Parp Inhibitors: Preferred Agent Selection
Given the presence of phase three evidence, Olaparib is the most commonly prescribed agent in patients with AR-directed therapy failure. Furthermore, it may be given in aforementioned non-BRCA HRD patients as well. However, lack of benefit on sub-group analysis and a weak comparator arm need to be kept in mind. Furthermore, given the taxane agnostic nature of the PROfound study, rucaparib may be preferred in patients failing on docetaxel as well although Olaparib may also be used given the efficacy outcomes in the TOPARP-A and the TOPARP-B study.
Parp: Prime Treatment Target For Prostate Cancer
Over the past decade, olaparib and rucaparib have become important treatments for women with ovarian and breast cancer, in whom genetic alterations that affect DNA repair processes are common. Among the most frequent such alterations are those in the BRCA1 and BRCA2 genes.
Its no accident that researchers have identified people who have alterations in BRCA genes as ideal candidates for treatment with PARP inhibitors.
BRCA proteins and some PARP proteins are both integral components of cells response to DNA damage. If that response is already dysfunctional because of BRCA1 or BRCA2 mutations, then researchers reasoned that blocking the activity of PARP proteins could further hamper any chance of repairakin to punching a hole in a tire that already has a slow leak. If the cancer cells cant fix the DNA damage, they will die.
Prostate cancer emerged as another strong candidate for PARP inhibitors after studies suggested that alterations in BRCA1 and BRCA2, as well as other genes involved in a cells ability to respond to DNA damage, may be present in approximately one-quarter of men with the disease. Other studies linked these genetic changes to an increased risk of prostate cancer, as well as more aggressive disease.
Those findings, Dr. Karzai explained, led to a series of clinical trials of PARP inhibitors in men with metastatic prostate cancer, laying the foundation for the new FDA approvals.
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
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Can You Discuss The Next Steps For Parp Inhibitors And Prostate Cancer Including Combination Therapy Trials Of Parp Inhibitors With Immunotherapies Or Androgen Receptor Pathway Inhibitors
There are at least 2 future directions for PARP inhibitor treatments. One is to combine these agents with other standard therapies for metastatic prostate cancer. We have been using drugs such as abiraterone acetate and enzalutamide for almost a decade now. These are natural combination partners with PARP inhibitors. There are a number of pivotal phase 3 studies that could lead to FDA approval of these combinations. For example, there is TALAPRO-2 , a phase 3 randomized study of talazoparib plus enzalutamide versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer.
In addition, there is also the MAGNITUDE trial, a phase 3 randomized study evaluating niraparib plus abiraterone in patients with metastatic castration-resistant prostate cancer. The goal of those studies is to see whether the combination of a PARP inhibitor and a novel hormonal therapy might be successful in genetically-unselected patients in other words, not just patients who might have 1 of these HRR gene mutations.
PARP inhibitors are also being studied in the metastatic hormone-sensitive setting. The recently launched AMPLITUDE trial is a phase 3 randomized study of abiraterone plus niraparib versus abiraterone alone in patients with metastatic hormone-sensitive prostate cancer who have a genetic mutation in 1 of these HRR genes. So that one is a biomarker-selected design.
Other Synthetically Lethal Opportunities
PARP inhibition exists as an attractive complement to current prostate cancer therapies, regardless of genetic DNA damage repair mutation presence, because of PARP1’s cooperation with the AR and AR signaling. PARP1 has been shown to be recruited to sites of AR action within the cell and to facilitate AR chromatin occupancy in both castration sensitive and resistant cancer cell types. PARP1 has also been shown to promote ligandindependent AR activation, suggesting a role in treatment resistance and disease progression to mCRPC .
Previous prostate cancer studies have shown the benefits of treating locally advanced disease with radiotherapy in combination with androgen deprivation therapy . The positive effects seen in these trials are likely due to the synergistic consequence of radiologicalinduced DNA damage along with ADT impairment of HR and DNA damage repair mechanisms . Resistance to this combination therapy has been observed and could be explained by reports showing an increase in PARP activity following ADT, thus allowing DNA damage repair to persist . These findings, along with the benefits of PARP inhibition in prostate cancer that have already been discussed, have influenced the use of olaparib and other PARP inhibitors in combination with current standard of care therapies in a number of clinical trials.
