Publications by authors named "Benjamin L Maughan"

48 Publications

Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

N Engl J Med 2021 11;385(22):2036-2046

From the University of Texas M.D. Anderson Cancer Center, Houston (E.J.); Aarhus University Hospital, Aarhus, Denmark (F.D.); Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (O.I.); Vanderbilt University Medical Center, Nashville (W.K.R.); University of Pennsylvania, Philadelphia (V.K.N.); the University of Utah, Salt Lake City (B.L.M.); Hôpital Européen Georges-Pompidou, University of Paris, Paris (S.O.); the University of Michigan, Ann Arbor (T.E.); the University of Pittsburgh, Pittsburgh (J.K.M.); Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom (S.J.W.); Merck, Kenilworth, NJ (S.T., E.K.P., R.F.P.); and the Center for Cancer Research, National Cancer Institute, Bethesda, MD (W.M.L., R.S.).

Background: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α).

Methods: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.

Results: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).

Conclusions: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2103425DOI Listing
November 2021

Treatment Pattern and Outcomes with Systemic Therapy in Men with Metastatic Prostate Cancer in the Real-World Patients in the United States.

Cancers (Basel) 2021 Sep 30;13(19). Epub 2021 Sep 30.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Background: Both novel hormonal therapies and docetaxel are approved for treatment of metastatic prostate cancer (mPC; in castration sensitive or refractory settings). Present knowledge gaps include lack of real-world data on treatment patterns in patients with newly diagnosed mPC, and comparative effectiveness of novel hormonal therapies (NHT) versus docetaxel after treatment with a prior NHT.

Methods: Herein we extracted patient-level data from a large real-world database of patients with mPC in United States. Utilization of NHT or docetaxel for mPC and comparative effectiveness of an alternate NHT versus docetaxel after one prior NHT was evaluated. Comparative effectiveness was examined via Cox proportional hazards model with propensity score matching weights. Each patient's propensity for treatment was modeled via random forest based on 22 factors potentially driving treatment selection.

Results: The majority of patients (54%) received only androgen deprivation therapy for mPC. In patients treated with an NHT, alternate NHT was the most common next therapy and was associated with improved median overall survival over docetaxel (abiraterone followed by docetaxel vs. enzalutamide (8.7 vs. 15.6 months; adjusted hazards ratio; aHR 1.32; = 0.009; and enzalutamide followed by docetaxel vs. abiraterone (9.7 vs. 13.2 months aHR 1.40; = 0.009). Limitations of the study include retrospective design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13194951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508241PMC
September 2021

Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study.

J Clin Oncol 2021 Nov 7;39(33):3725-3736. Epub 2021 Sep 7.

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.

Purpose: COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non-clear cell (ncc) renal cell carcinoma (RCC).

Methods: This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety.

Results: A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs.

Conclusion: The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601305PMC
November 2021

Radium-223 plus Enzalutamide Versus Enzalutamide in Metastatic Castration-Refractory Prostate Cancer: Final Safety and Efficacy Results.

Oncologist 2021 Aug 22. Epub 2021 Aug 22.

Genitourinary Oncology, Huntsman Cancer Institute, Salt Lake City, Utah, USA.

Lessons Learned: Long-term safety of radium-223 with enzalutamide was confirmed in this clinical trial. PSA-PFS2 was prolonged with the combination compared with enzalutamide alone.

Background: Previously, we showed the combination of radium-223 and enzalutamide to be safe and associated with improved efficacy based on a concomitant decline in serum bone metabolism markers compared with enzalutamide alone in a phase II trial of men with metastatic castration-resistant prostate cancer (mCRPC) [1].

Methods: Secondary endpoints were not included in our initial report, and we include them herein, after a median follow-up of 22 months. These objectives included long-term safety, prostate-specific antigen (PSA)-progression-free survival (PFS), and radiographic progression-free survival; PSA-PFS2 (time from start of protocol therapy to PSA progression on subsequent therapy); time to next therapy (TTNT); and overall survival (OS). Survival analysis and log-rank tests were performed using the R statistical package v.4.0.2 (https://www.r-project.org). Statistical significance was defined as p < .05.

