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Objective To study whether delivering definitive radiotherapy to sites of oligoprogression in metastatic renal cell carcinoma enabled deferral of systemic therapy changes without compromising disease control or survival. Materials/methods We identified patients with metastatic renal cell carcinoma who received radiotherapy to ≤3 sites of extracranial progressive disease in 2014-2019 at a large tertiary cancer center. Inclusion criteria were (1) controlled disease for ≥3 months before oligoprogression, (2) all oligoprogression sites treated with a biologically effective dose of ≥100 Gy, and (3) availability of follow-up imaging. Time-to-event endpoints were calculated from the start of radiotherapy. Results Seventy-two patients were identified (median follow-up time 22 months, 95% confidence interval [CI] 19-32 months), with oligoprogressive lesions in lung/mediastinum (n=35), spine (n=30), and non-spine bone (n=5). The most common systemic therapies before oligoprogression were none (n=33), tyrosine kinase inhibitor (n=23), and immunotherapy (n=13). At 1 year, the local control rate was 96% (95% CI 87%-99%); progression free survival, 52% (95% CI 40%-63%); and overall survival, 91% (95% CI 82%-96%). At oligoprogression, systemic therapy was escalated (n=16), maintained (n=49), or discontinued (n=7), with corresponding median progression free survival intervals of 19.7 months (95% CI 8.2-27.2 months), 10.1 months (95% CI 6.9-13.2 months), and 9.8 months (95% CI 2.4-28.9 months). Of the 49 patients maintained on the same systemic therapy at oligoprogression, 21 did not subsequently have systemic therapy escalation. Conclusion Patients with oligoprogressive metastatic renal cell carcinoma treated with radiotherapy had comparable progression free survival regardless of systemic therapy strategy, suggesting that radiotherapy may be a viable approach for delaying systemic therapy escalation. Randomized controlled trials comparing treatment of oligoprogression with radiotherapy vs. systemic therapy alone are needed.

INTRODUCTION Small cell prostate cancer (SCPC) is a rare histologic subtype of prostate cancer, for which the optimal staging strategy remains unclear. METHOD The Surveillance, Epidemiology, and End Results database was used to analyze the incidence and outcomes of SCPC between the years 2004 through 2016. Limited-stage SCPC (LS-SCPC) was defined as SCPC without any metastasis regardless of local invasion. Extensive stage SCPC (ES-SCPC) was defined as any metastasis to lymph nodes and/or to distant organs. RESULT A total of 403 SCPC patients were included in the study cohort, accounting for 0.056% of all prostate cancer cases (n=719,655). Of the 358 patients with known metastasis status, 275 (76.8%) patients had ES-SCPC, whereas 83 (23.2%) patients had LS-SCPC. LS-SCPC was associated with better overall survival (17 vs. 9 mo, P

