent platinum-sensitive EOC, fallopian tube cancer and primary peritoneal cancer.
While in triple-Durable Responses With Adp iniparib showed interesting results in a phase II trial , not confirmed in the phase III , in EOC addition of iniparib did not reached positive results [72–74]. Among the patients in the part A, 29 showed mutations in BRCA 1 or BRCA2. Twenty of these 22 patients had measurable disease, showing PR in 8 patients (40 %) with doses between 80 and 400 mg. Three of 9 patients with platinum-resistant EOC showed RECIST and Ca125 responses; another patient had SD for 120 days. Niraparib, a PARP1 and PARP2 inhibitor, has been studied in a phase I dose-escalation trial .
Only patients with measurable disease by RECIST 1.1 on computed tomography or magnetic resonance imaging at baseline were included. Patients with active secondary malignancies, those who failed entry screening for the trial, and/or those who did not receive any trial drug were excluded from this study. Data on patient and disease characteristic at trial entry were collected from electronic patient records. Platinum-sensitive cancer was defined as the recurrence of disease on platinum chemotherapy after more than 6 months, while platinum-resistant cancer was defined as the recurrence of disease on platinum chemotherapy after less than 6 months. These data suggest that there is likely to be a role for PARPi in the treatment of EOC.
- Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.
- Nine patients with stable disease received treatment for longer than 6 months; of these, 1 received treatment for at least 12.5 months and 1, for 13.2 months.
- These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair.
- Precision sampling that captures this tumor variability is essential for the implementation of precision oncology.
- A transient increase in serum cytokines, including interferon γ, interleukin -6, IL-8, and IL-10, was observed after ADP-A2M10 T-cell infusion in all patients.