Results: Of 47 patients (median age, 68 years), 35 received the combination and 12 enzalutamide alone. After a median follow-up of 22 months, final safety results did not show any increase in fractures or other adverse events in the combination arm. PSA-PFS2 was significantly improved, and other efficacy parameters were numerically improved in the combination over the enzalutamide arm.

Conclusion: The combination of enzalutamide and radium-223 was found to be safe and associated with promising efficacy in men with mCRPC. These hypothesis-generating results portend well for the ongoing phase III PEACE III trial in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13949DOI Listing
August 2021

Identification of Somatic Gene Signatures in Circulating Cell-Free DNA Associated with Disease Progression in Metastatic Prostate Cancer by a Novel Machine Learning Platform.

Oncologist 2021 09 7;26(9):751-760. Epub 2021 Jul 7.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

Purpose: Progression from metastatic castration-sensitive prostate cancer (mCSPC) to a castration-resistant (mCRPC) state heralds the lethal phenotype of prostate cancer. Identifying genomic alterations associated with mCRPC may help find new targets for drug development. In the majority of patients, obtaining a tumor biopsy is challenging because of the predominance of bone-only metastasis. In this study, we hypothesize that machine learning (ML) algorithms can identify clinically relevant patterns of genomic alterations (GAs) that distinguish mCRPC from mCSPC, as assessed by next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA).

Experimental Design: Retrospective clinical data from men with metastatic prostate cancer were collected. Men with NGS of cfDNA performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory at time of diagnosis of mCSPC or mCRPC were included. A combination of supervised and unsupervised ML algorithms was used to obtain biologically interpretable, potentially actionable insights into genomic signatures that distinguish mCRPC from mCSPC.

Results: GAs that distinguish patients with mCRPC (n = 187) from patients with mCSPC (n = 154) (positive predictive value = 94%, specificity = 91%) were identified using supervised ML algorithms. These GAs, primarily amplifications, corresponded to androgen receptor, Mitogen-activated protein kinase (MAPK) signaling, Phosphoinositide 3-kinase (PI3K) signaling, G1/S cell cycle, and receptor tyrosine kinases. We also identified recurrent patterns of gene- and pathway-level alterations associated with mCRPC by using Bayesian networks, an unsupervised machine learning algorithm.

Conclusion: These results provide clinical evidence that progression from mCSPC to mCRPC is associated with stereotyped concomitant gain-of-function aberrations in these pathways. Furthermore, detection of these aberrations in cfDNA may overcome the challenges associated with obtaining tumor bone biopsies and allow contemporary investigation of combinatorial therapies that target these aberrations.

Implications For Practice: The progression from castration-sensitive to castration-resistant prostate cancer is characterized by worse prognosis and there is a pressing need for targeted drugs to prevent or delay this transition. This study used machine learning algorithms to examine the cell-free DNA of patients to identify alterations to specific pathways and genes associated with progression. Detection of these alterations in cell-free DNA may overcome the challenges associated with obtaining tumor bone biopsies and allow contemporary investigation of combinatorial therapies that target these aberrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417886PMC
September 2021

New models for defining prostate cancer biology and patient prognosis.

Asian J Androl 2021 Jun 11. Epub 2021 Jun 11.

Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/aja.aja_48_21DOI Listing
June 2021

Complementary Role of Circulating Tumor DNA Assessment and Tissue Genomic Profiling in Metastatic Renal Cell Carcinoma.

Clin Cancer Res 2021 Sep 15;27(17):4807-4813. Epub 2021 Jun 15.

Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.

Purpose: The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC.

Experimental Design: Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed.

Results: ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays.

Conclusions: This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0572DOI Listing
September 2021

Olaparib and rucaparib for the treatment of DNA repair-deficient metastatic castration-resistant prostate cancer.

Expert Opin Pharmacother 2021 Aug 7;22(12):1625-1632. Epub 2021 Apr 7.

Department of Oncology and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: Metastatic prostate cancer is a heterogeneous disease characterized by clinical and genomic heterogeneity. Many prostate cancers harbor mutations causing DNA repair deficiency, specifically homologous recombination deficiency, sensitizing to drugs that inhibit poly ADP-ribose polymerase (PARP). PARP is an enzyme that is involved in single-stranded DNA repair and is the target of newly approved treatments for metastatic prostate cancer.

