Publications by authors named "Mary-Ellen Taplin"

162 Publications

Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer.

Cell Rep 2021 Sep;36(10):109665

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we perform whole-exome and transcriptome sequencing on pre-treatment multi-regional tumor biopsies from exceptional responders (ERs) and non-responders (NRs, pathologic T3 or lymph node-positive disease) to intensive neoadjuvant anti-androgen therapies. Clonal SPOP mutation and SPOPL copy-number loss are exclusively observed in ERs, while clonal TP53 mutation and PTEN copy-number loss are exclusively observed in NRs. Transcriptional programs involving androgen signaling and TGF-β signaling are enriched in ERs and NRs, respectively. These findings may guide prospective validation studies of these molecular features in large HRLPC clinical cohorts treated with neoadjuvant anti-androgens to improve patient stratification.
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http://dx.doi.org/10.1016/j.celrep.2021.109665DOI Listing
September 2021

Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer.

Cancers (Basel) 2021 Aug 12;13(16). Epub 2021 Aug 12.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana-Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between amplification and primary resistance to docetaxel ( = 0.58; odds ratio (OR) = 1.49) or cabazitaxel ( = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.
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http://dx.doi.org/10.3390/cancers13164055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391478PMC
August 2021

Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer.

Clin Cancer Res 2021 Aug 18. Epub 2021 Aug 18.

Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.

Purpose: In metastatic castration-resistant prostate cancer (mCRPC) low serum androgens prior to starting abiraterone acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in castration-resistant prostate cancer (CRPC) metastases and associations of intratumoral androgens with response.

Patients And Methods: We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2,000 mg at progression.

Results: Twenty-nine of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks ( < 0.001). Serum and tissue dehydroepiandrosterone sulfate (DHEAS) remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pretreatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on-therapy) associated with rapid progression (20 vs. 48 weeks, = 0.0018; 20 vs. 52 weeks, = 0.0003; 14 vs. 40 weeks, = 0.0001; 20 vs. 56 weeks, = 0.02, respectively). One of 16 men escalating to 2,000 mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild-type (WT) PTEN status associated with longer response (61 vs. 33 weeks, = 0.02).

Conclusions: Low-circulating adrenal androgen levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. Patients with CRPC with higher serum DHEAS levels may benefit from dual androgen receptor (AR)-pathway inhibition, while those in the lowest quartile may require combinations with non-AR-directed therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1819DOI Listing
August 2021

Prospective Evaluation of Clinical Outcomes Using a Multiplex Liquid Biopsy Targeting Diverse Resistance Mechanisms in Metastatic Prostate Cancer.

J Clin Oncol 2021 Sep 1;39(26):2926-2937. Epub 2021 Jul 1.

Department of Medicine, Carbone Cancer Center, University of Wisconsin, Madison, WI.

Purpose: Nearly all men with prostate cancer treated with androgen receptor (AR) signaling inhibitors (ARSIs) develop resistance via diverse mechanisms including constitutive activation of the AR pathway, driven by AR genomic structural alterations, expression of AR splice variants (AR-Vs), or loss of AR dependence and lineage plasticity termed neuroendocrine prostate cancer. Understanding these de novo acquired ARSI resistance mechanisms is critical for optimizing therapy.

Materials And Methods: A novel liquid biopsy technology was used to collect mRNA from circulating tumor cells (CTCs) to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers. An institutional review board-approved prospective cohort (N = 99) was used to identify patterns of gene expression. Two prospective multicenter phase II clinical trials of ARSIs for men with castration-resistant prostate cancer (ClinicalTrials.gov: NCT01942837 [enzalutamide, N = 21] and NCT02025010 [abiraterone, N = 27]) were used to further validate these findings.

Results: Hierarchical clustering of CTC transcripts identified two distinct clusters. Cluster 2 (C2) exhibited increased expression of AR-regulated genes and was associated with worse overall survival (median 8.6 22.4 months; < .01; hazard ratio [HR] = 3.45 [1.9 to 6.14]). In multivariable analysis, C2 was prognostic independent of other clinicopathologic variables. AR-V status was not significant when accounting for C2. Upon further validation in pooled multicenter phase II trials, C2 was associated with worse overall survival (15.2 months not reached; < .01; HR = 8.43 [2.74 to 25.92]), prostate-specific antigen progression-free survival (3.6 12 months; < .01; HR = 4.64 [1.53 to 14.11]), and radiographic progression-free survival (2.7 40.6 months; < .01; HR = 4.64 [1.82 to 17.41]).

Conclusion: We demonstrate that a transcriptional profile detectable in CTCs obtained from liquid biopsies can serve as an independent prognostic marker beyond AR-V7 in patients with metastatic prostate cancer and can be used to identify the emergence of multiple ARSI resistance mechanisms. This is currently being investigated in additional prospective trials.
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http://dx.doi.org/10.1200/JCO.21.00169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425833PMC
September 2021

Impact of Pathogenic Germline DNA Damage Repair alterations on Response to Intense Neoadjuvant Androgen Deprivation Therapy in High-risk Localized Prostate Cancer.

