PARP Inhibitors In Prostate Cancer Research Articles

Risk assessment of myelosuppression with PARP inhibitors in prostate cancer: Insights from FAERS.

12144 Background: DNA damage repair defects are prevalent in 15% of Prostate cancer. FDA has approved four PARP inhibitors to be used for metastatic castration resistant prostate cancer (mCRPC). Based on the approvals, currently Olaparib, Niraparib, Rucaparib and Talazoparib have been approved alone or in combination with an Androgen receptor pathway inhibitor (ARPI). All these agents have myelosuppressive (MS) events . We aimed to assess the pharmacovigilance (PV), reporting rate, and reaction outcomes of different approved PARP inhibitors in the mCRPC setting reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: We analyzed MS events in 2,137 patients on PARP inhibitors. MS event reports were submitted to FAERS between 2004-2023 and analyzed using the AERS Mine framework. MS incidences were analyzed within different PARP inhibitors utilized for prostate cancer. Our primary composite endpoint was the PV of MS caused by olaparib, rucaparib, niraparib and talazoparib for the treatment of mCRPC. PARP inhibitors were analyzed as mutually exclusive cohorts. Standard PV metrics were used to determine MS association with PARP inhibitors and two-way ANOVA testing was used to evaluate for statistical significance across the treatment groups. Results: 2,137 prostate cancer patients on PARP inhibitors were identified. MS events (n=677)– olaparib (227/831, 27.32%), rucaparib (n = 171/495, 34.55%), niraparib (63/111, 56.76%), and talazoparib (34/47, 72.34%). MS events were further categorized into five classes – anemia (n = 311, 45.94%), leukopenia (n = 123, 18.17%), thrombocytopenia (n = 107, 15.81%), pancytopenia (n = 102, 15.07%), and myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia (AML, 34, 5.02%). Anemia rates across the four cohorts were identical (table). Leukopenia rates were highest in talazoparib cohort (27.66%). Thrombocytopenia rates were highest in niraparib cohort (24.32%). For pancytopenia, rates were highest in talazoparib 10.64%. MDS/AML rates were Talazoparib (2.13%), Olaparib (1.8%). The relative rates of MS events were significantly different across the PARP inhibitors (p < 0.05, Table). Conclusions: This is the first study specific to prostate cancer analyzing the relative rates of MS events across different PARP inhibitors. Talazoparib exhibited the highest incidence of myelosuppression. This underscores the careful patient selection and vigilant monitoring needed in PARP inhibitors. Prompt recognition of myelosuppression is needed to optimize the safety and efficacy of PARP inhibitor therapies in prostate cancer. [Table: see text]

PARP Inhibitors in Prostate Cancer – Understanding the Current Landscape

Poly (ADP [adenosine diphosphate]-ribose) polymerase inhibitors (PARPi) are a current standard of care treatment option for patients with metastatic castration resistant prostate cancer (mCRPC), defined as prostate cancers that continue to progress despite treatment with the usual first-line androgen-deprivation therapies. PARPi’s function by targeting faulty homologous recombination repair pathways that result in cytotoxic double strand DNA break (DSB) accumulation in prostate cancer cells. While the efficacy of PARPi’s as a monotherapy option in mCRCP has been demonstrated clinically, the added utility of PARPi’s in combination with other anti-cancer agents is still being explored. This article will review the scientific rationale behind PARP-inhibitors, discuss the germline and somatic mutation testing critical to identifying predictive biomarkers for PARPi efficacy, and present the currently approved PARPi combination therapies and their indications. This review will also examine the incidence and management of PARPi toxicity, summarize ongoing trials, and propose areas of future study.

Hematological Toxicities with PARP Inhibitors in Prostate Cancer: A Systematic Review and Meta-Analysis of Phase II/III Randomized Controlled Trials.

Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events. To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer. A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews-Cochrane were queried from inception to 9 June 2023. The Mantel-Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities. The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37-4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97-10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60-6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06-11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80-10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77-17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities. PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient-physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs.

Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer.

PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research. The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments. We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission. Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.

The clinical value of homologous recombination deficiency score in prostate cancer.

e17011 Background: Aberrations in homologous recombination repair (HRR) genes serve as biomarkers for guiding the treatment decision of PARP inhibitors in prostate cancer (PCa). Homologous recombination deficiency (HRD) score which directly shows the consequence of the loss of HRR function (genomic scars) may be a more reliable biomarker for identifying patients who are sensitive to PARP inhibitors. Methods: This study involved 50 patients with PCa, including mHSPC (n = 37), mCRPC (n = 11), and locally advanced PCa (n = 2). Tumor tissue specimens were collected for targeted next-generation sequencing for 406 cancer-related genes and HRD detection. HRD score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. All the experiments were performed in OrigiMed, a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Results: The median HRD score was 34.5 (ranged from 14 to 64). With the median value as cutoff, the mutation rates of HRR were 32% (8/25) and 12% (3/25) in the high and low HRD score groups, respectively. BRCA2 mutations (P = 0.011), AR mutations (P = 0.032), RB1 mutations (P = 0.035) and altered HRR pathway (P = 0.017) were associated with high HRD scores. The mutation frequencies of AR and TP53 were significantly higher in mCRPC compared to mHSPC ( AR: 45.5% [5/11] vs 2.7% [1/37], P &lt; 0.001; TP53: 63.6% [7/11] vs 24.3% [9/37], P = 0.027). A total of 9 patients carried HRR germline mutations (5 BRCA2, 1 BRIP1, 1 RAD50, 1 RAD51D, and 1 ATM). It was found that patients with BRCA2 germline mutations had a higher HRD score (median = 37) than those with other germline mutations ( BRIP1: 25, RAD50: 19, RAD51D: 35, ATM: 36). In the 6 patients who received HRD-related treatments (including cisplatin based chemotherapy or olaparib), 1 of the 2 patients with low HRD score had PSA progression after 251 days (the other one was lost to follow up), while no PSA progression was observed in the 4 patients with high HRD score with a median follow-up of 107 days (range: 40-274 days). A mCRPC case with high HRD score (37) and HRR wild-type who received second line docetaxel+cisplatin even achieved undetectable PSA. Another mHSPC patient with a high HRD score (37) and a BRCA2 germline mutation also had no detectable PSA after first-line docetaxel+cisplatin therapy. Conclusions: To our knowledge, this is the first study in China reporting the association of HRD score and platinum-based treatments in PCa. Our results supported the possibility that HRD score could be predictive for the efficacy of platinum-based chemotherapy.