Areas Covered: Here, the authors' review the clinical trials leading to the recent approvals of two PARP inhibitors (PARPi), olaparib and rucaparib, specifically TOPARP-A, TOPARP-B, PROfound and TRITON-2. They also compare the different FDA approvals for both of these medications and outline the safety of this class of drugs in prostate cancer.

Expert Opinion: Because PARPi are particularly effective in men with somatic or germline alterations in BRCA1 and BRCA2, we recommend that all men be tested for DNA alterations with next-generation sequencing in tumor cells obtained from either tissue or blood. We also recommend that olaparib or rucaparib be considered relatively early in the treatment sequence in metastatic castration-resistant prostate cancer patients with BRCA1 or BRCA2 mutations. Other DNA alterations might also sensitize to PARPi though the response rates are lower, so other standard therapies should be prioritized first.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14656566.2021.1912015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419006PMC
August 2021

Tumor Frameshift Mutation Proportion Predicts Response to Immunotherapy in Mismatch Repair-Deficient Prostate Cancer.

Oncologist 2021 02 3;26(2):e270-e278. Epub 2020 Dec 3.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Genomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer.

Methods: To enrich for response to anti-PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort.

Results: Nineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy. The PSA response rate was 65%, and the median progression-free survival (PFS) was 24 (95% confidence interval 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment and with density of CD8+ tumor-infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort.

Conclusion: Tumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity.

Implications For Practice: Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti-PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873327PMC
February 2021

Optimized Management of Nivolumab and Ipilimumab in Advanced Renal Cell Carcinoma: A Response-Based Phase II Study (OMNIVORE).

J Clin Oncol 2020 12 27;38(36):4240-4248. Epub 2020 Oct 27.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473).

Methods: We enrolled patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B).

Results: Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed.

Conclusion: In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768333PMC
December 2020

Pathogenic Germline DNA Repair Gene and Mutations in Men With Metastatic Prostate Cancer.

JCO Precis Oncol 2020 4;4. Epub 2020 Mar 4.

Department of Medicine and the Duke Cancer Institute, Duke University School of Medicine, Durham, NC.

Purpose: Germline mutations in DNA repair (DR) genes and susceptibility genes and have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood.

Patients And Methods: To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, , and in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses.

Results: All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; /, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene . It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or G84E mutations.

Conclusion: These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.19.00284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446531PMC
March 2020

Recent developments in the treatment of non-metastatic castration resistant prostate cancer.

Cancer Treat Res Commun 2020 22;24:100181. Epub 2020 May 22.

University of Utah Hospital, UT 84103, United States.

Non-metastatic castration resistant prostate cancer (nmCRPC) is defined as a disease state withlack of radiographic evidence of metastatic disease, a confirmed rising PSA level on continuous ADT and maintaining a castrate level of testosterone following definitive therapy. Prior to the publication of PROSPER, SPARTAN and ARAMIS, no trials have demonstrated a clinical benefit for these patients. Recently enzalutamide, apalutamide, and darolutamide respectively, were tested in this disease setting with metastasis free survival (MFS) as the primary endpoint for each trial. In this review article, we define key terms related to the discussion of nmCRPC, examine the clinical trial design, and safety profile for each of these three key clinical trials and present updated overall survival (OS) results from these studies. Also we specifically discuss the key clinical trial results including the primary endpoint of MFS for each trial as well as quality of life effects of these three androgen receptor antagonists. Finally, this article examines the potential impact of molecular imaging testing on the applicability of these clinical trial results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctarc.2020.100181DOI Listing
May 2021

Neuroendocrine differentiation in usual-type prostatic adenocarcinoma: Molecular characterization and clinical significance.

Prostate 2020 09 10;80(12):1012-1023. Epub 2020 Jul 10.

Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Background: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain.

Methods: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55).

Results: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9).

Conclusion: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pros.24035DOI Listing
September 2020

Mini-Review: Cabozantinib in the Treatment of Advanced Renal Cell Carcinoma and Hepatocellular Carcinoma.