Eur Urol 2021 Sep 19;80(3):295-303. Epub 2021 Apr 19.

Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address:

Background: Intense neoadjuvant androgen deprivation therapy (ADT) before radical prostatectomy (RP) is an investigational approach to reduce recurrence rates in men with high-risk localized prostate cancer (PCa). The impact of germline DNA damage repair (gDDR) gene alterations on response to intense neoadjuvant ADT is not known.

Objective: To evaluate the prevalence of gDDR alterations among men with localized PCa at high risk of recurrence and evaluate their impact on response to intense neoadjuvant ADT.

Design, Setting, And Participants: We performed germline panel sequencing for 201 men with intermediate- and high-risk localized PCa from five randomized multicenter clinical trials of intense neoadjuvant ADT before RP.

Intervention: Intense neoadjuvant ADT followed by RP.

Outcome Measurements And Statistical Analysis: The prevalence of pathogenic gDDR alterations and their association with exceptional pathologic response (complete response or minimal residual disease, defined as residual tumor with the largest cross-section dimension ≤5 mm) to intense neoadjuvant ADT and rates of post-RP biochemical recurrence.

Results And Limitations: Pathogenic gDDR alterations were detected in 19 (9.5%) of the 201 PCa patients. The most frequently altered genes were BRCA2 (n = 6; 3.0%) and ATM (n = 4; 2.0%). Patients with gDDR alterations exhibited similar rates of exceptional pathologic response (26% vs 22%), pT3 disease (42% vs 53%), lymph node involvement (5.3% vs 10%), extraprostatic extension (35% vs 54%), and positive margins (5.3% vs 13%) to patients without gDDR alterations (all p > 0.05). The 3-yr biochemical recurrence-free survival was also similar at 45% (95% confidence interval 7.9-78%) for men with gDDR alterations and 55% (95% confidence interval 44-64%) for men without gDDR alterations.

Conclusions: gDDR alterations are common among men with intermediate- and high-risk localized PCa. Men with gDDR alterations appear to have a comparable response to intense neoadjuvant ADT to that among men without gDDR alterations and should not be excluded from consideration for this treatment approach.

Patient Summary: Intense therapy to inhibit the production of androgen hormones (eg, testosterone) before surgery may minimize the risk of cancer recurrence for men with high-risk localized prostate cancer. Inherited mutations in certain DNA repair genes are associated with particularly high rates of recurrence. We found that men with these mutations respond equally well to this intense androgen inhibition before surgery as men without the mutations.
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http://dx.doi.org/10.1016/j.eururo.2021.03.031DOI Listing
September 2021

Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance.

Clin Cancer Res 2021 Jul 13;27(13):3610-3619. Epub 2021 Apr 13.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance.

Patients And Methods: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing.

Results: A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in (mutations, amplifications) and tumor suppression genes (, and ), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased amplifications (64.7% at progression vs. 53.9% at baseline) and alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression.

Conclusions: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254786PMC
July 2021

Results of a Randomized Phase II Trial of Intense Androgen Deprivation Therapy prior to Radical Prostatectomy in Men with High-Risk Localized Prostate Cancer.

J Urol 2021 07 8;206(1):80-87. Epub 2021 Mar 8.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).

Materials And Methods: Eligible patients had a Gleason score ≥4+3=7, prostate specific antigen >20 ng/mL or T3 disease and lymph nodes <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide (AAPL) or abiraterone, prednisone, leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by radical prostatectomy. Surgical specimens underwent central review. The primary end point was the rate of pathologic complete response or minimum residual disease (minimum residual disease, tumor ≤5 mm). Secondary end points included prostate specific antigen response, positive margin rate and safety. Magnetic resonance imaging and tissue biomarkers of pathologic outcomes were explored.

Results: The study enrolled 118 patients at 4 sites. Median age was 61 years and 94% of patients had high-risk disease. The combined pathologic complete response or minimum residual disease rate was 22% in the AAPL arm and 20% in the APL arm (difference: 1.5%; 1-sided 95% CI -11%, 14%; 1-sided p=0.4). No new safety signals were observed. There was low concordance and correlation between posttherapy magnetic resonance imaging assessed and pathologically assessed tumor volume. PTEN-loss, ERG positivity and presence of intraductal carcinoma were associated with extensive residual tumor.

Conclusions: Intense neoadjuvant hormone therapy in high-risk prostate cancer resulted in favorable pathologic responses (tumor 5 mm) in 21% of patients. Pathologic responses were similar between treatment arms. Part 2 of this study will investigate the impact of adjuvant hormone therapy on biochemical recurrence.
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http://dx.doi.org/10.1097/JU.0000000000001702DOI Listing
July 2021

Transcriptional mediators of treatment resistance in lethal prostate cancer.

Nat Med 2021 03 4;27(3):426-433. Epub 2021 Mar 4.

Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. ). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8 T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.
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http://dx.doi.org/10.1038/s41591-021-01244-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960507PMC
March 2021

Enzalutamide With Radiation Therapy for Intermediate-Risk Prostate Cancer: A Phase 2 Study.

Int J Radiat Oncol Biol Phys 2021 08 23;110(5):1416-1422. Epub 2021 Feb 23.

Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: Androgen deprivation therapy (ADT) is often used as adjuvant treatment with radiation therapy (RT) for intermediate-risk prostate cancer. ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, antiandrogen monotherapy has been generally better tolerated. This study aimed to assess the effectiveness of enzalutamide (an antiandrogen) monotherapy with RT for the treatment of intermediate-risk prostate cancer.

Methods And Materials: This trial was an open-label, phase 2 study of 6 months of enzalutamide monotherapy with external beam RT for intermediate-risk prostate cancer. Enzalutamide was initiated 2 months before external beam RT. The primary endpoint was prostate-specific antigen (PSA) response measured at the end of enzalutamide administration at the 6-month timepoint. Secondary endpoints included assessment of toxicity and changes in anthropomorphic body measurement, sexual function, and metabolism. The sample size was 64 patients. The hypothesis was that if ≥60% of the patients did not achieve a PSA nadir of ≤0.2 ng/mL, the study results would be deemed negative.

Results: The results met the prespecified endpoint for efficacy in that PSA values ≤0.2 ng/mL were observed in 49 of 64 patients (77%), and 60 of 64 patients (94%) had PSA values ≤0.5ng/mL. The most frequent adverse events were hypertension and gynecomastia. There were no changes in anthropomorphic body measurements and only modest erectile dysfunction.

Conclusions: Using PSA response as an endpoint, enzalutamide monotherapy may be as effective as ADT in combination with external beam RT for patients with intermediate-risk prostate cancer, and it is associated with fewer side effects. Randomized trials comparing enzalutamide with ADT are justified.
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http://dx.doi.org/10.1016/j.ijrobp.2021.02.027DOI Listing
August 2021

Outcomes of Post-Neoadjuvant Intense Hormone Therapy and Surgery for High Risk Localized Prostate Cancer: Results of a Pooled Analysis of Contemporary Clinical Trials.

J Urol 2021 06 27;205(6):1689-1697. Epub 2021 Jan 27.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: We report on the post-radical prostatectomy outcomes of patients enrolled in 3 randomized, multicenter, clinical trials of intense neoadjuvant androgen deprivation therapy prior radical prostatectomy.

Materials And Methods: All patients included were enrolled in trials evaluating intense androgen deprivation therapy followed by radical prostatectomy. The primary end point was time to biochemical recurrence, defined as the time from radical prostatectomy to prostate specific antigen >0.1 ng/ml or start of first post-radical prostatectomy therapy, stratified by pathological response at radical prostatectomy (presence or absence of exceptional pathological response defined as residual tumor at radical prostatectomy measuring 0-5 mm). Secondary end points included metastasis-free survival, overall survival, and time to testosterone recovery.

Results: Overall, 117 patients were included in the analysis, of whom 78.6% (92) had high risk disease. Following neoadjuvant therapy, 21.4% (25) had 0-5 mm of residual tumor, including 9.4% (11) with a pathological complete response. Overall, 49 patients (41.9%) experienced biochemical recurrence and the 3-year biochemical recurrence-free rate was 59.1% (95% CI 49.0-67.9). Of the 25 patients with an exceptional pathological response, 2 patients (8.0%) developed biochemical recurrence while 51.1% of nonresponders (47/92) developed biochemical recurrence. Testosterone recovery was observed in 93.8% of patients (106/113). PTEN loss and intraductal carcinoma were associated with shorter time to biochemical recurrence.

Conclusions: In this pooled analysis of prospective trials, we demonstrate that exceptional pathological response following neoadjuvant therapy is associated with a favorable impact on biochemical recurrence. PTEN loss and intraductal carcinoma were associated with biochemical recurrence. Additional followup is warranted to evaluate the impact on long-term outcomes.
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http://dx.doi.org/10.1097/JU.0000000000001632DOI Listing
June 2021

Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update.

J Clin Oncol 2021 04 26;39(11):1274-1305. Epub 2021 Jan 26.

Nanhealth, Inc, Culver City, CA.

Purpose: Update all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer.

Methods: The Expert Panel based recommendations on a systematic literature review. Recommendations were approved by the Expert Panel and the ASCO Clinical Practice Guidelines Committee.

Results: Four clinical practice guidelines, one clinical practice guidelines endorsement, 19 systematic reviews with or without meta-analyses, 47 phase III randomized controlled trials, nine cohort studies, and two review papers informed the guideline update.

