Single-agent Poly ADP-ribose Polymerase Inhibitors Research Articles

Real-world effectiveness of PARP inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) by genomic homologous recombination repair (HRR) alterations and homologous recombination deficiency signature (HRDsig).

186 Background: Multiple randomized controlled trials have demonstrated efficacy of poly ADP-ribose polymerase (PARP) inhibitors in patients with metastatic castration resistant prostate cancer (mCRPC) harboring deleterious BRCA1 or BRCA2 alterations (BRCAalt). Alterations in other DNA HRR gene pathways are common and the efficacy of PARPi in these populations is less clear. We sought to evaluate the real-world effectiveness of PARPi in commonly defined HRR groups and explore clinical validity of HRDsig to additionally predict outcomes on PARPi. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Prostate Cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with mCRPC and tumor genomic profiling (tissue or liquid) who underwent single agent PARPi treatment were included, grouped by biomarkers with deleterious alterations detected: BRCA, ATM, other HRR ( ATR, ATRX, BAP1, BARD1, BRIP1, CHEK1/2, CDK12, FANCA, FANCL, MRE11, RAD51B/C/D, RAD54L, PALB2), or no HRR. Separately, patients with mCRPC and tumor tissue profiling were grouped by HRDsig status (+ vs -) using a machine learning- based algorithm built using a diverse set of copy number features. Kaplan Meier estimates and multivariable Cox PH models assessed time to next therapy (TTNT), time to treatment discontinuation (TTD), and real-world overall survival (rwOS). Results: 313 patients with mCRPC met inclusion criteria, of which 162 had tissue specimens for genomics evaluations and 151 had liquid profiling. In the tissue cohort, BRCAalt had more favorable TTNT (median 10.0 months, 95% CI 8.0 – 14.1) relative to ATM (median 3.8 months, 95% CI 2.7 – 6.9), other HRR (median 4.9 months, 95% CI 3.6 – 7.2) and no HRR (median 4.9, 95% CI 3.6 – 7.2 months). Other proxies for drug effectiveness (TTD, PSA kinetics) and rwOS had consistent results. More granular mutational analyses and liquid profiling data will be presented at the conference. Among evaluable patients without BRCAalt on tissue biopsy receiving PARPi, 5 of 75 (7%) were HRDsig(+) and had directionally more favorable (vs. HRDsig(-)) TTNT (HR: 0.39, 95%CI 0.14 – 1.12), TTD (0.46, 95%CI 0.16 – 1.31) and rwOS (HR: 0.27, 95%CI 0.07 – 1.14). Conclusions: We observe no significant outcomes difference between non- BRCAalt groups (defined as ATM, other HRR, and no HRR) in this cohort with respect to proxies of drug effectiveness. These results are largely consistent with biomarker-defined subgroup analyses from completed clinical trials. However, HRDsig may be able to identify a small non-BRCAalt subgroup with enhanced benefit. Associations of BRCAalt(-)/HRDsig(+) and PARPi performance deserve further attention in additional cohorts.

Coronado CLL: A Phase Ib/II Trial of Combination Rp-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refract ory Chronic Lymphocytic Leukemia

