Parp Inhibitors And Immune Checkpoint Inhibitors
There is also growing evidence into the synergy between PARP inhibitors and immune checkpoint inhibitors . The ligand programed death ligand-1 maintains an immunosuppressive tumor microenvironment and is activated in prostate cancer inhibition of PD-L1 may allow effective T-cell responses against tumor cells . Furthermore, PARP inhibition increases PD-L1 expression in cells with reduced BRCA2 expression . PD1 blockers, such as pembrolizumab and nivolumab, and PD-L1 blockers such as durvalumab, are being combined with PARP inhibitors in clinical trials . Karzai et al. showed efficacy of combining olaparib with durvalumab in mCRPC with 53% of patients having an over 50% decline in PSA, and median radiographic PFS in patients with DDR defects being 16.1 months compared to 4.8 months in patients without . There are ongoing trials investigating use of PARP inhibitors with immune checkpoint inhibitors in mCRPC .
Overall PARP inhibitors are a revolutionary treatment in the management of mCRPC in the era of targeted therapies with the future view of enabling personalized therapy with effective treatment results by determining prognostic and predictive factors as well as individual gene contributions . Several trials are in place to assess PARP inhibitor efficiency at different tumor stages as a monotherapy or polytherapy regime, and these will change the future of use of PARP inhibitors in years to come .
Finding The Optimal Tissue For Testing
The bulk of evidence in this regard comes from the analysis of samples screened for the aforementioned PROfound trial. Consisting of 4858 samples from 4425 screened patients, the study makes the following observations regarding the success rate of testing through a targeted NGS platform. First, newly collected samples have a higher yield than archived samples . Second, age of the sample has an impact . Third, metastatic sites have a higher yield than primary . Fourth, although the most common method, core biopsies have the least success rates by type of sample . Finally, the biopsy site impacts success rates as mentioned here in decreasing order: Lymph nodes , lungs , liver , prostate gland primary , and bony metastasis . The lowest yield from bone metastasis probably stems from the nucleic acid denaturation stemming from the decalcification process. Another study reported similar findings with 746 biopsy/surgical samples. With an overall success rate of 68%, the highest success rates were for prostate tumor samples . Among metastatic samples, lymph nodes and hepatic lesions had a success rate of > 69%, while bone and lung samples were more challenging .
These findings suggest that in the appropriate clinical setting, evaluation of a fresh sample may maximize our chances to find a targetable mutation.
Are Hrr Mutations And An Ar Mutation Different
There are over 20 genes involved in HRR that can become mutated and lead to disease. An AR gene is not an HRR gene. An AR gene is 1 that, when mutated, can show how your tumor may respond to certain hormones. Knowing whether you have these mutations can help provide information to your doctor about how to manage your disease.
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Association Between Hrr Gene Mutations And Clinical Outcome
Figure 4 Associations between HRR mutations and histopathologic subtypes, age, family history and multiple primary foci , and stage.
Patients with HGSOC who received platinum chemotherapy were followed up, and the median follow-up was 28.7 months . BRCA1 carriers had better PFS than HRRwt cases and BRCA2 carriers , while the PFS of other HRRm carriers was significantly shorter than HRRwt cases . Moreover, BRCA1/2 carriers had a trend of better OS than HRRwt and non-BRCA HRRm carriers . More specifically, the PFS of BRCA1m carriers was significantly longer than that of BRCA1wt carriers . BRCA1m carriers had a trend of better OS than BRCA1wt carriers . However, non-BRCA HRRm carriers had a trend of poorer PFS than HRRwt carriers . There were no significant differences between the OS of non-BRCA HRR mutation carriers and HRRwt carriers .
Figure 5 Progression-free survival and overall survival in ovarian carcinoma patients by HRR mutation category. PFS between deleterious BRCA1, BRCA2, non-BRCA HRR, and without HRR mutation carriers. OS between deleterious BRCA1, BRCA2, non-BRCA HRR, and without HRR mutation carriers. PFS with and without deleterious BRCA1 mutations. OS with and without deleterious BRCA1 mutations. PFS with and without non-BRCA HRR mutations. OS with and without non-BRCA HRR mutations.