Recommendations: Docetaxel, abiraterone, enzalutamide, or apalutamide, each when administered with androgen deprivation therapy (ADT), represent four separate standards of care for noncastrate metastatic prostate cancer. Currently, the use of any of these agents in any particular combination or series cannot be recommended. ADT plus docetaxel, abiraterone, enzalutamide, or apalutamide should be offered to men with metastatic noncastrate prostate cancer, including those who received prior therapies, but have not yet progressed. The combination of ADT plus abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer who have undergone radiotherapy, rather than castration monotherapy. Immediate ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo radiotherapy. Intermittent ADT may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer. The panel does not support use of either micronized abiraterone acetate or the 250 mg dose of abiraterone with a low-fat breakfast in the noncastrate setting at this time.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.20.03256DOI Listing
April 2021

Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer.

Clin Cancer Res 2021 Apr 18;27(7):2011-2022. Epub 2020 Nov 18.

Danish Cancer Society Research Center, Copenhagen, Denmark.

Purpose: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, , which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory -mutant cases.

Experimental Design: We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of deficiency and cisplatin sensitivity.

Results: We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses and , including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models.

Conclusions: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026514PMC
April 2021

Practical Considerations and Challenges for Germline Genetic Testing in Patients With Prostate Cancer: Recommendations From the Germline Genetics Working Group of the PCCTC.

JCO Oncol Pract 2020 12 28;16(12):811-819. Epub 2020 Sep 28.

Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, CA.

Germline genetic testing is now routinely recommended for patients with prostate cancer (PCa) because of expanded guidelines and options for targeted treatments. However, integrating genetic testing into oncology and urology clinical workflows remains a challenge because of the increased number of patients with PCa requiring testing and the limited access to genetics providers. This suggests a critical unmet need for genetic services outside of historical models. This review addresses current guidelines, considerations, and challenges for PCa genetic testing and offers a practical guide for genetic counseling and testing delivery, with solutions to help address potential barriers and challenges for both providers and patients. As genetic and genomic testing become integral to PCa care, developing standardized systems for implementation in the clinic is essential for delivering precision oncology to patients with PCa and realizing the full scope and impact of genetic testing.
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http://dx.doi.org/10.1200/OP.20.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735040PMC
December 2020

The Impact of COVID-19 on Clinical Trial Execution at the Dana-Farber Cancer Institute.

J Natl Cancer Inst 2020 Sep 22. Epub 2020 Sep 22.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Interventions designed to limit the spread of COVID-19 are having profound effects on the delivery of healthcare, but data showing the impact on oncology clinical trial enrollment, treatment, and monitoring are limited. We prospectively tracked relevant data from oncology clinical trials at Dana-Farber Cancer Institute (DFCI) from January 1, 2018 to June 30, 2020, including the number of open trials, new patient enrollments, in-person and virtual patient visits, dispensed investigational infusions, dispensed/shipped oral investigational agents, research biopsies, and blood samples. We ascertained why patients came off trials and determined on-site clinical research staffing levels. We used two-sided Wilcoxon rank sum tests to assess the statistical significance of the reported changes. Nearly all patients on interventional treatment trials were maintained, and new enrollments continued at just under half the pre-pandemic rate. The median number of investigational prescriptions shipped to patients increased from 0-74 (range: 22-107) per week from March-June 2020. The median number of telemedicine appointments increased from 0-107 (range: 33-267) per week from March-June 2020. Research biopsies and blood collections decreased dramatically after DFCI implemented COVID-19-related policies in March 2020. The number of research nurses and clinical research coordinators on-site also decreased after March 2020. Substantial changes were required to safely continue clinical research during the pandemic; yet, we observed no increases in serious adverse events or major violations related to drug dosing. Lessons learned from adapting research practices during COVID-19 can inform industry sponsors and governmental agencies to consider altering practices to increase operational efficiency and convenience for patients.
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http://dx.doi.org/10.1093/jnci/djaa144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543498PMC
September 2020

Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.

Clin Cancer Res 2020 12 17;26(23):6122-6131. Epub 2020 Sep 17.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC.

Patients And Methods: Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints.

Results: Twenty-four patients were enrolled in the dose-escalation ( = 16) and dose-expansion ( = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis ( = 2), fatigue ( = 1), hypertension ( = 1), pulmonary embolism ( = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8-21.2). Pharmacokinetics analysis at the MTD ( = 12) revealed a mean of 104 ± 45 ng/mL and AUC of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data ( , 315 ng/mL and AUC , 3,817 ng•h/mL).

Conclusions: Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935424PMC
December 2020

Genomic Predictors of Good Outcome, Recurrence, or Progression in High-Grade T1 Non-Muscle-Invasive Bladder Cancer.

Cancer Res 2020 10 31;80(20):4476-4486. Epub 2020 Aug 31.

Harvard Medical School University, Boston, Massachusetts.

High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analyses were performed, focusing on 95 genes known to be mutated in bladder cancer. Somatic mutations, copy-number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Tumor mutational burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients ( = 0.017). DNA damage response gene mutations were associated with higher TMB ( < 0.0001) and GO ( = 0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R ( = 0.047; = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO ( = 0.047; = 0.0002). pT1b microstaging was associated with a genomic cluster ( = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. SIGNIFICANCE: Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0977DOI Listing
October 2020

Treatment of metastatic castration resistant prostate cancer with radium-223: a retrospective study at a US tertiary oncology center.