Background: Genes within the DNA damage repair ( DDR) pathways are frequently mutated in relapsed/refractory ( R/R) chronic lymphocytic leukemia ( CLL) and clinically correlate with decreased response rates and shortened progression-free ( PFS) and overall survivals ( OS). The most commonly affected DDR genetic aberrations include deletion 17p13 [ del(17p)], deletion 11q22.3 [ del(11q)], and mutations in TP53, ATM, SF3B1, XPO1 and POT1. Due to their poor clinical outcomes, patients (pts) with DDR-deficient CLL remain an area of unmet need and the development of novel drugs and combinations will be critical to improving their prognosis. Mechanistically, CLL cells with DDR genetic alterations lack double-stranded DNA breakage repair and major cell cycle checkpoint pathways. Therefore, R/R CLL cells are dependent on single-stranded DNA breakage ( SSB) repair and alternative DNA replication arrest machinery to ensure DNA integrity, strand repair and cell survival. DNA damage at the replication fork is primarily recognized by ataxia telangiectasia and rad3 ( ATR) protein, which ensures mitotic arrest and recruitment of poly (ADP-ribose) polymerase ( PARP) based SSB repair mechanisms. In germline DDR-deficient breast and ovarian cancers with BRCA1/BRCA2 mutations, the use of both single agent PARP inhibitors ( PARPi) and ATR inhibitors ( ATRi) have led to significant disease response and improved OS. Furthermore, combination PARPi and ATRi have demonstrated synergistic activity in preclinical data producing increased apoptosis and cell death in BRCA2-mutated ovarian cell lines. In DDR-deficient CLL primary cell and murine models, single agent PARPi and ATRi have demonstrated significant cell death as compared to wildtype CLL and healthy donor lymphocytes. RP-3500 is a highly potent ATRi. In preclinical data generated in SUM149PT DDR-deficient breast cancer cell lines, combining RP-3500 with the PARPi, olaparib, substantially reduced tumor volume at lower doses than the previously determined maximum tolerated dose ( MTD) of each drug when used as monotherapy. Furthermore, intermittent dosing of both drugs (3 days per week) demonstrated equal cell apoptosis as continuous dosing. Therefore, we hypothesize that the combination of RP-3500 and olaparib will be a highly efficacious treatment for R/R DDR-deficient CLL pts and that the lower dosages and intermittent dosing schedule required of each drug when administered in combination will improve safety of the treatment. Study Design and Methods: This is a multi-site (University of Utah and the Ohio State University), phase Ib/II investigator-initiated clinical trial using combination RP-3500 and olaparib in R/R CLL pts with DDR pathway deficiencies to determine the safety and efficacy of the drug combination (NCT05405309). Primary objectives include determining the MTD in phase Ib leading to the recommended phase 2 dose ( RP2D), and overall response rate ( ORR) in phase II. Key secondary objectives include safety and tolerability, PFS, OS and duration of response of the combination. Eligibility: Key inclusion criteria include a diagnosis of CLL according to the 2018 iwCLL guidelines, age ≥18 years, ECOG performance status of ≤2, R/R after at least 2 prior lines of therapy. Primary CLL cells must exhibit any one of the following abnormalities: a) somatic mutation(s) in TP53, ATM, SF3B1, XPO1 or POT1, or b) positive FISH for either del(17p) or del(11q). Statistical Methods: Phase Ib: The phase Ib of the trial will utilizea keyboard design, which is a novel Bayesian method that typically underestimates the MTD. The target toxicity is 30% with an equivalence interval between 25-33% of pts. With an anticipated 3 dose levels ( DL) and an option for a DL-1, up to 18 pts may be required to determine the MTD and RP2D. Phase II: Any pt treated at the RP2D within phase Ib will be rolled into the phase II analysis for efficacy. With a planned 24 evaluable pts in phase II, the target ORR will be 60%, which was selected due to a recent phase I/II study of pirtobrutinib enrolling a similar CLL pt population demonstrating an ORR of the drug ~63%. ORR will be summarized by the observed proportion and an exact one-sided 95% confidence interval (Clopper-Pearson method). With 24 evaluable pts, the lower bound of the confidence interval will be approximately 17-20% below the observed proportion for observed ORR near 60%, which is an acceptable level of precision in a dose expansion cohort.

Poly (ADP-Ribose) Polymerase Inhibitors in Patients With Urothelial Cancer.

Poly ADP-ribose polymerase inhibitors (PARPis) have clinical activity in several cancers. The rationale of their therapeutic use in urothelial cancer (UC) resides in the high homologous-recombination repair (HRR) deficiency (HRD) prevalence and potential cross-sensitivity with platinum-based chemotherapy (PBCT). This review aims to summarize and analyze trials exploring the activity of PARPis in UC, focusing on patients who may benefit from those agents, the best clinical setting for the treatment and the benefit of the association with immune-checkpoint inhibitors (ICIs). We included all the available trials analyzing the activity of PARPis in UC in neoadjuvant, adjuvant, first or subsequent lines, and maintenance setting. We included PARPis in monotherapy and in association with other agents. The results in the maintenance setting are intriguing: ATLANTIS trial showed signals of improved progression-free survival in patients with known HRR aberrations, although the Meet-URO12 trial, with its negative results, suggested the failure of clinical selection based on platinum sensitivity only. Single-agent PARPis in pretreated patients showed discouraging results in an unselected population of chemo-refractory patients. Concerning the association of PARPis with ICIs, several trials are exploring their role in platinum-naïve setting; the results in the advanced setting were globally negative. Prior selection of HRD status is essential to identify patients who might benefit from PARPis. The ideal clinical settings seem to be the maintenance treatment and the combination with ICIs in platinum-naïve patients. Definitive results of ongoing and further trials will delineate the position for PARPis, if any, in UC therapy.

Combining Poly (ADP-Ribose) Polymerase (PARP) Inhibitors with Chemotherapeutic Agents: Promise and Challenges.