Somatic Mutations In Ddr Genes
In addition to germline mutations, somatic mutations also drive prostate carcinogenesis especially into the advanced stages . Oncogenes or inactivation of tumor suppressor genes can lead to uncontrolled tumor growth. The TSG p53 is commonly mutated in prostate cancer 1020% of primary and up to 42% of advanced prostate cancer . Similarly, the TSG PTEN mutations are found in 27% of primary and up to 60% of metastatic prostate cancer . The AR is a specific oncogene especially implicated in prostate cancer as AR-directed transcription allows growth of the tumor in all stages of prostate cancer . These somatic mutations are present in DNA repair pathwaysRobinson et al. found 23% of mCRPC had somatic DDR mutations . BRCA1/2 and ATM accounted for nearly 20% of these and were found more frequently in mCRPC. Furthermore, loss of BRCA2 was found in 12.7% of cases and 90% displayed biallelic loss . Abida et al. also found that somatic BRCA2 mutations were exhibited in tumors early on that then progressed to metastatic disease .
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Genet Med Off J Am College Med Genet
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Prostate cancer incidence and mortality have rapidly increased in China. Notably, unique epidemiological characteristics of PCa are found in the Chinese PCa population, including a low but rising incidence and an inferior but improving disease prognosis. Consequently, the current treatment landscape of PCa in China demonstrates distinct features. Establishing a more thorough understanding of the characteristics of Chinese patients may help provide novel insights into potential treatment strategies for PCa patients. Herein, we review the epidemiological status and differences in treatment modalities of Chinese PCa patients. In addition, we discuss the underlying socioeconomic and biological factors that contribute to such diversity and further propose directions for future efforts in optimizing the PCa treatment in China.
Genetic Mutations In Prostate Cancer
The heterogeneity of PCa is partly attributed to genetic factors, which make up 57% of the interindividual risk variation . Several genetic mutations are implicated in familial PCa, and these include defects in DNA repair genes as listed in Table 1 . DRGs have an important role in carcinogenesis, since mutations in these genes will induce cells to continue replication without error correction.
Table 1
With the advent of genetic testing in PCa, several essential questions have emerged: who to test, which genetic assay to use, what sample to test on, and which therapy to proceed with based on the results. Testing for these mutations may be performed via commercially available kits that typically use blood or saliva. However, there are no standardized panels for genetic testing, and the examined mutations differ between panels, which makes it challenging to select the appropriate test. In addition, widespread genetic testing for all patients diagnosed with PCa is unlikely to be cost-effective at present and may create some clinical confusion especially in early low-risk disease. Clear guidelines for treatment options after genetic testing based on validated results are lacking. For the purpose of this review, we will divide patients into three distinct categories based on their disease status.
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Summary Of Genetic Testing
While cotesting for somatic and germline abnormalities is of paramount importance for therapeutic decision making, a yield of somatic testing seems to be better with fresh samples in patients with more advanced diseases. Furthermore, if using liquid biopsy, progressive disease with rising PSA levels allows optimization of NGS performance. Given these findings, it may be prudent to order germline testing in all patients as per clinical guidelines and then subsequently procure tissue or liquid biopsy for somatic tissue testing as the need arises.
Deleterious Variants In Brca1/2 And Other Hrr Genes
Figure 3 Mutations landscape of BRCA1, BRCA2, RAD51D, RAD51C, and ATM genes. The X-axis represents the amino acid residues of the proteins, and the Y-axis represents the frequencies of each type of mutations. List of 11 novel non-BRCA HRR variants. Distribution of mutation types in BRCA1/2 and non-BRCA HRR genes . The symbol * means the variant is a nonsense mutation in HGVS.
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Treatment Combination With Parp Inhibitors
Even if sustained efficacy is observed with PARPi used alone, primary and secondary resistances are seen. To try to potentiate their action, trials are underway to evaluate the use of PARPi in combination with other drugs. The main studies are summarized in Table .
