Quevedo, J. Fernando

Abstract The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of second-generation antiandrogen trials and FDA approvals and outline a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer. All published phase II-III randomized controlled trials reporting outcomes with the use of second-generation antiandrogens in prostate cancer are included as well as all published trials and retrospective studies of second-generation antiandrogen sequencing and/or combinations. Complete tabular and graphical representation of all available evidence is provided regarding the use and sequencing of second-generation antiandrogens in prostate cancer. In metastatic castration-resistant prostate cancer, evidence suggests prioritization of abiraterone before chemotherapy, chemotherapy after second-generation antiandrogen failure, and postchemotherapy enzalutamide in select patients to maximize agent efficacy and tolerability. We conclude that a rational, optimized sequencing of second-generation antiandrogens with other treatment options is feasible with present data.

Abstract Purpose: Outcomes for resistant metastatic castration-resistant prostate cancer (CRPC) are poor. Stereotactic ablative radiotherapy (SABR) induces antitumor immunity in clinical and preclinical studies, but immunologic biomarkers are lacking. Patients and Methods: Eighty-nine patients with oligometastatic CRPC were identified by 11C-Choline-PET (Choline-PET) from August 2016 to December 2019 and treated with SABR. Prespecified coprimary endpoints were 2-year overall survival (OS) and PSA progression. Secondary endpoints included 2-year SABR-treated local failure and 6-month adverse events. Correlative studies included peripheral blood T-cell subpopulations before and after SABR. Results: 128 lesions in 89 patients were included in this analysis. Median OS was 29.3 months, and 1- and 2-year OS were 96% and 80%, respectively. PSA PFS was 40% at 1 year and 21% at 2 years. Local PFS was 84.4% and 75.3% at 1 and 2 years, respectively, and no grade ≥3 AEs were observed. Baseline high levels of tumor-reactive T cells (TTR; CD8+CD11ahigh) predicted superior local, PSA, and distant PFS. Baseline high levels of effector memory T cells (TEM; CCR7−CD45RA−) were associated with improved PSA PFS. An increase in TTR at day 14 from baseline was associated with superior OS. Conclusions: This is the first comprehensive effector T-cell immunophenotype analysis in a phase II trial before and after SABR in CRPC. Results are favorable and support the incorporation of immune-based markers in the design of future randomized trials in patients with oligometastatic CRPC treated with SABR.

AbstractIntroductionChemotherapy in combination with immunotherapy has a proven survival benefit compared to chemotherapy alone in extensive stage small cell lung cancer (SCLC) and is the new standard of care. Since extrapulmonary small cell carcinomas (SCCs) are less common, treatment paradigms are reasonably extrapolated from SCLC regimens. We examined our institution's experience utilizing the combination of chemotherapy and immunotherapy (as used in SCLC) for SCC and neuroendocrine carcinoma of the prostate.MethodsUtilizing an institutional database search tool, we queried the electronic medical record to identify patients with SCC or neuroendocrine carcinoma of the prostate who had been treated with atezolizumab and chemotherapy. We recorded patient characteristics, including age, pathology, and disease extent. Treatment characteristics included number of prior treatments, use of concominant androgen deprivation, number of cycles of immunotherapy, and prior systemic therapies (including those for adenocarcinoma of the prostate). Progression free survival (PFS) and overall survival (OS) were the primary outcomes.ResultsWe identified seven men who received atezolizumab for metastatic prostate cancer with a small cell or neuroendocrine component. In six of the seven patients, the combination of carboplatin, etoposide, and atezolizumab was the first‐line of treatment after diagnosis of small cell or neuroendocrine carcinoma. Two of the seven patients had de novo small cell/neuroendocrine pathology, while the other five had transformation from a preexisting adenocarcinoma. In the patients who received chemotherapy plus immunotherapy in the first‐line setting, at a median follow‐up of 6.5 months (range: 1.5–15.1) the median PFS was 3.4 months and median OS was 8.4 months.ConclusionSmall cell or neuroendocrine carcinoma of the prostate was associated with poor survival outcomes despite adding immunotherapy (atezolizumab) to chemotherapy (carboplatin and etoposide). To our knowledge, there has been no demonstrable benefit of adding immunotherapy to chemotherapy in this setting.