Prostate Cancer Prostatic Dis 2021 03 19;24(1):210-219. Epub 2020 Aug 19.

Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Guidelines for optimal sequencing of radium-223 and chemotherapy for metastatic castration resistant prostate cancer (mCRPC) do not exist. This study evaluated treatment patterns and overall survival (OS) among patients with mCRPC treated with radium-223 in an academic clinical setting.

Methods: A retrospective study was conducted of bone metastases-predominant mCRPC patients treated with radium-223. Treatment patterns from 2013 to 2018 were evaluated in patients treated with radium-223 pre- vs. post-chemotherapy. OS was examined using Kaplan-Meier medians and 95% confidence intervals.

Results: In total, 220 patients were treated with radium-223 (64 pre-chemotherapy, 83 post-chemotherapy, 73 no chemotherapy). Mean radium-223 injections per patient was 5.3 and 4.3 in the pre- vs. post-chemotherapy cohorts, respectively (p < 0.001). The number of chemotherapy cycles was similar for chemotherapy given pre- or post-radium-223. Mean line of mCRPC therapy of radium-223 was 3rd and 5th when given pre- and post-chemotherapy, respectively (p < 0.001). 41.8% patients were treated with radium-223 in combination with another mCRPC therapy, commonly abiraterone acetate (43.5%) or enzalutamide (52.2%). The majority received combination therapy for the duration of radium-223 treatment; 20.7% started another agent after radium-223 initiation; 20.7% initiated radium-223 while on established therapy. Median OS from first mCRPC treatment was 39.4 months (95% CI 33.0, 48.8) for patients with radium-223 pre-chemotherapy vs. 37.4 months (95% CI 32.0, 43.5) post-chemotherapy (and 35.2 months [95% CI 27.9, 43.3] vs. 32.0 months [95% CI 26.9, 36.0] for patients with radium-223 combination vs. monotherapy).

Conclusions: This retrospective analysis of patients treated with radium-223 demonstrates that administration of radium-223 pre-chemotherapy increased likelihood of completion of radium-223 treatment. Radium-223 given pre- or post-chemotherapy and with or without combination therapy did not result in significant differences in OS. Additional studies are needed to determine the optimal sequencing strategy of mCRPC in the modern era.
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http://dx.doi.org/10.1038/s41391-020-00271-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012208PMC
March 2021

Cancer and Leukemia Group B 90203 (Alliance): Radical Prostatectomy With or Without Neoadjuvant Chemohormonal Therapy in Localized, High-Risk Prostate Cancer.

J Clin Oncol 2020 09 24;38(26):3042-3050. Epub 2020 Jul 24.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression-free survival (BPFS) over RP alone.

Patients And Methods: Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS).

Results: In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 0.84, respectively; 95% CI for the difference, -0.01 to 0.11; = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone.

Conclusion: The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time.
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http://dx.doi.org/10.1200/JCO.20.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479762PMC
September 2020

Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer.

Cancer Cell 2020 08 16;38(2):279-296.e9. Epub 2020 Jul 16.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20185, USA. Electronic address:

Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.
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http://dx.doi.org/10.1016/j.ccell.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472556PMC
August 2020

Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.

J Clin Oncol 2020 08 9;38(24):2798-2811. Epub 2020 Jun 9.

Advocate Aurora Health, Milwaukee, WI.

Purpose: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.

Methods: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).

Results: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included and mismatch repair genes, with broader testing, such as , for clinical trial eligibility. was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for carriers, with consideration in , and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.

Conclusion: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.
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http://dx.doi.org/10.1200/JCO.20.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430215PMC
August 2020

Androgens and Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Docetaxel.

Clin Genitourin Cancer 2020 06 17;18(3):222-229.e2. Epub 2019 Oct 17.

Duke University Medical Center, Durham, NC.

Background: Pre-treatment androgen levels are associated with overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) treated with androgen synthesis inhibitors. The current study sought to determine whether pre-treatment serum androgens predict clinical outcome among patients with metastatic CRPC treated with docetaxel chemotherapy.

Materials And Methods: Data were obtained from 1050 men who were chemotherapy-naive prior to treatment with docetaxel, prednisone, and either bevacizumab or placebo (CALGB 90401). Pretreatment serum assays for testosterone, androstenedione, and dehydroepiandrosterone (DHEA) were performed with tandem liquid chromatography-mass spectrometry.

Results: Median values for testosterone, androstenedione, and DHEA were 1.00, 13.50, and 8.12 ng/dL, respectively. The median was used to define the midpoint between low and high values. In univariate analysis, median OS for low versus high levels was 21.4 and 24.2 months for testosterone, 23.8 and 21.9 months for androstenedione, and 20.2 and 25.2 months for DHEA (P = NS). In multivariable analysis of all androgens, baseline DHEA was prognostic of ≥ 50% PSA decline from baseline (P = .008). In multivariable analysis adjusting for 10 known prognostic values and prior ketoconazole use for metastatic CRPC, a 10-unit increase in baseline testosterone increased risk of death (hazard ratio, 1.11; 95% confidence interval, 1.01-1.23; P = .039), whereas a 10-unit increase in androstenedione lowered risk of death (hazard ratio, 0.92; 95% confidence interval, 0.88-0.97; P = .001).