Better understanding of molecular drivers and dysregulated pathways has furthered the concept of precision oncology and rational drug development. The role of DNA damage response (DDR) pathways has been extensively studied in carcinogenesis and as potential therapeutic targets to improve response to chemotherapy or overcome resistance. Treatment with small molecule inhibitors of PARP has resulted in clinical response and conferred survival benefit to patients with ovarian cancer, BRCA-mutant breast cancer, HRD-deficient prostate cancer and BRCA-mutant pancreatic cancer, leading to US Food and Drug Administration (FDA) approvals. However, the observed clinical benefit with single agent PARP inhibitors is limited to few tumor types within the relevant genetic context. Since DDR pathways are essential for repair of damage caused by cytotoxic agents, PARP inhibitors have been evaluated in combination with various chemotherapeutic agents to broaden the therapeutic application of this class of drugs. In this chapter, we discuss the combination of PARP inhibitors with different chemotherapeutics agents, clinical experience to date, lessons learnt, and future directions for this approach.

PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline.

To provide recommendations on the use of poly(ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer (EOC). Randomized, controlled, and open-labeled trials published from 2011 through 2020 were identified in a literature search. Guideline recommendations were based on the review of the evidence, US Food and Drug Administration approvals, and consensus when evidence was lacking. The systematic review identified 17 eligible trials. The guideline pertains to patients who are PARPi naïve. All patients with newly diagnosed, stage III-IV EOC whose disease is in complete or partial response to first-line, platinum-based chemotherapy with high-grade serous or endometrioid EOC should be offered PARPi maintenance therapy with niraparib. For patients with germline or somatic pathogenic or likely pathogenic variants in BRCA1 (g/sBRCA1) or BRCA2 (g/sBRCA2) genes should be treated with olaparib. The addition of olaparib to bevacizumab may be offered to patients with stage III-IV EOC with g/sBRCA1/2 and/or genomic instability and a partial or complete response to chemotherapy plus bevacizumab combination. Maintenance therapy (second line or more) with single-agent PARPi may be offered for patients with EOC who have not received a PARPi and have responded to platinum-based therapy regardless of BRCA mutation status. Treatment with a PARPi should be offered to patients with recurrent EOC that has not recurred within 6 months of platinum-based therapy, who have not received a PARPi and have a g/sBRCA1/2, or whose tumor demonstrates genomic instability. PARPis are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Recommendations for managing specific adverse events are presented. Data to support reuse of PARPis in any setting are needed.Additional information is available at www.asco.org/gynecologic-cancer-guidelines.

Medical Management of newly diagnosed breast cancer in a BRCA1/2 mutation carrier.

Germline BRCA1/2 mutations may be infrequent in unselected breast cancer population but are concentrated in those with triple-negative breast cancer or high-risk family history. Insight into the biology of BRCA mutation is now allowing a targeted therapeutic approach to these carriers with breast cancer. Functional BRCA genes play a critical role in DNA damage repair. Agents such as platinum salts and poly (ADP-ribose) polymerase (PARP) inhibitors exploit this vulnerability of impaired DNA damage repair mechanism in BRCA mutant cancers to leverage therapeutic benefit. Research has demonstrated improved response rates to platinum salts in BRCA-mutated compared with non-BRCA-mutated breast cancer, particularly in the metastatic setting. Additionally, clinical trials of single-agent PARP inhibitors have shown encouraging response rates and progression-free survival in patients with BRCA1/2-mutated breast cancer. In this review, we summarize the medical management of BRCA-associated breast cancer.

Abstract 2820: Synergistic antileukemic activity of the antibody-drug conjugate (IMGN779) combined with PARP inhibition in preclinical human acute myeloid leukemia models