Those with metastatic urothelial carcinoma generally respond more poorly to chemotherapy after they have progression on a checkpoint inhibitor (CPI). There is interest in combining CPIs with conventional cytotoxic chemotherapies as a strategy to exploit the efficacy and immunomodulatory effects of chemotherapy. We conducted a single institution, retrospective analysis including all patients treated between May 2018 and May 2020 with carboplatin and paclitaxel, concurrently or sequential with pembrolizumab, after having progression on a CPI alone. Clinical characteristics, response by RECIST 1.1, progression-free survival, and safety/tolerance of the treatment are reported. Median age was 80 years (64–85). Five patients (100%) had visceral metastases when starting carboplatin and paclitaxel. Chemotherapy was given with concurrent pembrolizumab (four patients) or following pembrolizumab (one patient) and continued until maximum response, significant toxicity, or progression. Two patients subsequently remained on maintenance pembrolizumab. There were four partial responses and one patient with stable disease. All patients on follow-up have progressed with median time to progression of 47 weeks (18–75). Two patients died from disease progression. This case series suggests that the combination of carboplatin, paclitaxel, and pembrolizumab leads to durable freedom from progression in some with metastatic urothelial cancer, who have progressed on a CPI alone. Larger studies of chemoimmunotherapy for metastatic urothelial carcinoma are warranted.

e16103 Background: At present, androgen ablation (AA) therapy ± radiation therapy represents a first-line treatment for patients with unresectable locally advanced prostate cancer (CAP), typically resulting in palliative disease control. Immunotherapy, in the form of CTLA-4 blockade, has been shown to potentiate T-cell responses, representing a potential antitumoral immunotherapy for treating CAP. Here, we discuss the outcomes of 5 locally advanced CAP patients treated with the monoclonal antibody MDX-CTLA-4 (MDX-010) + AA who subsequently underwent radical prostatectomy (RP), 2 of whom exhibited striking down-staging of their disease. Methods: A Phase II trial testing AA + MDX-010 therapy for treatment of locally or systemically advanced CAP is currently ongoing at our institution. To date, 5/85 patients have electively opted for off-study RP with extended pelvic lymphadenectomy after documentation of robust treatment response by PSA, staging digital rectal exam, and 3-D imaging. Results: All men had unresectable, locally advanced disease (stage T2c-T4) prior to treatment with AA + MDX-010 and subsequently underwent RP. Median blood loss was 400mL (400–900). All patients had negative surgical margins. Of the 5 patients, 2 exhibited dramatic and indisputable down-staging of their disease. These two patients presented with 80% of biopsies involved with cancer, extraprostatic extension, seminal vesicle (SV) invasion, and bladder base involvement. On final pathology, both exhibited extensive treatment effect, remission of SV involvement, and robust disaggregation of solid tumors resulting in only microscopic, non-contiguous foci of residual intraprostatic cancer. Both had T4 disease pre-treatment, and had stage T2c on final pathology. One patient is free of disease with undetectable PSA for 19 months following adjuvant radiation treatment but no further therapy, while the other patient is awaiting follow-up. Conclusions: We have been able to demonstrate true down-staging of locally advanced prostate cancer with neoadjuvant AA + MDX-010 therapy. This therapeutic modality exhibits significant promise for men with unresectable disease and may provide durable and potentially curative cancer control. No significant financial relationships to disclose.

Abstract Introduction: The role of surveillance imaging in diffuse large B-cell lymphoma (DLBCL) after treatment with curative intent is debated. In 2013, the American Society of Hematology (ASH) Choosing Wisely® campaign (Hicks LK, et al. Blood 2013) released a recommendation to "limit surveillance CT scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma." This was based on previous studies demonstrating a lack of survival benefit as well as a significant impact on the patient in terms of cost, anxiety, incidental findings and radiation exposure. Similar findings have been described regarding the use of PET imaging, especially in low risk patients. We aimed to study the changes in practice patterns of surveillance imaging for DLBCL survivors treated with curative intent before and after the publication of the ASH Choosing Wisely® campaign. Methods: Administrative claims data from a large U.S commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify adult patients with an incident diagnosis of DLBCL between 2008 and 2016 and at least one year of follow-up. We excluded those who did not receive treatment with curative intent: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) x 6 cycles or RCHOP x 3-5 cycles plus radiation. Patients were also excluded if they had a co-existing or second cancer, or if they received any chemotherapy/radiation during their surveillance period, as to exclude anyone with a recurrence of their lymphoma. The surveillance period started 90 days after the last chemotherapy or radiation and continued for the duration of follow-up. Surveillance imaging was defined as any PET, PET-CT, CT chest, CT abdomen, and/or CT pelvis. To examine trends over time, three time periods were defined: 2008-2010, 2011-2013 and 2014-2016. The Cochran Armitage test was used to test the trend hypothesis. Results: A total of 1,472 patients were included. Cohort characteristics by time period are described in Table 1. Surveillance imaging frequency decreased from 84% in Year 1 of surveillance to 43% in Year 5 (Figure 1). Overall, surveillance imaging during the first 3 surveillance years significantly decreased over the three time periods (Figure 2) (P<0.01 for Years 1 and 2, P=0.04 for Year 3). Imaging surveillance for the first two years of surveillance did not significantly decrease from 2008-2010 to 2011-2013 (P>0.05), but significantly decreased from 2011-2013 to 2014-2016 (P<0.01). Of the groups that received imaging surveillance during year 1, the median number of scans during the first year was 2 (inter-quartile range, 1-2) and did not significantly change over time. In addition, PET/PET-CT surveillance decreased from 49% in Year 1 to <10% in Year 5. PET/PET-CT also decreased over the three time periods, from 62% (2008-2010) to 48% (2011-2013) to 43% (2014-2016) during the first year of surveillance and 40% to 31% to 25% during the second year. Younger age (<65 years versus ≥65 years) was associated with higher imaging utilization (86% versus 81%, respectively), and specifically PET/PET-CT utilization (55% versus 43%, respectively), during the first year of surveillance. However, race (white versus non-white) did not significantly affect imaging (85% versus 83%) or PET utilization (50% versus 47%) during the first year of surveillance. Conclusions: Our study demonstrates that the rate of surveillance CT and PET imaging in DLBCL patients treated with curative intent decreased significantly in the years after the publication of the ASH Choosing Wisely® campaign. However, over half of the DLBCL patients diagnosed in 2014-2016 continued to undergo surveillance imaging, indicating either incomplete guideline dissemination or ongoing debate regarding optimal surveillance practice. Future studies are necessary to determine whether such a decline in surveillance imaging is sustained and to examine factors (patient, provider, and payer) associated with surveillance imaging in DLBCL. Disclosures No relevant conflicts of interest to declare.

We present a rare cause of superior vena cava syndrome (SVC) in a previously healthy male aged 31 years. Malignancy was suspected due to unintentional weight loss and childhood exposure to radioactive fallout from a nuclear facility accident. A very large anterior mediastinal mass was identified and demonstrated to be an extragonadal seminoma. Extragonadal germ cell tumours are rare tumours with a high potential for cardiovascular, pulmonary and vascular sequelae. Studies have documented an increased risk of developing seminoma in patients with radioactive exposure. Chemotherapy was initiated, during which the patient experienced progressive and new symptoms, found to be due to extensive thromboembolic disease, which responded well to anticoagulation. Seventy-two months after completing chemotherapy, without need for surgical management, he remains free of the disease.

Abstract Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3′ terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31–12.2; P = 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704–15. ©2017 AACR.

Objectives To evaluate the prognostic significance of germline variation in candidate genes in patients with castration‐resistant prostate cancer (CRPC). Methods Germline DNA was extracted from peripheral blood mononuclear cells of patients with CRPC enrolled in a clinically annotated registry. Fourteen candidate genes implicated in either initiation or progression of prostate cancer were tagged using single nucleotide polymorphisms (SNPs) from HapMap with a minor allele frequency of >5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP‐level results the per allele hazard ratios (HRs) and 95% confidence intervals (CIs) under the additive allele model were estimated using Cox regression, adjusted for age at CRPC and Gleason score (GS). Results A total of 240 patients with CRPC were genotyped (14 genes; 84 SNPs). The median (range) age of the cohort was 69 (43–93) years. The GS distribution was 55% with GS ≥8, 32% with GS = 7 and 13% with GS <7 or unknown. The median (interquartile range) time from castration resistance to death for the cohort was 2.67 (1.6–4.07) years (144 deaths). At the gene level, a single gene, JAK2 was associated with OS ( P < 0.01), and 11 of 18 JAK2 SNPs were individually associated with OS after adjustment for age and GS. A multivariate model consisting of age, GS, rs2149556 (HR 0.67; 95% CI 0.38–1.18) and rs4372063 (HR 2.17; 95% CI 1.25–3.76) was constructed to predict survival in patients with CRPC (concordance of 0.69, P < 3.2 × 10 −9 ). Conclusions Germline variation in the JAK2 gene was associated with survival in patients with CRPC and warrants further validation as a potential prognostic biomarker.