Response prediction biomarkers and drug combinations of PARP inhibitors in prostate cancer.

PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors.

PARP inhibition in prostate cancer.

Defects in DNA damage repair genes are more common in prostate cancer than previously thought. These alterations provide an opportunity for precision oncology approaches and a number of studies have now shown that PARP inhibitors can have significant antitumor activity in men with DNA damage repair-deficient metastatic castration-resistant prostate cancer. This review summarizes the key clinical trials related to the use of PARP inhibitors in prostate cancer. Besides clinical outcomes, toxicity, and PARP inhibitor resistance, the role of different DNA repair genes in the response to PARP inhibition will be discussed.

Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

SummaryHomologous repair deficiency is a clinically relevant molecular aberration in prostate cancer. The goal of this short review is to summarize the study landscape of treatments targeting these aberrations through discussion of the most relevant clinical trials. Due to its shortness, this review does not claim to be exhaustive and a major focus is being laid on PARP inhibitors in clinical development for prostate cancer.

Abstract IA18: Sensitivity and resistance biomarkers to PARP inhibitors in Mcrpc

A better understanding of the molecular underpinnings of prostate cancer renders the opportunity for more precise patient care by individualizing therapeutic strategies according to predictive biomarkers of benefit. Until now, clinical management of patients with prostate cancer, either localized or metastatic, has not yet incorporated precision medicine strategies. To pursue this, a new classification of the disease needs to be based on molecular features that are clinically relevant. Several studies have now confirmed genomic defects in the DNA damage response pathways (DDR), and primarily in the homologous recombination mediated repair pathway (HR), as a cornerstone of prostate cancer biology. This is particularly relevant in patients with metastatic castration-resistant prostate cancer (mCRPC). Among this population with lethal disease, around 20-25% of cases present genomic loss (by pathogenic mutations or by homozygous deletion) of at least one gene involved in HR, and in half of this cases the mutation is inherited, which makes these findings also relevant for patients’ relatives, considering how some of this events are linked to increased risk of prostate and others cancers. The HR gene most commonly lost in advanced prostate cancer is BRCA2 (8-12% in different series), followed by ATM (4-6%), CDK12 (3-5%), BRCA1, and PALB2 ( PARP-1 and 2 are key proteins in DNA single-strand break repair and a therapeutic target using a family of drugs (PARP inhibitors) already approved for the treatment of ovarian cancer associated to HR defects, primarily BRCA2 mutations. We completed a first stage of a phase II adaptive clinical trial evaluating the antitumor activity of the PARP inhibitor olaparib in mCRPC (TOPARP), as well as investigating predictive biomarkers associated with response to PARP inhibition. In a cohort of 49 evaluable patients who previously to docetaxel (49/49) and abiraterone and/or enzalutamide (48/49), 16 (32%) achieved a response to olaparib, using the trial preplanned definition of response (radiologic response by RECIST and/or 50% PSA fall and/or CTC conversion from >5 to On one hand, it is possible that different genes have a different weight in determining HR proficiency, and hence, synthetic lethality with PARP inhibition. It is possible that loss of some genes may be partially or totally compensated for by other proteins, whereas loss of some other genes may be more catastrophic for the tumor cell. On the other hand, it is also feasible that the presence of secondary biologic events in prostate cancer, such as AR aberrations, TP53/Rb1 loss, or others, may modulate the impact of HR defects. Analytical validation and clinical qualification of functional assays as predictive biomarkers of PARP inhibitor sensitivity would help towards integrating complex genomic, transcriptome, and epigenetics data with regards to defining the optimal predictive biomarkers for treatment stratification. The complex interaction between androgen receptor (AR) signaling and DDR may be relevant for PARP inhibition stratification. Preclinical studies suggest that blocking AR may render the cell sensitive to PARP inhibition; however, the impact of these findings on therapeutic strategies in the clinic is still not clear and further studies in localized and advanced disease are needed. Previously, a synthetic lethal interaction for PARP inhibition with PTEN loss or with the presence of ERG rearrangements in prostate cancer has been postulated from preclinical studies; to date, these data have not translated into clinical data supporting that these are optimal biomarkers to stratify patients for PARP inhibitors. It is possible these data are, however, very relevant to designing rational combination trials. Lastly, HR gene mutations are also relevant towards secondary resistance mechanisms to PARP inhibitors, which further supports their relevance in determining sensitivity. In a follow-up study we identified how in patients with germline or somatic BRCA2 and PALB2 mutations responding to olaparib, secondary genomic events (basically small fragment deletions) emerged in the region of the original mutation, reverting the gene reading frame to normal. These events occur in a polyclonal manner and may be restoring HR function. These have now been confirmed by other studies in prostate, breast, and ovarian cancer. Citation Format: Joaquin Mateo. Sensitivity and resistance biomarkers to PARP inhibitors in Mcrpc [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA18.

PARP Inhibitors in Prostate Cancer.

The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.