Abstract Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy of immature myeloid cells. Antibody-drug conjugates (ADC) comprising humanized anti-CD33 monoclonal antibodies linked to cytotoxic payloads are known to exert clinical activity in AML patients. However, dose-dependent effects of ADC therapy, specifically hepatotoxicity, myelosuppression and veno-occlusive disease, have limited their clinical utility in patients. Inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP), so-called PARP inhibitors (PARPi), enhance tumor death by preventing repair of single-stranded DNA breaks. We have previously shown (Portwood S et al., ASH 2016) that the PARPi olaparib improves the activity of the anti-CD33 ADC (IMGN779) in preclinical AML models. Here we assessed the efficacy of multiple PARPi (olaparib, niraparib, rucaparib, veliparib, and talazoparib) alone and in combination with IMGN779 for AML therapy. Materials and Methods: Human AML cell lines (HEL, HL60) were characterized for CD33 expression using flow cytometry after staining with antibody-linked fluorescent QuantiBrite Beads. Cells were treated with varying doses of IMGN779 (100pM-1nM) and PARPi (10nM-100uM) alone and in combination for 96h. Viability was measured after treatment utilizing a WST-1 colorimetric assay. Induction of apoptosis, cell cycle effects, and DNA damage were characterized by flow cytometry following 72h of treatment. Synergy reports were generated using Compusyn software. Results: All PARPi demonstrated dose-dependent inhibition of AML (HEL, HL60) growth with the following IC50 ranges: talazoparib 200-400nM, niraparib 2.5-7.3 μM, olaparib 7.4-8.9 μM, rucaparib 39-75 μM, and veliparib 88-100 μM. Combination therapy with IMGN779 and four PARPi (veliparib, niraparib, olaparib, talazoparib) resulted in synergistic in vitro antileukemic effects with CI values <1. Statistically significant improvements in antiproliferative effects, apoptosis induction, and DNA damage as measured by γH2AX phosphorylation (p<0.05) were observed with combination PARPi and 779 therapy as compared with monotherapy. While single-agent PARPi largely induced G2 cell cycle arrest, combination IMGN779 and PARPi resulted in prominent S phase cell cycle arrest. Conclusions: Our results demonstrate that PARP inhibitors as a class exert dose-dependent antitumor activity against human CD33+ AML cells. Moreover, PARPi consistently induce in vitro synergistic antileukemic effects against human AML cells when combined with the anti-CD33 ADC (IMGN779). Studies evaluating the mechanisms of action and the efficacy of combinatorial therapy in primary AML cells are under way. These findings support further clinical studies of PARP inhibition as a potential means of enhancing the activity of ADCs for acute myeloid leukemia therapy. Citation Format: Claire Fritz, Scott M. Portwood, Julie Adams, Eunice S. Wang. Synergistic antileukemic activity of the antibody-drug conjugate (IMGN779) combined with PARP inhibition in preclinical human acute myeloid leukemia models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2820.

Abstract IA10: Targeting the DNA damage response in cancer: Progress in the clinic

Abstract Genomic instability is a recognized hallmark of cancer and is associated with a predilection for cumulative DNA damage. In contrast to cytotoxic chemotherapy and radiotherapy, targeting critical aberrations involved in the DNA damage response (DDR) of cancer cells permits greater tumor selectivity against tumors with deficient DDR function, while sparing normal tissue. Poly(ADP-ribose) polymerase (PARP) inhibitors are the first class of antitumor agents to exploit cellular weaknesses in DNA repair through the concept of synthetic lethality. Since the pivotal studies in 2005 that demonstrated the exquisite sensitivity of BRCA1 and BRCA2 (BRCA1/2) mutant cell lines and xenografts to PARP inhibition, great progress has been made in developing single agent PARP inhibitors for use in the Clinic. Early phase clinical trials demonstrated that olaparib was well tolerated, with single agent activity in patients with BRCA1/2 mutation ovarian, breast, pancreatic and castration-resistant prostate cancers. In 2014, olaparib (Lynparza; AstraZeneca) was the first PARP inhibitor to be approved by the European Medicines Agency (EMA) as maintenance therapy for responding patients with BRCA1/2 mutant ovarian cancer following platinum-based chemotherapy, and the first to obtain accelerated approval by the US Food and Drug Administration (FDA) for advanced BRCA1/2 mutant ovarian cancer. There are also multiple other potent and bona fide PARP inhibitors, including rucaparib (AGO14699; Clovis), talazoparib (BMN673; Medivation), niraparib (MK4827; Tesaro) and veliparib (ABT-888; Abbvie), which are all currently in late phase clinical trial development. A number of critical questions remain in terms of optimizing and widening the clinical efficacy and utility of PARP inhibitors, respectively. While benefits are observed following PARP inhibitor treatment in patients with a range of tumor types with germline BRCA1/2 mutations, it is now clear that clinical efficacy is not restricted to this niche population of patients. Potential antitumor strategies may include successfully characterizing other predictive biomarkers of response or defining unique PARP inhibitor combination regimens. Such novel combinations include those with molecularly targeted agents against the PI3K-AKT and angiogenic pathways, as well as immune checkpoint inhibitors. Apart from PARP inhibitors, other novel antitumor agents against key DDR targets such as ATR and Wee1 kinase are showing promise in early phase clinical trials. The first-in-class ATR inhibitor VX-970 (Vertex Pharmaceuticals) was well tolerated as monotherapy and in combination with carboplatin chemotherapy, with preliminary evidence of target modulation and early signals of antitumor activity in DDR aberrant cancers. VX-970 is currently being explored in early phase I/II studies involving multiple tumor types, including triple-negative breast cancer and non-small cell lung cancer; and in patients with DDR aberrations. AZD1775 (AstraZeneca) is a first-in-class Wee1 inhibitor, which was well tolerated with preliminary single-agent activity in patients harboring BRCA1/2 mutations. AZD1775 was also well tolerated in combination with carboplatin chemotherapy, with promising antitumor activity in p53 mutated ovarian cancer refractory or resistant to standard first line therapy. Citation Format: Timothy A. Yap. Targeting the DNA damage response in cancer: Progress in the clinic. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA10.