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Clinical Testing For Hrr Mutations In Prostate Cancer
Multiple studies have now confirmed the high prevalnece of HRR-associated gene mutations in advanced prostate cancer . This enrichment in late-stage disease has led to some controversy with regards to the use of archival, primary prostate tumor biopsies for genomic profiling once patients have developed mCRPC. As part of the screening process for the randomized PROFOUND trial of olaparib, over 4000 patients underwent next-generation sequencing targeted profiling the overall rate of HRR-associated genes mutations was 27%, with no differences observed based on the use of a primary vs metastatic sample for NGS testing . Similarly, in a study pursuing targeted NGS from 470 primary tumors of patients who all later developed mCRPC, the prevalence of these mutations was similar to what has been reported for metastatic biopsy cohorts . Moreover, a recent study comparing primary tumor biopsies and cfDNA samples acquired later at the time of mCRPC also confirmed that BRCA2, ATM and CDK12 defects are already present in the primary tumors of these patients . This is different to the study of alterations in AR or tumor suppressors such as TP53, RB1 or PTEN, which seem to evolve as a result of hormonal therapy-induced selective pressure.
Rucaparib Get Green Light In Hrr
Rucaparib received accelerated FDA approval in May 2020 for patients with mCRPC based on data from the phase 2 TRITON2 trial , a single-arm study that treated men with somatic or germline alterations in an HRR gene with rucaparib 600 mg twice daily.16,17 Among the 115 patients with a BRCA alteration with or without measurable disease, the objective response rate was 43.5% per independent radiology review, and 50.8% per investigator assessment.17 The confirmed prostate-specific antigen response rate was 54.8% .17
TRITON2 also included 78 patients with non-BRCA HRR gene alterations, including 49 with ATM, 15 with CDK12, and 12 with CHEK2 alterations. The findings in these patients suggest that some of the other fairly common HRR gene alterations found in mCRPC may not sensitize cells to PARP inhibition, as there were limited radiologic and PSA responses however, patients who harbored some less frequently observed alterations in HRR genes, such as PALB2, were found to derive some benefit from PARP inhibition .
Were waiting for data from the phase 3, Barata said. shows that patients benefit from rucaparib. When we put all these data together again, a biomarker-based approach. In addition to the ongoing phase 3 TRITON3 study assessing rucaparib as a monotherapy ,19 rucaparib is being studied in combination with enzalutamide as a first-line treatment for mCRPC in the phase 3 CASPAR trial .20
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Germline Or Somatic Mutation Testing
Although germline and somatic mutation testing typically require different platforms and samples , it is prudent to go for cotesting for the following reasons. First, diagnostic yield is maximized. Second, germline testing allows for early family member screening and counseling, which may be lifesaving. Third, there is no difference in the responses and outcomes of patients with germline or somatic mutations when treated with PARP inhibitors . Of note, certain somatic mutation assays may hint at an underlying germline defect. If such an assay is being used, prior counseling and consent regarding germline testing are of paramount importance. In addition, given that many somatic mutations are truncal, retesting as per the clinical scenario remains prudent.
Basis Behind Combination Therapy
Seminal conceptualization of AR-inhibition enhancing DNA-damage mediated killing stems from trials reporting enhanced efficacy of radiotherapy in patients receiving androgen deprivation therapy , which reflects in biopsy specimen as well.In vitro models also suggest enhanced killing with radiotherapy in presence of ADT. Among multiple postulated mechanisms, AR-blockade-mediated impairment of DNA repair mechanisms has gained the most traction. In this regard, a study reported an increase in the expression of DNA repair proteins in response to AR signaling. PARP1 specifically modulates the transcriptional activity or AR and ETS activity and consequently can lead to ligand independent AR-signaling. In addition, AR-signaling in CRPC is known to potentiate the expression of HRR genes and its inhibition may induce a state of BRCAness.In vitro studies have corroborated this through synthetic lethality assays as well.
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Parp Inhibitors: From Bench To Bedside
Poly polymerases , a family of enzymes sharing a catalytical domain whose main function is to add poly-ADP-ribose chains to other proteins as signaling transmitter and/or to regulate transcription. PARP1, predominantly, and PARP2, are critical to DNA single-strand break repair. They detect ssDNA breaks, bind to them and synthesize PAR using NAD+, initiating the call for DNA repair mediators and effectors, which then will require PARP1/2 to be removed from the site of damage for the ssDNA repair process to properly ensue. PARP inhibitors are drugs that compete with NAD+ to bind to the enzyme, and therefore prevent proper activation of the ssDNA break repair cascade.
Unrepaired ssDNA breaks will progress to double-strand DNA breaks. However, cells have specific pathways to repair toxic dsDNA breaks, including the error-prone non-homologous end joining and microhomology-mediated end joining pathways and the preferred, error-free, homologous recombination repair pathway.