Cancer Manag Res 2020 20;12:3741-3749. Epub 2020 May 20.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Cabozantinib is an oral, tyrosine-kinase inhibitor with potent activity against VEGFR2 and MET, along with multiple other tyrosine kinases involved in cancer development and progression. Herein, we will focus on preclinical and clinical studies leading to the approval of cabozantinib in advanced renal cell carcinoma and hepatocellular carcinoma. Covered studies include NCT01100619, CABOSUN, METEOR, NCT00940225 and the CELESTIAL trial. Finally, we review future directions of cabozantinib development by highlighting some ongoing clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CMAR.S202973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246323PMC
May 2020

-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors.

JCO Precis Oncol 2020 21;4:370-381. Epub 2020 Apr 21.

Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL.

Purpose: In prostate cancer, inactivating mutations lead to gene fusion-induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize -aberrant prostate cancers.

Methods: We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors.

Results: Sixty men with at least monoallelic (51.7% biallelic) alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months.

Conclusion: -altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates deficiency in immunotherapy sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/po.19.00399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252221PMC
April 2020

Definitive Chemoradiotherapy for Locally Advanced, Lymph-node Positive, Nonmetastatic Penile Squamous Cell Carcinoma.

Clin Genitourin Cancer 2020 10 3;18(5):e573-e584. Epub 2020 Mar 3.

Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. Electronic address:

Introduction: Locally advanced penile cancer is rare, with few reported studies on the therapeutic role of chemoradiotherapy. We sought to characterize the efficacy and toxicity of definitive chemoradiotherapy for locally advanced, node-positive, squamous cell carcinoma of the penis.

Materials And Methods: Six patients who had refused or were ineligible for surgical resection of clinically staged node-positive squamous cell penile cancer were treated with definitive chemoradiotherapy using either weekly cisplatin or 2 cycles of mitomycin C/5-fluorouracil. The mean radiation dose to the primary sites, involved lymph nodes, involved nodal basins, and uninvolved nodal basins was 57.2, 55.0, 49.7, and 42.3 equivalent dose delivered in 2-Gy fractions.

Results: With a median follow-up of 7.2 years, 4 of the 6 patients were recurrence-free and 2 had developed recurrence. One of the latter died of penile-specific complications after salvage surgery to treat the recurrence. Of the 6 patients, 4 experienced long-term penectomy-free survival. No patient developed distant metastasis after therapy. The 4 patients with durable penectomy-free survival reported excellent urologic, sexual, and bowel function, as assessed by various validated patient-reported outcome surveys and subjective reports. One of the 2 patients with recurrence was successfully salvaged with penectomy. Lymphedema and stricture were not reported by any of the patients.

Conclusions: Definitive chemoradiotherapy is an effective organ-sparing treatment of node-positive penile cancer, with durable disease control and maintenance of quality of life. This treatment option should be offered to carefully counseled patients within the context of expert multidisciplinary teams and should be incorporated into expert consensus treatment guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2020.02.007DOI Listing
October 2020

F-fluciclovine PET CT detection of biochemical recurrent prostate cancer at specific PSA thresholds after definitive treatment.

Urol Oncol 2020 07 18;38(7):636.e1-636.e6. Epub 2020 Apr 18.

University of Utah Health Sciences - Huntsman Cancer Institute, Salt Lake City, UT.

Objectives: To evaluate various Prostate-Specific Antigen (PSA) thresholds at which a F-fluciclovine PET scan could be considered in the setting of biochemical recurrent prostate cancer after definitive treatment.

Methods: We analyzed available records of men who underwent a F-fluciclovine PET scan after definitive therapy at a single academic institution between November 2016 to May 2018. The primary outcome was the rate of positive imaging findings at specific PSA thresholds. We then employed empiric strategies including a ROC curve and decision curve analysis to identify a specific threshold for which obtaining a positive result would be optimized.

Results: A total of 115 men underwent imaging with F-fluciclovine PET. No concerning lesions were identified in 25 (21.7%) patients, 32 (27.8%) had a solitary lesion identified, 45 (39.1%) had 2 to 5 lesions, and 13 (11.3%) had greater than 5 suspicious lesions identified. At PSA thresholds of less than 0.5, 0.5 to 2.0, and greater than 2, lesions were detected in 55.5% (12/22), 70.6% (24/34), and 91.5% (54/59) of patients respectively [P < 0.001]. Our ROC analysis yielded a PSA threshold of 2.10 while our decision curve analysis provided a PSA cutoff of 1.38.

