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

Immune-Checkpoint Inhibition in the Treatment of Gastro-Esophageal Cancer: A Closer Look at the Emerging Evidence

To date, several trials have evaluated the safety and efficacy of immune-checkpoint inhibitors (ICI) for the treatment of gastroesophageal cancers (GEC). In the US, ICIs have established indications for second-line treatment of microsatellite unstable tumors, while their use in third-line settings was recently withdrawn. Notably, the use of ICIs for first-line therapy of GEC is rapidly evolving, which currently includes high PD-L1 expressing tumors, irrespective of HER2 status, and in the adjuvant setting after neoadjuvant chemoradiotherapy in select patients. In this article, we review the results of studies that have evaluated the utility of ICI in the third-line, second-line, first-line, and peri-operative treatment settings of GECs. Considerations should be made before making any cross-trial comparisons since these trials vary in chemotherapy backbone, anatomical and histological eligibility, biomarker assessment, PD-L1 diagnostic antibodies, and definition of PD-L1 positivity. Regardless, the totality of the data suggest that first-line ICI use may most benefit GEC patients with high PD-L1 combined positivity score (CPS) ≥5 or ≥10, irrespective of histology or anatomy. Moreover, although PD-L1 by CPS has a good negative predictive value for significant benefit from ICIs, it has a low positive predictive value. Therefore, there is a pressing need to identify better biomarkers to predict benefit from ICIs among these patients

Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease

The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided P = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study. SIGNIFICANCE: This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial.This article is highlighted in the In This Issue feature, p. 211

Therapy-related acute lymphoblastic leukemia is a distinct entity with adverse genetic features and clinical outcomes

Therapy-related ALL is a distinct entity associated with poor-risk cytogenetics and inferior survival compared with de novo ALL. Hematopoietic stem cell transplantation may improve outcomes and should be considered for all eligible patients with therapy-related ALL. Patients with therapy-related acute lymphoblastic leukemia (t-ALL) represent a small subset of acute lymphoblastic leukemia (ALL) patients who received genotoxic therapy (ie, chemotherapy or radiation) for a prior malignancy. These patients should be distinguished from patients with de novo ALL (dn-ALL) and ALL patients who have a history of prior malignancy but have not received cytotoxic therapies in the past (acute lymphoblastic leukemia with prior malignancy [pm-ALL]). We report a retrospective multi-institutional study of patients with t-ALL (n = 116), dn-ALL (n = 100), and pm-ALL (n = 20) to investigate the impact of prior cytotoxic therapies on clinical outcomes. Compared with patients with pm-ALL, t-ALL patients had a significantly shorter interval between the first malignancy and ALL diagnosis and a higher frequency of poor-risk cytogenetic features, including KMT2A rearrangements and myelodysplastic syndrome-like abnormalities (eg, monosomal karyotype). We observed a variety of mutations among t-ALL patients, with the majority of patients exhibiting mutations that were more common with myeloid malignancies (eg, DNMT3A , RUNX1 , ASXL1 ), whereas others had ALL-type mutations (eg, CDKN2A , IKZF1 ). Median overall survival was significantly shorter in the t-ALL cohort compared with patients with dn-ALL or pm-ALL. Patients who were eligible for hematopoietic cell transplantation had improved long-term survival. Collectively, our results support t-ALL as a distinct entity based on its biologic and clinical features

Supplemental Table 1 from <i>ERBB3</i> Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Supplemental Table 1. Self-reported Race vs. Ancestry Admixture.</p

Supplemental Figure 1 from <i>ERBB3</i> Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Supplemental Figure 1: ERBB3 Expression between Patient Datasets and Kinase Family Member Expression in ERBB3 High vs. Low.</p

Supplemental Figure 2 from <i>ERBB3</i> Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Supplemental Figure 2: HER3 Gain-of-function in Additional Models.</p

Supplemental Figure 3 from <i>ERBB3</i> Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Supplemental Figure 3: ERBB3 Expression and Preliminary Clinical Outcomes.</p

Supplemental Table 2 from <i>ERBB3</i> Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Supplemental Table 2. Prevalence of Black/AA/AFR Patients in Consolidated RNA-seq Datasets.</p