Conclusion: Consistent with prior studies, higher androstenedione levels in patients with metastatic CRPC treated with docetaxel are associated with improved survival. However pretreatment levels of other androgen levels are associated with varied effects on clinical outcome in chemotherapy-treated patients.
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http://dx.doi.org/10.1016/j.clgc.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252587PMC
June 2020

Volume of Gleason pattern 4 stratifies risk of metastasis and death in patients with Gleason score 3+5=8/5+3=8 positive prostate core biopsies.

Hum Pathol 2020 05 11;99:62-74. Epub 2020 Mar 11.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115 USA. Electronic address:

Implementation of Grade Groups (GrGrs) has been widely accepted for reporting prostate cancer grade since the 2014 International Society of Urological Pathology consensus meeting. Despite their undisputed value for risk stratification, some GrGr are, a priori, quite heterogeneous in that they contain multiple Gleason patterns (GPs). In this regard, the prognostic significance of GP5 in biopsies with highest GrGr4 is uncertain and evaluated in this study. A search of all core biopsies positive for prostate cancer reviewed after 2005 was performed, and 71 cases with highest GrGr4 containing GP5 (i.e., 3 + 5 = 8 or 5 + 3 = 8; referred to as GrGr4/GP5pos) eligible for inclusion were identified. In addition, 95 core biopsy cases with highest GrGr4 and no GP5 (i.e, 4 + 4 = 8; referred to as GrGr4/GP5neg) were selected for comparison. Multiple pathologic parameters, including volume and amount of GP4, and clinical variables were collected to evaluate the influence of GP5 on disease recurrence, development of metastases, and disease-specific death. GrGr4/GP5pos cases did not show, as a group, statistically significant differences in prostatectomy findings, disease recurrence, metastases, and disease-specific mortality when compared with GrGr4/GP5neg cases. In addition, the risk of all outcomes evaluated in the study did not differ between the whole GrGr4/GP5pos and GrGr4/GP5neg groups. However, Kaplan-Meier analysis found that GrGr4/GP5pos cases with a significant amount of GP4 did show a higher risk of prostate cancer-specific death as well as bone and visceral metastases. Univariate Cox regression demonstrated that preoperative prostate specific antigen (PSA), total number of positive cores, and global GrGr5 were also associated with a higher chance of disease-specific death. In a multivariate model, only global GrGr5 and PSA >20 ng/dL remained statistically significant. This study suggests that the mere presence of GP5 in core biopsies with highest GrGr4 disease may not portend a worse prognosis. In these cases, accounting for the case-wide volume of GP4 by reporting a global GrGr appears to be more relevant as it identifies a subset of GrGr4/GP5pos patients with global GrGr5 who have a higher risk of metastases and prostate cancer-specific mortality.
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http://dx.doi.org/10.1016/j.humpath.2020.03.001DOI Listing
May 2020

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy.

PLoS One 2020 5;15(3):e0229754. Epub 2020 Mar 5.

Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America.

Purpose: To determine whether SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in CRPC.

Patients And Methods: In a Local CRPC cohort, 42 prostatic specimens were collected from patients who were diagnosed as CRPC and underwent transurethral resection of the prostate (TURP) at Massachusetts General Hospital (MGH). In a metastatic CRPC (Met CRPC) cohort, 12 metastatic biopsies were collected from CRPC patients who would be treated with abiraterone plus dutasteride (Clinical Trial NCT01393730). As controls, 36 benign prostatic specimens were collected from patients undergoing prostate reduction surgery for symptoms of bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). The methylation status of cytosine-phosphate-guanine (CpG) site(s) at SRD5A2 promoter regions was tested.

Results: Compared with benign prostatic tissue, CRPC samples demonstrated higher SRD5A2 methylation in the whole promoter region (Local CRPC cohort: P < 0.001; Met CRPC cohort: P <0.05). In Local CRPC cohort, a higher ratio of methylation was correlated with better OS (R2 = 0.33, P = 0.013). Hypermethylation of specific regions (nucleotides -434 to -4 [CpG# -39 to CpG# -2]) was associated with a better OS (11.3±5.8 vs 6.4±4.4 years, P = 0.001) and PFS (8.4±5.4 vs 4.5±3.9 years, P = 0.003) with cutoff value of 37.9%. Multivariate analysis showed that SRD5A2 methylation was associated with OS independently (whole promoter region: P = 0.035; specific region: P = 0.02).

Conclusion: Our study demonstrate that SRD5A2 methylation in promoter regions, specifically at CpG# -39 to -2, is significantly associated with better survival for CRPC patients treated with ADT. Recognition of epigenetic modifications of SRD5A2 may affect the choices and sequence of available therapies for management of CRPC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229754PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058338PMC
June 2020

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019.