Conclusion: This study constitutes an early single institution series evaluating the use of F-fluciclovine PET scans in the assessment of biochemically recurrent prostate cancer after definitive treatment. The probability of having positive imaging findings and increasing numbers of suspicious lesions rises with increasing PSA. Utilization of a lower PSA threshold of 0.5 may allow earlier intervention with salvage therapies in biochemical recurrence. However, using a threshold below 1 carries a higher risk of negative scans. Employing a higher PSA threshold of 1 to 2 carries greater sensitivity and specificity and may maximize identifying individuals with early BCR who may benefit from early intervention, while minimizing negative scans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urolonc.2020.03.021DOI Listing
July 2020

Does sequencing order of antiandrogens in prostate cancer matter?

Nat Rev Urol 2020 04;17(4):197-198

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41585-020-0289-9DOI Listing
April 2020

A Phase I Study of Alpha-1,3-Galactosyltransferase-Expressing Allogeneic Renal Cell Carcinoma Immunotherapy in Patients with Refractory Metastatic Renal Cell Carcinoma.

Oncologist 2020 02 6;25(2):121-e213. Epub 2019 Sep 6.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

Lessons Learned: HyperAcute Renal immunotherapy was well tolerated and demonstrated antitumor activity in patients requiring salvage-line treatment for metastatic renal cell carcinoma (mRCC). HyperAcute Renal immunotherapy was safely administered with concomitant salvage-line treatments for mRCC, and it may be a candidate for inclusion in novel combinations for salvage treatment of mRCC because of its unique mechanism of action.

Background: HyperAcute Renal (HAR) immunotherapy exploits a naturally occurring barrier to xenotransplantation and zoonotic infections in humans to immunize patients against metastatic renal cell carcinoma (mRCC) cells. HAR consists of two allogeneic renal cancer cell lines genetically modified to express α(1,3)Gal, to which humans have an inherent pre-existing immunity.

Methods: Patients with refractory mRCC were eligible for this phase I dose-escalation trial. Concomitant treatment was permitted after the initial 2 months of HAR monotherapy. HAR was injected intradermally weekly for 4 weeks then biweekly for 20 weeks, totaling 14 immunizations. The primary endpoint was safety and determination of a maximum tolerated dose (MTD).

Results: Among 18 patients enrolled, two grade 3 adverse events (AEs) were attributed to HAR, lymphopenia and injection site reaction, and no grade 4/5 AEs occurred. The recommended phase II dose (RP2D) was 300 million cells. One patient had a partial response and eight patients had stable disease, for a disease control rate of 50% (9/18). Median overall survival with low-dose HAR was 14.2 months and was 25.3 months with high-dose HAR.

Conclusion: In pretreated mRCC, HAR immunotherapy was well tolerated and demonstrated antitumor activity. HAR immunotherapy may be a candidate for inclusion in novel combinations for salvage treatment of mRCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2019-0599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011628PMC
February 2020

Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion Mutations among Patients with Advanced Solid Tumors.

Clin Cancer Res 2020 06 7;26(11):2546-2555. Epub 2020 Feb 7.

Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) mutations. Acquired reversions can restore function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of mutations.

Experimental Design: Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion-deletion mutations (indels) in , and distinguishes somatic/reversion from germline mutations with high accuracy.

Results: Among 828 patients, one or more deleterious mutations were detected in 60 (7.2%) patients, including germline ( = 42) and somatic ( = 18) mutations. Common coexisting mutations included (61.6%), (30%), (26.6%), (15%), and (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.

Conclusions: cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2933DOI Listing
June 2020

Prospective Evaluation of Bone Metabolic Markers as Surrogate Markers of Response to Radium-223 Therapy in Metastatic Castration-resistant Prostate Cancer.

Clin Cancer Res 2020 05 14;26(9):2104-2110. Epub 2020 Jan 14.

Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

Purpose: Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMMs) as surrogate markers of response to radium-223 in mCRPC.

Patients And Methods: A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination.

Results: Thirty-nine men were randomized to RE ( = 27) or enzalutamide ( = 12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% confidence interval, 0.51-0.81; = 0.00048) favored RE versus enzalutamide. Overall, BMMs decreased with the RE therapy compared with enzalutamide. Improved PSA response rate in RE versus enzalutamide ( = 0.024), correlated with decline in BMMs.

Conclusions: BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radium-223 in real-time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2591DOI Listing
May 2020

Developing a Highly Specific Biomarker for Germ Cell Malignancies: Plasma miR371 Expression Across the Germ Cell Malignancy Spectrum.

J Clin Oncol 2019 11 25;37(33):3090-3098. Epub 2019 Sep 25.

BC Cancer, Vancouver Centre, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: Our objective was to evaluate operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumor.

Patients And Methods: One hundred eleven male patients with a history of or newly diagnosed germ cell tumors were evaluable. Biospecimens obtained before confirmed clinical events were analyzed for miR371 expression with blinding of providers and laboratory personnel to analytic results or clinical status, respectively. Cases (patients with clinically confirmed active germ cell malignancy [aGCM]) and controls (patients with no clinically confirmed aGCM) were assigned over the course of the management. Patients were assigned risk status (high, low, or moderate) based on the composite clinical picture at time points in management.

Results: Considering all cases and controls and results of prospectively obtained biosamples analyzed for miR371 expression, 46 (35%) of 132 samples had clinically confirmed aGCM over the course of management; 44 (96%) of these 46 patients had plasma miR371 expression (true positives) with no false positives. Two (4%) of 46 patients had no miRNA expression despite pathologic confirmation of aGCM (false negatives). Plasma miR371 expression in confirmed aGCM had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively. Interpretation of sensitivity and negative predictive value is limited by modest follow-up. Specificity and sensitivity were 100% and 98%, 100% and 92%, and 100% and 97% in the low-, moderate-, and high-risk groups, respectively, with a median follow-up time of 15 months.

Conclusion: Plasma miR371 expression predicts aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 await longer follow-up for more complete definition, the findings of a highly specific liquid biopsy strongly support moving forward with large-scale, real-world clinical trials to further define full operating characteristics and to identify clinical utility and areas of patient benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.02057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351323PMC
November 2019

Patterns of treatment in metastatic renal cell carcinoma for older versus younger patients.

J Geriatr Oncol 2020 05 8;11(4):724-726. Epub 2019 Aug 8.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States of America. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgo.2019.07.002DOI Listing
May 2020

Treatment Decisions for Metastatic Clear Cell Renal Cell Carcinoma in Older Patients: The Role of TKIs and Immune Checkpoint Inhibitors.

Drugs Aging 2019 05;36(5):395-401

Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr, Suite 2161, Salt Lake City, UT, 84112, USA.

Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data, we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients. For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40266-019-00644-1DOI Listing
May 2019

Evolution of the genomic landscape of circulating tumor DNA (ctDNA) in metastatic prostate cancer over treatment and time.

Cancer Treat Res Commun 2019 6;19:100120. Epub 2019 Feb 6.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive Suite 5726, Salt Lake City, UT 84112, USA. Electronic address:

Background: Targeted therapies have shown promise for men with metastatic castration-resistant prostate cancer (mCRPC). Due to the difficulty with obtaining tumor tissue in bony metastases, liquid biopsies are a promising alternative to guide treatment selection. While concurrent tissue next-generation sequencing (tNGS) and liquid biopsy has high concordance, it is unknown whether the genomic landscape of metastatic prostate cancer (mPC) changes over time or treatment. Herein, we hypothesize that the genomic landscape of mPC evolves with new treatments and/or time between tests.

Patients And Methods: Men with mPC from the University of Utah with matched tNGS and liquid biopsy were included. Clinical data was collected retrospectively. Exonic regions from 69 genes covered by both platforms were included for analysis. Paired t tests were used to assess number of genomic alterations (GAs) between testing platforms. Number of alterations was assessed by time and number of treatments between testing by multivariate nonparametric trend tests.

