Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) ...polymerase (PARP) inhibition in patients with prostate and other cancers.
We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in
,
, or
; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review.
In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib.
In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).
Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic ...castration-resistant prostate cancer who were at high risk for the development of metastasis.
We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death.
A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval CI, 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%).
Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).
Adipocytic tumors are the most common type of soft tissue neoplasms. Distinguishing atypical lipomatous tumor-well-differentiated liposarcoma (WDL) from benign adipocytic neoplasms and ...dedifferentiated liposarcoma (DDL) from pleomorphic or myxoid liposarcoma (LPS) can be difficult. WDL and DDL characteristically harbor amplifications of the MDM2 and CDK4 cell cycle oncogenes with protein overexpression and can also overexpress the cell cycle regulator p16. We assessed the utility of immunohistochemistry for CDK4, MDM2, and p16 in the routine histopathologic diagnosis of WDL/DDL from other adipocytic tumors. Immunohistochemistry for the trio of markers was performed on 216 adipocytic neoplasms (31 WDLs, 57 DDLs, 11 myxoid LPS, 2 pleomorphic LPS, 91 lipomas (including intramuscular, fibro, angio, and ossifying subtypes), 18 spindle/pleomorphic lipomas, and 6 hibernomas. Sixty-eight percent of WDLs and 72% of DDLs expressed all 3 antigens, whereas 100% of WDLs and 93% of DDLs expressed at least 2 antigens. The sensitivity and specificity of the trio for detecting WDLs/DDLs were 71% and 98%, respectively. The sensitivity and specificity of CDK4 for detecting WDLs/DDLs were 86% and 89%, those of MDM2 were 86% and 74%, and those of p16 were 93% and 92%, respectively. The immunohistochemical trio of CDK4, MDM2, and p16 is a useful ancillary diagnostic tool that provides strong support in distinguishing WDLs and DDLs from other adipocytic neoplasms and is potentially more sensitive than previously assessed combinations of CDK4 and MDM2. p16 was the most sensitive and specific marker for detecting WDL/DDL, and the combination of CDK4 and p16 is of more discriminatory value than the combination of either with MDM2, the least sensitive and specific of the 3 markers.
One of the most promising developments in translational cancer medicine has been the emergence of circulating tumor cells (CTC) as a minimally invasive multifunctional biomarker. CTCs in peripheral ...blood originate from solid tumors and are involved in the process of hematogenous metastatic spread to distant sites for the establishment of secondary foci of disease. The emergence of modern CTC technologies has enabled serial assessments to be undertaken at multiple time points along a patient's cancer journey for pharmacodynamic (PD), prognostic, predictive, and intermediate endpoint biomarker studies. Despite the promise of CTCs as multifunctional biomarkers, there are still numerous challenges that hinder their incorporation into standard clinical practice. This review discusses the key technical aspects of CTC technologies, including the importance of assay validation and clinical qualification, and compares existing and novel CTC enrichment platforms. This article discusses the utility of CTCs as a multifunctional biomarker and focuses on the potential of CTCs as PD endpoints either directly via the molecular characterization of specific markers or indirectly through CTC enumeration. We propose strategies for incorporating CTCs as PD biomarkers in translational clinical trials, such as the Pharmacological Audit Trail. We also discuss issues relating to intrapatient heterogeneity and the challenges associated with isolating CTCs undergoing epithelial-mesenchymal transition, as well as apoptotic and small CTCs. Finally, we envision the future promise of CTCs for the selection and monitoring of antitumor precision therapies, including applications in single CTC phenotypic and genomic profiling and CTC-derived xenografts, and discuss the promises and limitations of such approaches. See ALL articles in this CCR focus section, "Progress in pharmacodynamic endpoints."
Abstract Context For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. ...Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification. Objective To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease. Evidence acquisition A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers , and hereditary cancer. Evidence synthesis We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC. Conclusions Relevant studies have identified genomic defects in DNA repair in PCs in 20–30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies. Patient summary Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed.
Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These ...alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum chemotherapy, while other defects might identify cases that are more likely to benefit from immune checkpoint inhibition. The potential prognostic impact and relevance for treatment selection together with the decreasing costs and broader accessibility to next-generation sequencing have already resulted in the increased frequency of genetic profiling of prostate tumours. Remarkably, almost half of all DDR genetic defects can occur in the germline, and prostate cancer patients identified as mutation carriers, as well as their families, will require appropriate genetic counselling. In this review, we summarise the current knowledge regarding the biology and clinical implications of DDR defects in prostate cancer, and outline how this evidence is prompting a change in the treatment landscape of the disease.
Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome ...measure.
Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.
A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.
A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.
Germline and somatic aberrations in DNA damage repair (DDR) genes are more prevalent in prostate cancer than previously recognized, with
as the most commonly altered gene. Germline mutations in
have ...been linked to poor prognosis when patients are managed under the protocols currently approved for prostate cancer. The impact of germline mutations in other DDR genes beyond
remain unclear. Importantly, a quarter of prostate cancer patients identified as germline mutation carriers lack a family history of cancer. The clinical implications of somatic DDR defects are yet to be elucidated. Poly ADP-ribose polymerase (PARP) inhibitors and platinum-based chemotherapy have proven to be effective in the treatment of other tumor types linked to
and
alterations and several trials are currently evaluating their efficacy in prostate cancer. Here, we summarize the available evidence regarding the prevalence of somatic and germline DDR defects in prostate cancer; their association with clinical outcomes; the trials assessing the efficacy of new therapies that exploit DDR defects in prostate cancer and briefly discuss some uncertainties about the most appropriate management for these patients.
To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) ...outcomes.
This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1).
PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses MVA P = .015; hazard ratio HR = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.
Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.
Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal ...disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles.
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