Eur Urol 2020 04 27;77(4):508-547. Epub 2020 Jan 27.

Division of Medical Oncology, National Cancer Centre, Singapore.

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.

Objective: To present the results from the APCCC 2019.

Design, Setting, And Participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.

Outcome Measurements And Statistical Analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.

Results And Limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.

Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.

Patient Summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
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http://dx.doi.org/10.1016/j.eururo.2020.01.012DOI Listing
April 2020

Multiparametric MRI as a Biomarker of Response to Neoadjuvant Therapy for Localized Prostate Cancer-A Pilot Study.

Acad Radiol 2020 10 18;27(10):1432-1439. Epub 2019 Dec 18.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Rationale And Objectives: To explore a role for multiparametric MRI (mpMRI) as a biomarker of response to neoadjuvant androgen deprivation therapy (ADT) for prostate cancer (PCa).

Materials And Methods: This prospective study was approved by the institutional review board and was HIPAA compliant. Eight patients with localized PCa had a baseline mpMRI, repeated after 6-months of ADT, followed by prostatectomy. mpMRI indices were extracted from tumor and normal regions of interest (TROI/NROI). Residual cancer burden (RCB) was measured on mpMRI and on the prostatectomy specimen. Paired t-tests compared TROI/NROI mpMRI indices and pre/post-treatment TROI mpMRI indices. Spearman's rank tested for correlations between MRI/pathology-based RCB, and between pathological RCB and mpMRI indices.

Results: At baseline, TROI apparent diffusion coefficient (ADC) was lower and dynamic contrast enhanced (DCE) metrics were higher, compared to NROI (ADC: 806 ± 137 × 10 vs. 1277 ± 213 × 10 mm/sec, p = 0.0005; K: 0.346 ± 0.16 vs. 0.144 ± 0.06 min, p = 0.002; AUC: 0.213 ± 0.08 vs. 0.11 ± 0.03, p = 0.002). Post-treatment, there was no change in TROI ADC, but a decrease in TROI K (0.346 ± 0.16 to 0.188 ± 0.08 min; p = 0.02) and AUC (0.213 ± 0.08 to 0.13 ± 0.06; p = 0.02). Tumor volume decreased with ADT. There was no difference between mpMRI-based and pathology-based RCB, which positively correlated (⍴ = 0.74-0.81, p < 0.05). Pathology-based RCB positively correlated with post-treatment DCE metrics (⍴ = 0.76-0.70, p < 0.05) and negatively with ADC (⍴ = -0.79, p = 0.03).

Conclusion: Given the heterogeneity of PCa, an individualized approach to ADT may maximize potential benefit. This pilot study suggests that mpMRI may serve as a biomarker of ADT response and as a surrogate for RCB at prostatectomy.
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http://dx.doi.org/10.1016/j.acra.2019.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297658PMC
October 2020

Androgen Receptor Modulation Optimized for Response-Splice Variant: A Phase 3, Randomized Trial of Galeterone Versus Enzalutamide in Androgen Receptor Splice Variant-7-expressing Metastatic Castration-resistant Prostate Cancer.

Eur Urol 2019 12 18;76(6):843-851. Epub 2019 Sep 18.

Medical Oncology, Royal Marsden/The Institute of Cancer Research, London, UK.

Background: Detection of androgen receptor (AR) splice variant-7 (AR-V7) messenger RNA (mRNA) in circulating tumor cells (CTCs) is associated with a suboptimal response to abiraterone and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). Galeterone inhibits CYP17 and AR, and induces AR protein degradation. We hypothesized that galeterone would be clinically superior to enzalutamide in AR-V7-positive (AR-V7+) mCRPC.

Objective: To screen and characterize AR-V7+ mCRPC, and evaluate galeterone compared with enzalutamide.

Design, Setting, And Participants: This was a multicenter randomized phase 3 trial; enzalutamide-, abiraterone-, and chemotherapy-naïve mCRPC patients had AR-V7 prescreening using a CTC-based mRNA assay.

Intervention: AR-V7+ patients were randomized (1:1) to open-label galeterone or enzalutamide; planned sample size was 148.

Outcome Measurements And Statistical Analysis: The primary endpoint was radiographic progression-free survival (rPFS). Baseline AR-V7 status was correlated with patient characteristics.

Results And Limitations: Overall, 953 men were prescreened for AR-V7; 323 (34%) had detectable CTCs, and 73/323 had AR-V7 mRNA. The AR-V7+ prevalence was 8% (73/953; 95% confidence interval [CI] 6-10%). AR-V7 was associated with indicators of advanced and high-volume disease at baseline, including higher prostate-specific antigen (PSA) level (p < 0.001), more bone metastases (p < 0.001), docetaxel for hormone-sensitive disease (p < 0.001), prior first-generation androgen deprivation therapy (p < 0.001), and shorter time from diagnosis to enrollment (p < 0.001). Of 73 eligible patients, 38 were randomized to galeterone (n=19) or enzalutamide (n=19); 35 dropped out before randomization. Owing to high censorship for the rPFS events, the data monitoring committee recommended early closure based on interim evidence that the primary endpoint would not be met. The PSA50 values were 2/16 (13%) and 8/19 (42%) for galeterone and enzalutamide respectively (proportion difference=-0.278, 95% CI -0.490 to 0.097).