Results: 101 men with mPC were eligible and included. In men with no new treatments and ≤ 1 year between tests, a similar number of GAs were detected in both tests (2.0 vs. 2.2). In contrast, men with ≥ 1 new treatment between tests had significantly more GAs after treatment (5.0 vs. 2.4, p = 0.005). Total number of GAs was correlated with number of new treatments between testing (p = 0.003) and not time between testing (p = 0.76).

Conclusion: The genomic landscape of mPC evolves with subsequent therapies. This finding suggests that contemporary tumor genomic profile upon disease progression may optimize guidance towards subsequent therapy selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctarc.2019.100120DOI Listing
September 2019

Management of Nonmetastatic Castration-Resistant Prostate Cancer: Recent Advances and Future Direction.

Curr Treat Options Oncol 2019 02 11;20(2):14. Epub 2019 Feb 11.

Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Opinion Statement: Nonmetastatic castration-resistant prostate cancer (nmCRPC) comprises a relatively narrow niche of advanced prostate cancer, but the treatment landscape for men with nmCRPC has drastically changed over the past year. Prior to the SPARTAN and PROSPER trials, men with nmCRPC were commonly treated with first-generation androgen receptor antagonists, such as bicalutamide or flutamide, or with estrogens or ketoconazole, none of which were associated with any proven survival benefit. The SPARTAN trial evaluated apalutamide versus placebo for men with nmCRPC and found that apalutamide significantly improved metastasis-free survival (MFS), the primary endpoint of this trial. Similarly, the PROSPER trial showed that enzalutamide significantly improved MFS compared with placebo for men with nmCRPC. In both trials, the data for overall survival was immature at the time of analysis. The SPARTAN and PROSPER trials led to the approval of apalutamide and enzalutamide, respectively, for men with nmCRPC. More recently, the phase 3 trial ARAMIS showed that darolutamide, a novel androgen receptor antagonist, also improves MFS compared with placebo for men with nmCRPC, and this trial is expected to garner regulatory approval for darolutamide in the nmCRPC setting. Novel imaging modalities are becoming more prevalent for the diagnostic evaluation of men with prostate cancer and are more sensitive than conventional bone or CT scans for detection of oligometastatic disease that previously was undetected. These modalities are likely to reduce the incidence and prevalence of nmCRPC in the near future. Ultimately, the treatment options for men with nmCRPC have significantly improved over the past 2 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11864-019-0611-zDOI Listing
February 2019

Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-T alone in patients with metastatic castrate resistant prostate cancer.

Cancer Treat Res Commun 2019 20;19:100116. Epub 2018 Dec 20.

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States.

Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC). Since radiation therapy (RT) can suppress bone marrow function and immune responses, previous studies evaluating sipuleucel-T excluded patients who received RT less than or equal to 28 days prior to sipuleucel-T therapy. Recent evidence suggests that RT may act synergistically with immunotherapy to enhance and broaden antitumor immune response.

Methods: Patients who met standard criteria for sipuleucel-T were randomized to receive sipuleucel-T alone (Arm A) or sipuleucel-T initiated 1 week after completing sensitizing RT to single metastatic site (Arm B). RT was delivered at 300cGy/day to 3000 cGy total. The primary endpoint was the ability to safely combine sipuleucel-T preceded by RT and generate sipuleucel-T with adequate product immune activation parameters. Secondary endpoints included the measurement of systemic immune responses to prostatic acid phosphatase (PAP), a target for sipuleucel-T immune therapy and PA20204 (recombinant fusion protein utilized in the generation of sipuleucel-T).

Results: 51 pts were enrolled, 2 did not receive any sipuleucel-T because of vascular access problems and were excluded. 24 were treated on Arm A, 25 on Arm B. 47/49 patients received all 3 sipuleucel-T infusions. Median age was 66 yrs (range 45-90). Sipuleucel-T product parameters including: total nucleated cell (TNC) count, antigen presenting cell (APC) count were similar in both groups. Cumulative APC upregulation was higher in Arm A. 1 patient in Arm A demonstrated PSA response. Median progression free survival (PFS) was 2.46 months on Arm A and 3.65 months on Arm B (p = 0.06). Both arms showed similar increases in humoral responses to PA2024 and PAP. IFN-ƴ ELISPOT T-cell activation responses to PA20204 were observed in both arms, but were more robust in the Arm A (p = 0.028). Both arms were well-tolerated, with fatigue as the most common grade 2 adverse event (1 patient in Arm A and 3 patients in Arm B).

