Professor Yan Ru Tie: HRD test expands the benefit of recurrent ovarian cancer after-line treatment, domestic products are used for the first time in PARPi clinical trial group HRD testing

Recurrence is a difficult point in the treatment of ovarian cancer, and the treatment of patients with multiple recurrences will become more and more difficult, for recurrent platinum sensitive and platinum-resistant patients, what is the status of post-line treatment? As tumor therapy enters the era of precision, what is the research progress of post-line therapy as the first real target drug PARP inhibitor for ovarian cancer? What are the biomarkers of the population benefiting from the post-line treatment of PARP inhibitors? What is the application and clinical significance of HRD detection in postline therapy of PARP inhibitors?platinum sensitivity and platinum resistance relapsed after-line treatment statusovarian cancer is a tumor prone to recurrence, its characteristics can be summarized in three 70%:, early diagnosis difficulties, about 70% of patients at the time of discovery
is late;patients have been fighting the disease for life as ovarian cancer continues to recurbackline therapy is the treatment of patients who have relapsed after at least two or more rounds of chemotherapyWith the increase of the number of treatment lines, the non-platinum interlateral period is getting shorter and shorter, drug resistance occurs gradually, and disease-free survival (PFS) and total survival (OS) are shortened accordinglyFor patients with progress after third-line treatment, the survival period is generally less than 1 year without using PARP inhibitorsrelapses were classified as platinum-sensitive recurrence and platinum-resistant recurrence, which were more than 6 months and less than 6 months after the end of the last treatment, respectivelyNCCN guidelines recommend the treatment of platinum-sensitive relapse and platinum-resistant relapse patients:platinum-sensitive recurrent ovarian cancer, platinum-based combination chemotherapy is recommended for treatment, andplatinum-resistant patients treated with non-platinum monotherapy or hormone therapy, targeting, and immunojointrecurrent treatment of ovarian cancer: PARP inhibitors bring new options
as mentioned above, regardless of platinum-sensitive or platinum-resistant backline recurrence of ovarian cancer patients, objective mitigation rate (ORR), median PFS and OS are lower than first-line treatment after recurrence of patients The emergence of PARP inhibitors adds new options for these patients Its toxicity is low, oral medication is convenient, can be home-based treatment During treatment, regular visits should be made to the hospital to evaluate the efficacy in order to adjust the dose there are currently three types of PARP inhibitors approved by the FDA for backline therapy: Olapari, Nirapali and Luca Pari Olapari were involved in clinical studies of Study 42, with the average group receiving 4.3-line chemotherapy for gBRCA mutations, and the results showed a 31% ORR in platinum-resistant patients The median PFS in patients was 7 months and the median OS was 16.6 months the Nirapali QUADRA study, the patients were treated with 3 lines of chemotherapy, HRD (homologous recombination defects) and BRCA tests, the median OS in the BRCA gene mutation subgroup was 26 months, hrD positive and HRD negative or state unknown group of median OS for 19 months and 16.6 months, respectively Lukapali's related studies include ARIEL2 and Study 10, as well as HRD and BRCA tests A combination of data from patients with BRCA mutations and 2-line treatment in two studies showed that the ORR was 25% in platinum-resistant patients, 66% in platinum-sensitive patients and 54% of the total ORR in the population from the above studies can be concluded that PARP inhibitors in the recurrent ovarian cancer in the backline treatment can play a more ideal role another important study, SOLO3 PHASE III Clinical Study, compared PARP inhibitors and non-platinum monodrugary chemotherapy in patients with gBRCA mutant platinum-sensitive relapse who received 2-line platinum-containing chemotherapy, and the results showed that the ORR in both groups was 72.2% vs 51.4% The CLIO II study evaluated Olapari single drug and doctor-selected chemotherapy in patients with platinum-resistant recurrence, with ORR in both groups being 18% vs 6%, and according to molecular biomarkers, the ORR in the Oapali group was 36% and BRCA wild patients 13% The CLIO study was for platinum-resistant relapse patients, and SOLO3 was for platinum-sensitive relapses Whether platinum-resistant or platinum-sensitive, PARP inhibitors in general have an advantage over chemotherapy drugs in backline therapy HRD testing can further expand the population benefiting from PARP inhibitors, offering hope for post-line therapy in BRCA-negative patients
in terms of molecular characteristics, FDA and NCCN guidelines for the three TYPES of PARP inhibitors recommended for the population generally the same, although the recommendation for Olapari slightly different FDA-approved Olapari is a patient who has received at least three-line chemotherapy, and the ncCN guidelines recommend the right population to change from at least three-line chemotherapy to at least second-line chemotherapy the Chinese Medical Association Gynaecological Oncology Association organization prepared the "Ovarian Cancer PARP inhibitor clinical application guide", the post-line clinical application of PARP inhibitors for platinum-sensitive and platinum-resistant patients recommended platinum-sensitive patients: Olapari recommended for BRCA mutations (class 2B) for at least second-line chemotherapy, Nirapari recommended for HRD-positive patients (class 2B) who have undergone at least third-line chemotherapy; and Lucapari recommended for BRCA mutations (class 2B) who have undergone at least second-line chemotherapy platinum-resistant patients: Olapari recommended for BRCA mutations (class 2B) for at least three-line chemotherapy, Lucapari recommended for BRCA mutations (class 2B) patients who have undergone at least two-line chemotherapy; and nilapali combined with Paboli-Zumai as a category 3 evidence recommendation the applicable population of the three PARP inhibitors differed in biomarker characteristics Nirapali is recommended for HRD-positive patients The QUADRA study included not only patients with BRCA mutations, but also PATIENTs with BRCA-negative or unknown conditions, which were closer to the real world According to foreign reports, BRCA mutations account for less than 20% of the total population of ovarian cancer, while HRD-positive populations account for as high as 48%, meaning that nearly 30% of BRCA wild but HRD-positive beneficiaries have been added As a result, HRD testing can further expand the benefit of the population, for BRCA-negative patients in the back line treatment of hope, the importance of HRD testing can be seen in patients with HRD-negative, backline therapy is relatively limited in benefiting from PARP inhibitors, and currently AVANOVA and TOPACIO studies are currently experimenting with the treatment of PARP inhibitors and joint immuno-checking inhibitors, and have initially observed the benefits three genomic scar markers (LOH, TAI, LST) combined to evaluate HRD, apply ingress ertoum in clinical trials