Table 2 Phase II or III trials using PARP inhibitors in combination to treat prostate cancers
PARP inhibitors and new hormonal therapies
Based on these results, the ongoing phase III trial PROpel randomizes patients with mCRPC between abiraterone with olaparib and abiraterone with placebo, as first-line treatment, irrespective of HRR status. The primary endpoint is rPFS secondary endpoints include OS and health-related quality of life. The effect of HRR alteration will be studied in exploratory analyses.
Several ongoing studies are evaluating the association of a PARPi combined with NHT with mainly rFPS as primary endpoint. MAGNITUDE and AMPLITUDE phase III trials randomize patients with advanced prostate cancer between abiraterone or abiraterone and niraparib in castration resistance and castration sensitive setting, respectively. The CASPAR trial is investigating a combination of enzalutamide and rucaparib compared to enzalutamide in patients with mCRPC . Talazoparib is being evaluated in association with enzalutamide in the TALAPRO-2 trial.
PARP inhibitors and immunotherapy
Other combinations
Confirming An Unexpected Result
The study was sparked by an unexpected result of an earlier study. As the researchers were profiling genomic changes in metastatic prostate cancers, they sequenced DNA from normal tissues in the same patients for comparison purposes. They found that 8% of men with metastatic prostate cancer in that study had inherited a mutation in a DNA-repair gene.
The proportion of inherited, or germline, mutations was so unexpectedly high that the researchers conducted the current study in part to see whether the high frequency of mutations was reproducible when we were looking at a large population of men, explained coauthor Colin C. Pritchard, M.D., Ph.D., of the University of Washington.
The answer, he added, was a resounding yes.
In fact, the frequency of germline mutations in 16 DNA-repair genes among 692 men with metastatic prostate cancer turned out to be even higher11.8%. The researchers detected harmful germline mutations in a DNA repair gene among 82 of the 692 participants.
The frequency of inherited DNA-repair gene mutations in men in the study was higher than the prevalence of 4.6% among 499 men with localized prostate cancer who participated in The Cancer Genome Atlas project, the researchers noted.
DNA-repair genes may play a role in the progression to metastatic prostate cancer, and more research should be done to look at mutations in these genes in men with prostate cancer, Dr. Gulley added.
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Your Patients Hrrm Status May Be Used For:
ATM, ataxia-telangiectasia mutated BRCA1, breast cancer susceptibility gene 1 BRCA2, breast cancer susceptibility gene 2 HRRm, homologous recombination repair gene mutations.
1. Abida W, et al. JCO Precis Oncol. 2017:PO.17.00029. 2. Pezaro CJ, et al. Am Soc Clin Oncol Educ Book. 2018 38:382-390. 3. Na R, et al. Eur Urol. 2017 71:740-747. 4. Cheng HH, et al. J Natl Compr Canc Netw. 2019 17:515-521. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer V.4.2022. ©National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed May 10, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Biomarkers Of Response To Parp Inhibitors
As mentioned before, not all HRR alterations have the same impact on PARPi efficacy. The TOPARP-B trial showed good CRR and ORR for BRCA1/2 and PALB2 altered-patients , while almost no RECIST or biological responses were observed in ATM or CDK12 altered-patients . The PROfound trial confirmed these results and showed an OS improvement only in the BRCA/ATM group, however within this cohort ATM alterations did not show the same magnitude of efficacy neither in rPFS, nor in OS . The same results were observed for niraparib, with an ORR of 41% in the BRCA group compared to 9% in the non-BRCA group . TRITON-2 showed an ORR of 43.5% in the BRCA group, and long-lasting response for BRIP1 and RAD51 mutated-patients. But almost no response was observed for ATM, CHEK2 or CDK12. Moreover, the ORR was lower for mono-allelic alterations compared to bi-allelic alterations . No differences were observed between somatic and germline BRCA1/2 mutations . TALAPRO-1 showed a good ORR in the BRCA group and no, or few, responses for other HRR genes . Finally, it is noteworthy that within the BRCA group, a recent study reported better outcomes in patients with BRCA2 compared to BRCA1 mutations, with no differences in terms of allelic fraction or germinal versus somatic mutations. This small retrospective study remains hypothesis -generating with, as expected, 10 times more BRCA2 than BRCA1 alterations .