Conclusions: The prevalence of CTC mRNA AR-V7 in first-line mCRPC was 8% (95% CI 6-10%). AR-V7+ was associated with the characteristics of aggressive and advanced disease. These men had rapid disease progression. Development of galeterone will not be pursued.

Patient Summary: Of men with metastatic castration-resistant prostate cancer, 8% had the androgen receptor splice variant-7 (AR-V7) blood biomarker. The AR-V7+ patients had features of aggressive disease. Thirty-eight men were treated with either galeterone or enzalutamide; the trial was stopped early prior to determining efficacy because too many patients transitioned off the trial due to advancing cancer before having required radiographs.
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http://dx.doi.org/10.1016/j.eururo.2019.08.034DOI Listing
December 2019

Germline Genetic Testing in Advanced Prostate Cancer; Practices and Barriers: Survey Results from the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium.

Clin Genitourin Cancer 2019 08 18;17(4):275-282.e1. Epub 2019 Apr 18.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA. Electronic address:

Background: Germline genetic testing increasingly identifies advanced prostate cancer (PCa) patients who are candidates for precision therapies. The Prostate Cancer Clinical Trials Consortium (PCCTC) established the Germline Genetics Working Group to provide guidance and resources to expand effective use of germline genetic testing.

Materials And Methods: A 14-item questionnaire was e-mailed to academic oncologists at 43 PCCTC sites to collect information on germline genetic testing patterns, including patients considered, choice of assays, barriers slowing adoption, and actions to overcome barriers.

Results: Twenty-six genitourinary oncologists from 19 institutions responded. Less than 40% (10 of 26) reported referring patients to a genetics department, whereas the remainder take personal responsibility for genetic testing and counseling; 16 (62%) consider testing all metastatic PCa patients, whereas 3 (12%) consider testing all patients with high-risk local disease; and 7 (27%) use multigene comprehensive pan-cancer panels, and 14 (54%) use smaller or targeted cancer gene panels. Barriers to widespread use are: (1) delayed or limited access to genetic counseling; (2) no insurance coverage; (3) lack of effective workflows; (4) insufficient educational materials; and (5) time and space constraints in busy clinics. The primary limitation was the <50% (19 of 43) response from PCCTC sites and no coverage of nonacademic cancer treatment facilities.

Conclusion: Joint efforts by urologists, oncologists, genetics counselors, insurers, and cancer centers can accelerate implementation of integrated germline genetic services for personalized treatment and clinical trial eligibility for PCa patients.
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http://dx.doi.org/10.1016/j.clgc.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662206PMC
August 2019

Genomic correlates of clinical outcome in advanced prostate cancer.

Proc Natl Acad Sci U S A 2019 06 6;116(23):11428-11436. Epub 2019 May 6.

Prostate Cancer Clinical Trials Consortium, New York, NY 10065.

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor () variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only alteration was significantly associated with poor survival, whereas alterations in , , and were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
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http://dx.doi.org/10.1073/pnas.1902651116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561293PMC
June 2019

Androgen decline and survival during docetaxel therapy in metastatic castration resistant prostate cancer (mCRPC).

Prostate Cancer Prostatic Dis 2020 03 3;23(1):66-73. Epub 2019 May 3.

Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.

Background: Multiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS.

Methods: Data from 1050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were evaluated. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment, 6 week and progression serum assays for T, A and DHEA were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Changes in T, A and DHEA levels from baseline to 6 weeks were calculated as the ratio of 6-week over baseline. The proportional hazards model was used to assess the prognostic significance of changes in T, A, and DHEA from baseline to 6 weeks in predicting OS adjusting for known prognostic factors.

Results: Median baseline values for T, A, and, DHEA were 1.0, 13.5, and 8.1 ng/dL respectively while 6 week levels were 0.64, 7.0, and 6.8 ng/dL respectively. Median OS for low testosterone decline is 20.9 months vs 26.3 months for high testosterone decline. In multivariable analysis including known prognostic variables, change in testosterone levels was independently associated with greater OS; the hazard ratio for death with each unit increase in the 6-week/baseline ratio is 1.02 (95% CI = 1.01-1.03, p = 0.001). Decline in A and DHEA were not significant predictors of OS. In multivariable analysis change in the serum changes did not predict PFS however the ratio of T at 6-weeks over baseline was prognostic of ≥50% decline in PSA with an odds ratio of 0.93 (95% CI = 0.85-0.98, p-value = 0.039).

Conclusions: Declines in testosterone during docetaxel treatment is associated with a longer survival, consistent with a favorable prognostic significance of higher serum androgens in the CRPC.
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http://dx.doi.org/10.1038/s41391-019-0152-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825875PMC
March 2020
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