Conclusions: Sensitizing RT completed 1 week before generation of sipuleucel-T did not affect the majority of product parameters and the ability to deliver sipuleucel-T therapy. RT did not enhance the humoral and cellular responses associated with sipuleucel-T therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctarc.2018.100116DOI Listing
September 2019

Predictive genomic markers of response to VEGF targeted therapy in metastatic renal cell carcinoma.

PLoS One 2019 25;14(1):e0210415. Epub 2019 Jan 25.

Department of Internal Medicine, Division of Medical Oncology, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, United States of America.

Background: First-line treatment for metastatic renal cell carcinoma (mRCC) is rapidly changing. It currently includes VEGF targeted therapies (TT), multi-target tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and immunotherapy. To optimize outcomes for individual patients, genomic markers of response to therapy are needed. Here, we aim to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection.

Methods: From an institutional database, primary tumor tissue was obtained from 79 patients with clear cell mRCC, and targeted sequencing was performed. Clinical outcomes were obtained retrospectively. Progression-free survival (PFS) on first-line VEGF TT was correlated to genomic alterations (GAs) using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of significant GAs predicting PFS in the first-line setting was developed.

Results: Absence of VHL mutation was associated with inferior PFS on first-line VEGF TT. A trend for inferior PFS was observed with GAs in TP53 and FLT1 C/C variant. A composite model of these 3 GAs was associated with inferior PFS in a dose-dependent manner.

Conclusion: In mRCC, a composite model of TP53 mutation, wild type VHL, and FLT1 C/C variant strongly predicted PFS on first-line VEGF TT in a dose-dependent manner. These findings require external validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210415PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347137PMC
October 2019

Germline Variant in and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC).

Mol Cancer Ther 2019 03 26;18(3):726-729. Epub 2018 Dec 26.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of are common and predict improved response to first-line abiraterone acetate in men with mCRPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0739DOI Listing
March 2019

Modulation of Premetastatic Niche by the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Localized High-Risk Prostate Cancer Followed by Radical Prostatectomy: A Phase II Randomized Trial.

Oncologist 2018 12 1;23(12):1413-e151. Epub 2018 Nov 1.

Department of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

Lessons Learned: Pazopanib was not effective in altering the premetastatic niche in the neoadjuvant setting.Pazopanib was safe and well tolerated without any new safety signals.

Background: Vascular endothelial growth factor receptor 1 (VEGFR1) expressing myeloid-derived suppressor cells (VEGFR1+ MDSCs) potentially foster metastases by establishing a premetastatic niche. In a preclinical study, VEGFR1+ clustering in lymph nodes (LNs) independently predicted time to biochemical recurrence (TTBR) in localized prostate cancer [1]. The hypothesis was that neoadjuvant pazopanib therapy will decrease VEGFR1+ clusters in pelvic lymph nodes and improve outcomes.

Methods: This is a phase II trial (NCT01832259) of neoadjuvant pazopanib 800 mg versus placebo daily for 4 weeks in high-risk localized prostate cancer. The primary endpoint was a decrease in VEGFR1+ MDSC clustering assessed by immunohistochemistry (IHC) analysis. Secondary endpoints were safety, feasibility, and TTBR.

Results: Thirty patients were randomized to pazopanib versus placebo, with 15 patients randomized to each arm. Demographic and disease characteristics were similar in both arms. There was no difference in the VEGFR1+ clustering between the treatment arms (p = .345). Neoadjuvant therapy with pazopanib was well tolerated, and surgical complications were similar in both arms.

Conclusion: Neoadjuvant pazopanib therapy did not alter the premetastatic niche; however, treatment targeting vascular endothelial growth factor (VEGF) in the preoperative period was safe and feasible, which may open up the avenue to investigate novel combinatorial regimens, including a VEGF inhibitor in combination with immune checkpoint inhibitor in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2018-0652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292560PMC
December 2018
-->