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Implications For The Treatment
The first line treatment of metastatic prostate cancer is androgen deprivation therapy , which can be combined with chemotherapy agents yet the majority eventually develop resistant disease defined as castration resistant prostate cancer . Thus, new clinical targets are essential . This section will discuss PARP inhibitors in detail along with their conducted clinical trials. PARP inhibitors alter, by PARylation, target proteins with ADP-ribose, a process present in several cellular processes such as cell growth and differentiation, transcriptional regulation, and apoptosis . PARP has a significant role in DNA repair during complex signalling pathways in DNA damage response . PARP is involved in single strand break repair, hence why they are particularly effective as therapeutics in this pathology . The mechanism of action of PARP inhibitors have led to the current use of PARP inhibitors in cancer treatment, particularly targeting BRCA-mutant cancer cells and, more recent studies have shown a wider therapeutic potential beyond BRCA-mutant cancer cells . Multiple clinical trials are studying PARP inhibitors as either monotherapy or part of combination therapy for prostate cancer.
Germline Predisposition In Carcinoma Prostate
Findings of the aforementioned studies indicate a significant impact of germline alterations on the risk and natural history of the disease. The heterogenous pace of progression is well documented in carcinoma prostate. Furthermore, inherited susceptibility accounts for more than half of the relative risk of carcinoma prostate. Studies have shown that patients with HRR gene mutations have a higher propensity for distant spread and recurrence. Given these findings, germline HRR gene mutations may show enrichment in more aggressive diseases. This is supported by incremental rates of BRCA mutations in the normal population , patients with high risk localized carcinoma prostate , and patients with metastatic disease at diagnosis .
Along these lines, a study evaluated 692 samples of patients with metastatic carcinoma prostate at diagnosis and reported the following findings. First, 11.8% of all carcinoma prostate cases had a germline alteration involving an HRR gene . Second, the prevalence of carcinoma prostate in a first-degree relative did not vary with germline mutation status. However, the presence of an underlying germline mutation was associated with a higher Gleason score, as well as a higher risk of other cancers in first-degree relatives .
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Study Population And Clinical Data Collection
A total of 280 patients diagnosed with EOC in the years 20152016 were collected from five hospitals. After excluding 7 unqualified samples with tumor content less than 20%, 273 patients were included in this study from Fudan University Shanghai Cancer Center , The First Affiliated Hospital of Nanjing Medical University , National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Guangdong Provincial Peoples Hospital, Guangdong Academy of Medical Sciences , and Southeast University, Zhongda Hospital . Patients were enrolled at diagnosis and were not selected by age, familial cancer history, or histological subtype. The project was approved by the Institutional Review Board of the hospitals. Tumor histology was confirmed by two independent pathologists. Clinical and pathological information was extracted from the database of the institutional patient, including age at diagnosis, tumor histopathology, stage , and personal and family history of cancer when available. Hereditary breast and ovarian cancer syndrome-related tumors were defined as breast, ovarian, and pancreatic cancers in women and cancers of the breast and prostate in men. Samples with incomplete or undetermined information were described as unknown.
How Do Parp Inhibitors Work: A Primer On Synthetic Lethality
A plethora of chemical and physical agents can induce cell death in cancer cells, but a similar impact on normal cells narrows their therapeutic index and impairs clinical utility. However, epigenetic and genetic alterations within cancer cells or in the tumor microenvironment may create an opportunity for selective killing. On these lines, two genes are synthetic lethal if mutations in both are lethal, but mutation in either has no impact on viability. PARP inhibitors utilize the synthetic lethality of PARP1 with the HR machinery. A multitude of mechanisms has been postulated for the same.
Accumulation of SSB was among the initial mechanisms postulated. However, the following observations undermine this hypothesis. First, PARP inhibitor-exposed cells do not show accumulation of SSB. Second, siRNA-mediated depletion of XRCC1 does not enhance sensitivity to PARP inhibitors. Other postulated mechanisms with lesser evidence are NHEJ upregulation, disrupting the processing of Okazaki fragments, and disrupted transcription.
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