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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

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.

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.