Current Evidence Behind Combination Therapy
Among the first studies evaluating PARP inhibitor, in addition to AR-directed therapy was the NCI-9012 study which evaluated the addition of veliparib to abiraterone therapy regardless of DRD status. Regardless of the treatment given, patients with an underlying HRD mutation fared better. However, veliparib addition did not lead to improved outcomes in the entire cohort, or in the ETS translocation subset. The impact of veliparib addition specifically in the HRD subset remains unknown. Although a negative study, the NCI-9012 study informs us of the potential efficacy of AR-directed therapy in HRD subsets, the futility of universal PARP inhibitor prescription, and futility of ETS translocations as a potential biomarker. Given these findings, the BRCAAway study is currently evaluating HRD CRPC patients in terms of optimal combinations and sequencing. A similar phase two study evaluating Olaparib addition to abiraterone therapy after docetaxel failure reported a higher PFS in all patients regardless of the HRR gene status. The findings of this study prompted the PROpel trial .
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Talazoparib Looks To Build Off Positive Results In Breast Cancer
Talazoparib, which is currently FDA approved for metastatic breast cancer, is being studied for mCRPC in the phase 3 TALAPRO-2 study .23,24 TALAPRO-2 is comparing rPFS between talazoparib plus enzalutamide and enzalutamide plus placebo in men with and without tumors harboring DNA damage response alterations. There are over 20 secondary outcome measures, including OS and ORR.23,24
Could You Provide An Overview Of Parp Inhibitors How Do They Work
PARP inhibitors work on a principle called synthetic lethality. Briefly, PARP inhibitors increase the amount of DNA damage in the cancer cell. As a general principle, a little bit of DNA damage is a good thing for a cancer cell it helps it survive and metastasize and grow more rapidly and proliferate. But too much DNA damage can be a bad thing because it can lead to catastrophic genomic instability and subsequent cancer cell death.
PARP inhibitors work best in cancers that have mutations in homologous recombination repair genes. The most well-known of these in prostate cancer is BRCA2. BRCA2 is a gene that is responsible for fixing double-strand DNA breaks. There is another way that cancer cells can fix DNA breaks, which is called single-strand repair, fixing 1 DNA strand at a time. So if you have a patient with a BRCA2 mutation, that cancer cells ability to fix double-strand DNA breaks is impaired. It then relies on the other pathway, the single-strand repair pathway, to fix its DNA damage. That single-strand repair pathway is done by an enzyme called PARP, primarily PARP1. If PARP1 is inhibited by a drug, such as a PARP inhibitor, in a patient who already has a mutation in the alternative mechanism of DNA repairin other words, BRCA2then that cancer cell develops catastrophic DNA damage, so that the next time it replicates its not able to survive and it dies.
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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 .
Profound Trial: Most Benefit In Men With Brca2 Alterations
Olaparibs approval, announced on May 19, was based on the results of a large clinical trial called PROFOUND.
The trial enrolled men with mutations in DNA repair genes and divided them into two cohorts. Cohort A included men with alterations in the BRCA1, BRCA2, or ATM genes, each of which plays an important role in DNA repair. Cohort B included men who had alterations in a group of 12 other genes that have some involvement in repairing DNA.
All of the men in the trial had cancer that had worsened despite treatment with either abiraterone or enzalutamide , which work in different ways to block hormones in prostate cancer cells.
The 387 men in the trial were randomly assigned to either the treatment group, which received olaparib, or the control group, which received either abiraterone or enzalutamide .
In cohort A, men treated with olaparib lived more than twice as long without evidence of their cancer getting worse than men treated with abiraterone or enzalutamide: a median of 7.4 months versus 3.6 months. The treatment group in cohort A also lived longer overall, with olaparib improving survival by more than 4 months .
In addition, men treated with olaparib were far more likely to see their tumors shrink than men treated with one of the other two drugs .
In cohort B, olaparib did appear to provide some benefit in men whose tumors had alterations in some unusual genes involved in DNA repair, Dr. Sartor continued, including RAD54L and PALB2.
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Fanca Palb2 And Rad51
FANCA, PALB2, and RAD51 occupy roles in the Fanconi anemia /BRCA HR pathway for repair of DSBs. Data concerning PARP inhibitor treatment of patients harboing each of these mutations are provocative but limited. FA is an autosomal recessive disease that is characterized by congenital abnormalities and hypersensitivity to DNA crosslinking agents . This observation led investigators to identify the FA class of genes as important mediators in DSB repair that ultimately activate and aid BRCA1 and BRCA2 in repair .
FANCA is a component of the FA core complex responsible for the activation of interstrand crosslink repair . FANCA and the seven other FANC essential proteins in the FA core complex activate the FA/BRCA repair pathway through monoubiquitination of FANCD2 and FANCI. FANCA is the most commonly altered FA gene , and its significant role in DDR implies patients with mutations in FANCA could benefit from PARP inhibition treatment plans. FANCA aberrations were found in 8% of primary tumors analyzed by The Cancer Genome Atlas , the majority of which were deep deletions . In the preliminary TRITON2 data, one patient with a monoallelic truncating mutation had complete radiographic and PSA responses . One patient with a nonsense FANCA mutation achieved a PSA response in the TOPARPB trial .