Background: The mutation, selection, and adaptation of tumor cells along disease progression exhibits a spectrum of phenotypic and genotypic heterogeneity. The importance of distinguishing phenotypic states of CTC in addition to genomic alterations has been addressed for identifying predictive biomarkers and understanding CTC biology. Current liquid biopsy usually relies on only one phenotypic state of CTCs without further genomic validation of cancer cell identity. Here, we developed HDSCA3.0, a multi-omic platform, which could distinguish various phenotypic states of CTCs followed by genomic characterization. Methods: Paired peripheral blood (PB) and bone marrow aspirate (BMA) samples were collected prospectively from 80 metastatic castrate resistant prostate cancer (mCRPC) patients for retrospective analysis. Seventy-nine of them were part of Cabazitaxel With or Without Carboplatin Trial (NCT01505868) and one independent index patient was included with aggressive disease and unfavorable prognosis. CTCs were detected, classified, enumerated through a four-channel immunostaining assay (DAPI|Cytokeratin|Vimentin|CD45/CD31) and a computational pipeline followed by manual curation, and subjected to single-cell copy-number profiling for clonality analysis and aggressive variant prostate cancer molecular signature (AVPC-MS) detection i.e. 2+ defects in PTEN, RB1, and TP53 genes. Results: CTC subtypes were categorized from Cytokeratin-positive rare cell groups based on the presence of mesenchymal features and platelet attachment. Of 79 trial cases, 77 (97.5%) had CTCs, 24 (30.4%) were positive for platelet-coated CTCs (pc.CTCs) and 25 (38.5%) of 65 sequenced patients exhibited AVPC-MS in CTCs. Survival analysis indicated that the presence of pc.CTCs identified the subset of patients who were AVPC-MS-positive with the worst prognosis. In AVPC-MS-negative patients, its presence showed significant survival improvement from combination therapy. In index patient, we uniquely identified genetically clonal mesenchymal-like CTCs (mes.CTCs) and their presence was significantly associated with one subclone emerged along clonal lineage. Meanwhile, differences of CTC abundance and phenotypic diversity were observed between paired PB and BMA as well as genomic variations. Conclusion: Our findings suggest pc.CTCs and AVPC-MS in CTCs as a multi-omic predictive biomarker to stratify mCRPC subpopulations with the worst prognosis and the most significant benefit of additional platinum therapy and illustrate a robust approach to analyze intra-patient CTC genotypic and phenotypic heterogeneity and association. Citation Format: Shoujie Chai, Nicholas Matsumoto, Ryan Storgard, Chen-Ching Peng, Ana Aparicio, Benjamin Ormseth, Kate Rappard, Cunningham Kate, Anand Kolatkar, Rafael Nevarez, Kai Han Tu, Ching-Ju Hsu, Amin Naghdloo, Paymaneh Malihi, Liya Xu, Paul Corn, Amado Zurita-Saavedra, James Hicks, Carmen Ruiz-Velasco, Peter Kuhn. Dissecting CTC phenotypic heterogeneity for predictive biomarker identification and its association with clonal lineage through single-cell multi-omic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1957.

Introduction Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA‐approved as front‐line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off‐protocol and post‐front‐line experience with combination TKI–IO approaches. Methods We conducted a retrospective analysis of mRCC patients who received combination TKI–IO post‐first‐line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1. Results We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI–IO combinations included nivolumab–cabozantinib (N +C; 24 patients), nivolumab–pazopanib (N+P; 13), nivolumab–axitinib (6), nivolumab–lenvatinib (2), and nivolumab–ipilimumab–cabozantinib (3). The median progression‐free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event. Conclusion To our knowledge, this is the first case series reporting off‐label use of combination TKI–IO for mRCC. TKI–IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO., Real world use of combination anti‐angiogenic tyrosine kinase inhibitor (TKI)—anti‐PD1 immunotherapy (IO) is feasible, well tolerated and efficacious for metastatic renal cell carcinoma in the second line setting and beyond. Although further prospective research is essential to define optimal use of salvage TKI‐IO, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either a TKI or IO.

Introduction: Pre-clinical models show that the addition of the mTORC1/2 inhibitor sapanisertib (TAK-228) restores sensitivity to platinum chemotherapy and dramatically enhances paclitaxel-induced cancer cell killing. Carboplatin plus paclitaxel is an established therapy in a variety of cancers including non-small cell lung cancer, ovarian cancer and others. This phase 1 study (NCT03430882) assessed the safety and tolerability of sapanisertib in combination with carboplatin plus paclitaxel in patients with advanced solid malignancies enriched with mTOR pathway alterations. Methods: Eligible patients, enriched for mTOR pathway aberrant tumors by CLIA-certified next-generation sequencing, received increasing sapanisertib doses on day 2-4 of each week at 2mg (Dose level 1; 4 patients), 3mg (Dose level 2; 4 patients) and 4mg (Dose level 3; 4 patients) combined with carboplatin (AUC 5) intravenously every 3 weeks on day 1 of each cycle plus paclitaxel 40mg/m2 (Dose levels 1-3), 60mg/m2 (Dose level 4; 7 patients) on day 1, 8, and 15 of each cycle. Results: Among the patients enrolled, males were 8/19 (42%), median age was 59 (range: 33-74). Of the 12 patients treated with Dose levels 1-3, 11 patients were evaluable for dose-limiting toxicities (DLTs) and no DLTs were observed. Seven patients were treated in Dose level 4 and among the 6 patients that were evaluable for DLTs, 1 patient had a DLT. Genomic alterations included PI3K/PTEN in 11/19 (58%), NF1 in 2/19 (10.5%), NF2 in 2/19 (10.5%), TSC1 in 1/19 (5%), TSC2 in 1/19 (5%), and EWSR1-POU5F1 fusion in 1/19 (5%). Of 17 patients evaluable for response, disease control rate (CR+PR+SD) was 76.4 % including 2 patients who achieved partial response. Responders were a patient with sarcomatoid renal cell carcinoma harboring EWSR1-POU5F1 fusion, who remains on therapy for more than 18 months. In addition, a patient with castrate resistant prostate cancer who progressed on cabazitaxel but harbors PTEN loss and remained on therapy for 7.3 months. There were no unanticipated toxicities. Grade 3-4 treatment-related adverse events included anemia (4/19; 21%), neutropenia (4/19; 21%), thrombocytopenia (2/19; 10.5%), and transaminitis (1/19; 5%). Conclusion: Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in patients with advanced malignancies harboring mTOR pathway alterations. Citation Format: Omar Alhalabi, Aung Naing, Roman Groisberg, Andrew Hahn, Shizhen Zhang, Samantha C. Berkey, Apostolia M. Tsimberidou, Jordi Rodon, Timothy A. Yap, Shubham Pant, Amishi Y. Shah, Amado Zurita-Saavedra, Nizar Tannir, Funda Meric-Bernstam, Vivek Subbiah. Phase I study of mTORC1-2 inhibitor sapanisertib (TAK-228) in combination with carboplatin plus paclitaxelin patients with advanced solid malignancies and mTOR pathway alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT109.

Background Multimodality therapies for men with high- and very high-risk prostate cancer, including neoadjuvant systemic therapy followed by subsequent radical prostatectomy (RP) are being increasingly explored despite the lack of adequate morbidity data. Materials and Methods We analyzed the data from 215 consecutive patients with high- and very high-risk prostate cancer who were previously untreated or had received neoadjuvant systemic therapy. All patients underwent RP with extended pelvic lymph node dissection from 2006 to 2010 at a single tertiary care academic center. All complications within 90 days of surgery were defined and categorized by a 5-grade and 10-domain modification of the Clavien system. Univariable and multivariable logistic regression analyses were used to identify preoperative predictors for complications. Results Of the 215 patients, 29% experienced a complication of any grade ≤ 90 days after surgery; 6% experienced grade ≥ 3, with no significant difference between either cohort (P = .50). On multivariate analysis, open RP (odds ratio [OR], 2.08; 95% confidence interval [CI], 1.11-3.90; P = .02) and preoperative hemoglobin (OR, 1.98; 95% CI, 1.05-3.72; P = .03) were independent predictors of the occurrence of any grade complication. For major complications (Clavien ≥ 3), a Charlson comorbidity index of 6 to 7 versus 3 to 5 (OR, 5.45; 95% CI, 1.57-18.98; P = .008) and the most recent year of surgery (OR, 4.73; 95% CI, 1.36-16.39; P = .01) were significant predictors on multivariable analysis. Conclusion The use of neoadjuvant systemic therapy did not appear to increase the risk of perioperative complications. These findings support current clinical trials, which might elucidate the oncologic benefit of this multimodality approach.

Background: Advanced androgen signaling inhibition, a prevailing therapy approach in advanced prostate cancer, incurs variable response Therapy selection guided by predictors is an unmet need Methods: We reviewed MDACC GU department and Hellenic Sister Institute records for Abiraterone Acetate (AA) treated mCRPC patients (pts) with extraordinary response (absence of radiographic/clinical progression for ≥3 years) We compared to reported findings for COU-AA-302 and real world experience to identify candidate predictors of outcome We applied a previously proposed COU-AA-302 response prognostic model Archived diagnostic and subsequent tumor specimens were retrieved for molecular characterization Results: Forty four of 430 reviewed mCRPC pts had extraordinary response Table depicts features Median time to AA discontinuation was 5 8 yr (range 3-12 5+) and 20 pts are on treatment Safety profile is acceptable with no overt increase in fractures or cardiovascular, metabolic morbidity All pts experienced >50% PSA decline with nadir ≤0 1 in 80%, occurring within 5mo (median) (range

Background: Most cancer cells depend more on glycolysis for their energy need compared with their normal counterparts incubated under identical condition. In addition to glycolysis, tumor cells also engage mitochondrial ox-phos to support growth. Here, we show that PCa cells surviving under anti-androgen enzalutamide (ENZA) treatment switch from glycolysis to ox-phos for their energy need and are more vulnerable to mitochondria-targeted metabolic inhibitors. We have also standardized a high-resolution quantitative fluorescence microscopic method to detect this metabolic switch in patient circulating tumor cells (CTCs). Methods: Seahorse assay has been used to compare mitochondrial metabolism in ENZA treated anti-androgen-sensitive LNCaP and -resistant C4-2 and PCa2b cells. The Seahorse data were supported by mass spectroscopic analysis of corresponding metabolites and metabolic fluxes. An ex vivo fluorescence staining for the CTC mitochondria with high ox-phos followed by high-resolution quantitative microscopic image analysis method has been standardized to follow such changes in cultured cells and patient CTCs. Results: Seahorse, mass spectroscopy and high-resolution microscopy of mitochondrial ox-phos showed that ENZA significantly decreases glycolysis and increases ox-phos in all surviving PCa cells within 24h of treatment. These cells are more vulnerable to treatment with mitochondrial ox-phos inhibitor IACS-010759 and a glutaminase inhibitor CB-839. High-resolution microscopic analysis of CTCs has thus far been performed in 18 patient blood samples. Six out of the 18 patients developed resistance to anti-androgen therapy within 0-6 months of sample collection. CTCs from all six patients showed a relatively higher average fluorescence due to high mitochondrial ox-phos as compared with the rest of the patients. Discussion: The data presented here may lead to informed combination therapy for selected PCa patients developing resistance to anti-androgen therapy for better clinical outcome. Citation Format: Hirak S. Basu, Nathaniel Wilganowski, Samantha Robertson, Sumankalai Ramachandran, Amado Zurita-Saavedra, Mark Titus, Evan Cohen, James Reuben, George Wilding. Metabolic switch from glycolysis to oxidative phosphorylation (ox-phos) provides survival advantage to anti-androgen-treated prostate cancer cells and make them vulnerable to mitochondrial metabolism inhibitors IACS-010759 and CB-839 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4791.

Targeting a T-cell inhibitory checkpoint with the anti-CTLA-4 monoclonal antibody, ipilimumab, represents a scientific breakthrough in immunotherapy for the treatment of cancer. However, ipilimumab therapy is also associated with unique side effects, known as immune-related adverse events (irAEs), which need to be recognized and managed with immunosuppressive agents. To date, the majority of our knowledge regarding ipilimumab-associated side effects is based upon clinical studies in melanoma. Here we provide a review of ipilimumab-induced irAEs and our experience in a cohort of 44 patients with prostate cancer who were treated at the MD Anderson Cancer Center on two different clinical trial protocols.

We evaluated the patterns of progression and determined clinical predictors of survival in patients with castration-resistant prostate cancer (CRPCa) who received sipuleucel-T. We retrospectively analyzed 56 consecutive patients with asymptomatic or minimally symptomatic CRPCa treated with sipuleucel-T. Age, number of bone metastases, history of prior systemic treatment, and alkaline phosphatase level (ALP) were tested as predictors of survival in a multivariate Cox proportional hazards regression model. The Kaplan–Meier method was used to estimate event-free probabilities. The 56 patients were a median age of 67 years (range 51–84 years). After sipuleucel-T treatment, 25 patients developed bone progression after a median of 22 months of follow-up (54% of patients were event free at 2 years) and 10% (6/56 patients) developed rapid progression. Eleven deaths were observed after a median of 28 months of follow-up. Forty-eight patients were included in the multivariate analysis for overall survival. The analysis showed that age >70 years (p = 0.012), number of bone metastases >20 (p = 0.018), prior systemic treatment (p = 0.018), and ALP level >90 IU/L (p = 0.010) significantly predicted worse overall survival. Two-year overall survival was 36% among the 16 patients with two or more of these factors and was 93% among the 32 patients with one or none of these factors (p = 0.0004). CRPCa patients with age (>70 years), increased tumor burden in bone (>20 metastases and/or elevated ALP level), and/or prior systemic treatment are more likely to experience rapid deterioration after sipuleucel-T. These results need to be prospectively validated.

Background: Androgen deprivation therapy (ADT) is a standard treatment that, although not curative, often induces dramatic responses in patients with advanced prostate cancer by inducing tumor cell death, which may provoke antigen release to initiate T cell responses. Ipilimumab blocks the inhibitory immune checkpoint, CTLA-4, which enhances T cell responses and induces both clinical benefit and unique toxicities in a subset of patients with advanced cancer. We designed a clinical study combining ipilimumab with finite ADT in men with metastatic prostate cancer to estimate therapeutic efficacy, determine safety, and identify predictive biomarkers for clinical outcomes. Methods: We screened 30 patients and enrolled 27 patients between July, 2011 and June, 2013 for an open-labelled, single-center, Phase II study of ipilimumab plus finite ADT as first-line therapy for metastatic non-castrate prostate cancer. Eligible patients had histological confirmation of prostate carcinoma and radiographic documentation of metastatic disease. ADT was given for a finite duration of eight months with concurrent ipilimumab (10 mg/kg) for up to four doses, each given four-weeks apart. The primary endpoint was the proportion of patients with undetectable PSA (≤0.2 ng/mL) at seven months post-treatment initiation with ADT. In addition, we performed comprehensive immune monitoring of the peripheral blood using multi-parametric flow cytometry and next-generation sequencing of T cell receptors. Findings: All 27 of the enrolled patients were evaluable for safety and toxicity, and 24 of these patients were evaluable for therapeutic effectiveness. Ten of the 24 (42%) patients achieved the primary endpoint of undetectable PSA levels at seven months post-treatment initiation. The median time to PSA progression was 10.0 (IQR 5.9-13.3) months from treatment initiation, and one (4%) of the 24 patients continues to have a PSA response that is ongoing for 40.7 months. The trial was closed as prespecified due to grade 3 toxicities that occurred in 12 (44%) of 27 patients. The most common grade 3 adverse events were transaminitis, colitis/diarrhea, and hypophysitis. Immunological biomarkers were identified that potentially predict for clinical benefit and grade 3 toxicities in this small study. No grade 4 or 5 toxicities were observed. Interpretation: Although the combination of 10 mg/kg ipilimumab plus finite ADT led to toxicities that met a prespecified endpoint for closure of the trial, our current knowledge and experience about combination therapies and dose of ipilimumab leads us to postulate that additional clinical trials evaluating ipilimumab at 3 mg/kg plus ADT is warranted. In addition, we identified candidate immunological biomarkers that need to be further tested as predictive markers of clinical benefit and grade 3 toxicities. Citation Format: Sumit K. Subudhi, Ana Aparicio, Jianjun Gao, Amado Zurita-Saavedra, John C. Araujo, Christopher J. Logothetis, Korivi R. Brinda, Jim P. Allison, Luis Vence, Ryan O. Emerson, Erik Yusko, Marissa Vignali, Harlan S. Robins, Jingjing Sun, Padmanee Sharma. Exploratory biomarkers that predict for clinical outcomes in a Phase II trial with ipilimumab plus finite androgen deprivation therapy for metastatic non-castrate prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1402.