both Foundation Medicine and Myriad Genetics can now offer HRD testing and have FDA approval: Foundation Focus CDx BRCALOH is primarily used for auxiliary diagnostics of Lucali
; It is an accompanying diagnosis for the treatment of ovarian cancer in the backline of Nirapani in terms of the technique itself, both methods were detected using genomic scarring, and the difference was that they used a different number of genomic scar markers to determine the state of HRD If there is a problem with DNA repair, cells with homologous recombinant repair defects (HRD) can cause tumors, resulting in genomic damage and scarring HrD can be determined by scar markers Foundation Medicine's HRD test is mainly used to evaluate HRD through hetero-loyathing deficiency (LOH), which is called LOH-High when the LOH ratio is 16%, indicating HRD positive Myriad Genetics' HRD test, which is based on genomic instability, evaluates HRD status, including heterogeneous deficiency (LOH), telomere allele imbalance (TAI), and large fragment migration (LST), which is considered HRD-positive when HRD scores of 42 the combined use of three genomic scar markers seems to have an advantage in terms of detection performance From the point of view of clinical application, myChoice is more widely used, has been used in several clinical trials, and the effect is better because Foundation Focus CDx BRCA LOH is primarily validated in the clinical trial AREIL3 associated with Luca Pari for the auxiliary diagnosis of lukapali in the maintenance treatment of recurrent ovarian cancer There are currently no relevant clinical trials in the back line treatment of ovarian cancer, it is expected that the follow-up clinical trial data can be supported to assist ovarian cancer patients backline treatment domestic Benchmark HRD testing based on Chinese genetic background development, has been used in PARP inhibitor postline therapy clinical trial into the group testing currently listed in China's PARP inhibitors, Nirapali is in China's post-line ovarian cancer patients to carry out active research, this is an II single arm The study focused on the effectiveness and safety of Nirapali in patients who had received third or fourth-line chemotherapy, carried BRCA mutations, or tumor HRD-positive and platinum-sensitive, advanced recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer In this study, we not only included BRCA-positive patients, but also HRD-positive patients, and we hope that this study will bring new options and hope steamed treatment for ovarian cancer patients in China, especially BRCA wild patients we are very careful about the choice of group testing, although foreign countries have been approved two kinds of testing, but the current stage for domestic patients is not yet within reach, more importantly, whether the foreign HRD testing is suitable to guide the use of CHINESE patients PARP inhibitors, to answer this question, need to be considered from two aspects First of all, the current HRD testbased on genomic instability scoring, are required through the whole genome-wide single nucleotide polymorphism (SNP) type, to output the genome scar three markers of the score, whether the two foreign products are compatible with the Chinese group of high polymorphism sites, and whether it can fully represent the genetic background of the Chinese group, I think the answer is no, therefore, based on the genome scar marker HRD detection, the need for Chinese background of the background of the development of the human Second, it needs to be validated in the Chinese patient population in order to be tested in more local clinical trials clinically enrolled HRD testing in China's post-line ovarian cancer patient Nirapali, we are using HRD Score testing developed by The Prebenchmark This is an HRD Score model based on genetic data from the Chinese patient population, which has been tested and validated by Chinese group samples, covering the whole genome-wide Chinese group of high polymorphism SNP sites, precision computing LOH, LST, TAI, and scoring genomic instability In China, in fact, this is the first time to use China's HRD testing products for THE clinical group testing of PARP inhibitors This allows us to provide more accurate HRD state stratification for the genetic background of Chinese groups, more suitable for Chinese patients It is expected that Priu's HRD testing will be further validated by this clinical trial, which will bring new breakthroughs to the post-line precision treatment of PARP inhibitors in ovarian cancer patients in China HRD testing, which promotes the standard use of PARP inhibitors
Although Olapari and Nirapali have been approved in China, the adaptation certificate is the first-line maintenance of ovarian cancer and the maintenance of post-recurrence treatment, and no post-line treatment adaptation certificate has been approved In the real world, however, because two PARP inhibitors are precision-treated drugs, doctors use them as life-saving straws for backline therapy Until HRD detection technology matures, the beneficiaries are relatively narrow, and when the technology matures, the number of beneficiaries is bound to increase In backline therapy, not only the efficacy, but also the quality of life and health economics HRD-positive patients far outnumbered the number of BRCA mutations, and this group has been clearly able to benefit from precise PARP inhibitor treatment Therefore, we Chinese Medical Association gynaecological oncology credit association experts in the preparation of "ovarian cancer PARP inhibitor clinical application guide", also unanimously recognized that HRD testing in all stages of treatment of ovarian cancer are important, hope that through the guide, promote the standardized use of PARP inhibitors, promote HRD testing in china and follow-up research and development author: Yan Ru-Iron Source: