Prateek Mendiratta

Emerging immunotherapy in advanced renal cell carcinoma

Immunotherapy has recently catapulted to the forefront of treatments for patients with solid tumors. Given its inherent immunogenic properties, renal cell carcinoma (RCC) has historically responded to immunotherapy and remains primed for further development. Although immunotherapy with high-dose interleukin 2 was a primary treatment for advanced RCC (aRCC), recent discoveries of key molecular and immunological alterations have led to the FDA-approval of nivolumab, an antiprogrammed cell death inhibitor, which has demonstrated an overall survival in patients with previously treated aRCC. However, despite recent therapeutic advances, aRCC remains an incurable disease for most patients. In this review, we assess the current landscape and future developments of immunotherapy in aRCC.

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer

BACKGROUND. A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3&bgr;-hydroxysteroid dehydrogenase 1 (3&bgr;HSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3&bgr;HSD1 to multiple steroidal metabolites, including 3-keto-5&agr;-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5&agr;-abiraterone synthesis in patients. METHODS. First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5&agr;-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS. Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5&agr;-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION. Increased generation of 3-keto-5&agr;-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING. Prostate Cancer Foundation Challenge Award, National Cancer Institute.

Treatment selection for men with metastatic prostate cancer who progress on upfront chemo-hormonal therapy

Androgen deprivation therapy plus docetaxel (D‐ADT) increases overall survival (OS) in men with high‐volume, metastatic hormone‐sensitive prostate cancer (mHSPC). Although the vast majority of men initially respond to D‐ADT, most will progress and develop castration‐resistant prostate cancer (CRPC). Little is known about the optimal treatment sequence for men with progressive disease on D‐ADT.

Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study

IntroductionTumor profiling by targeted next-generation sequencing (tNGS) and personalized treatment based on these results is becoming increasingly common in patients with metastatic solid tumors, but it remains unclear whether this strategy results in benefit to patients with metastatic prostate cancer (mPCa).ObjectiveTo assess the clinical utility of tNGS in treatment decision-making for patients with mPCa.Patients and MethodsPatients with available genomic profiling using tumor tissue (FoundationOne, F1) or cell-free DNA (FoundationACT, Guardant360) were included. Targetable genomic alterations (tGA) included a change in the copy number or mutations in DNA repair genes, mismatch repair genes, PTEN, cyclin-dependent kinases, ERBB2, BRAF, TSC, and the PIK3/mTOR pathway.ResultsThe study included 66 patients, 86% of which had metastatic castration-resistant prostate cancer (mCRPC), and who had received a median of 3 (range 0–7) treatments prior to tNGS. The most frequent alterations were found in TP53 (42%), PTEN (35%), androgen receptor (AR) (30%), DNA repair (30%), PIK3CA signaling pathway (21%), cyclin-dependent kinases (15%), BRAF (9%),xa0and MMR/MSIxa0(6%) genes. Among the 45 (68%) tGA+ patients, tNGS influenced treatment in 13 (29%) [PARP inhibitor (nu2009=u20097), mTOR inhibitor (nu2009=u20094), anti-PD-1 (nu2009=u20092), anti-HER2 (nu2009=u20091)]. The median progression-free survival (PFS) was 4.1xa0months [95% confidence interval (CI), 2.8–5.4]. Among tGA+ patients who did not receive tNGS-based therapy, systemic treatment (nu2009=u200917) included chemotherapy (71%), new generation anti-androgen therapy (24%), and cabozantinib (6%); the median PFS was 4.3xa0months (95% CI, 2.6–6.0; pu2009=u20090.7xa0for tGA+ with personalized therapy vs. tGA+ without personalized therapy).ConclusionIn this cohort, the use of tNGS was feasible, detected frequent genomic alterations, and was used late in the disease course. Further studies and larger portfolios of targeted therapy trials are needed to maximize the benefit of tNGS in this population.

Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies

BackgroundLittle is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials.ObjectivesThe objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials.Patient and MethodsThis is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200xa0mg every 3xa0weeks between May 2016 and April 2017.ResultsSeventy-nine patients, median age 72xa0years (range 29–93), 71% men and 76% ECOG PS 0–1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7xa0months (95%CI, 1.8–3.6) and median PFS was 3.2xa0months (95%CI, 1.6–4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8xa0months (95%CI, 0.0–5.0) while 42% were referred to palliative care/hospice or died.ConclusionsPatients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC.

ATM/RB1 mutations predict shorter overall survival in urothelial cancer

Background Mutations of DNA repair genes, e.g. ATM/RB1, are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of ATM/RB1 mutations in UC can inform clinical decision making and trial designs. Results In the discovery dataset, ATM/RB1 mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45–4.92, p = 0.002). There was a higher mutation load in patients carrying ATM/RB1 mutations (median mutation load: 6.7 versus 5.5 per Mb, p = 0.072). In the validation dataset, ATM/RB1 mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97–3.59, p = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, p = 0.126). Materials and Methods Exome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM/RB1 mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS). Conclusions ATM/RB1 mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of ATM/RB1 mutation status to immunotherapy and platinum-based chemotherapy.

Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma

BackgroundWe previously reported early on-treatment significant modulation in circulating regulatory T cell (Treg), myeloid derived suppressor cells (MDSC) and antigen-specific type I CD4+ and CD8+ T cells that correlated with clinical outcome in regionally advanced melanoma patients treated with neoadjuvant ipilimumab. Here, we investigated the long term immunologic impact of CTLA4 blockade.MethodsPatients were treated with ipilimumab given at 10xa0mg/kg IV every 3xa0weeks for 2 doses bracketing surgery. Blood specimens were collected at baseline and during treatment for up to 9xa0months. We tested immune responses at 3, 6, and 9xa0months utilizing multicolor flow cytometry. We compared frequencies of circulating Treg and MDSC on-study to baseline levels, as well as frequencies of CD4+ and CD8+ T cells specific to shared tumor-associated antigens (Gp-100, MART-1, NY-ESO-1).ResultsLevels of Treg significantly increased when measured at 6xa0weeks following ipilimumab but returned to baseline by 3xa0months, with no significant difference in Treg levels between relapsed and relapse-free groups at 3, 6 or 9xa0months. However, lower baseline levels of circulating Treg (CD4+CD25hi+CD39+) were significantly associated with better relapse free survival (RFS) (pu2009=u20090.04). Levels of circulating monocytic HLA-DR+/loCD14+ MDSC were lower at baseline in the relapse-free group and further decreased at 6xa0weeks, though the differences did not reach statistical significance including measurements at 3, 6 or 9xa0months. We detected evidence of type I (interferon-γ producing), activated (CD69+) CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) as well as melanocytic lineage (MART-1, gp100) antigens in the absence of therapeutic vaccination. These responses were significantly boosted at 6xa0weeks and persisted at 3, 6 and 9xa0months following the initiation of ipilimumab.ConclusionsLower Treg levels at baseline are significantly associated with RFS and increased Treg frequency after CTLA4 blockade was only transient. Lower MDSC was also associated with RFS and MDSC levels were further decreased after ipilimumab. Tumor specific effector immune responses are boosted with CTLA4 blockade and tend to be durable.Trial registration ClinicalTrials.gov Identifier: NCT00972933

Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study

SummaryIntroduction Ketoconazole is CYP-17 inhibitor with demonstrated activity in men with castration-resistant prostate cancer (CRPC). Lenalidomide is an antiangiogenic and immunomodulatory agent with broad antitumor activity. We hypothesized that the modulation of the cellular immune response to apoptosis caused by ketoconazole may be increased with the addition of lenalidomide. Methods This is an open-label, non-randomized, single-arm phase II study evaluating the efficacy and safety of the combination of ketoconazole and lenalidomide in patients with CRPC. Treatment schema included standard ketoconazole 400xa0mg orally three times daily plus hydrocortisone orally (20xa0mg in the morning and 10xa0mg at night) in combination with lenalidomide 25xa0mg orally daily for 21xa0days in a 28-dayxa0cycle and aspirin 75xa0mg daily. The primary endpoint of this study was response (either by ≥ 50% PSA decline or objective disease assessed by RECIST v1.0). Exploratory endpoints included changes in T cell, dendritic cell (DC) marker counts, and their correlation with PSA response to treatment. Results A total of 34 CRPC patients, median age 69xa0years, 76% ECOG 0 and 76% with metastases participated in the study. Patients received a median of 2xa0cycles (range 1–35); nine patients (26%) received >10xa0cycles of treatment. PSA responses were observed in 17 patients (50%) with 11 patients (32%) achieving a PSA decline of >90%. Among the 9 patients with measurable disease, 2 patients (22%) had PR and 2 other (22%) had SD as best response. Median time to failure (TTF) was 2.7xa0months (range 0.2–32.8); and 8 patients were treated for ≥ 15xa0months. Most common adverse events included fatigue (76%), skin reactions (62%), lymphopenia (44%) and anemia (44%). One possible treatment-related death was noted. For 16 patients with available serial correlative data, there was a significant increase in the dendritic cells subsets BDCA-1 (+146.7, −20.1 to +501.1%, pu2009=u20090.018) and BDCA-3 (39.8%, −100 to 282.6%, pu2009=u20090.001) after 8xa0weeks of treatment. No association between immune cell counts and PSA response at 8xa0weeks was observed. Conclusion The combination of ketoconazole and lenalidomide was well tolerated but did not meet the primary endpoint of response, despite durable responses were observed in a selected group of patients. Although ketoconazole has now been replaced with more active novel agents, the combination of novel CYP-17 inhibitors with agents capable of modulating the immune system warrants further prospective investigation. NCT00460031.

Androgen Deprivation Fortified

There are no curative therapies for patients with recurrent or de novo metastatic prostate cancer (1). The cornerstone of treatment for these men was androgen deprivation therapy (ADT) (2, 3) alone until 2 landmark studies demonstrated survival benefits with docetaxel in combination with ADT when given earlier to men with metastatic hormonesensitive prostate cancer (mHSPC) (4, 5). Consistent survival benefits were also seen with the addition of the oral biosynthesis inhibitor abiraterone acetate (AA) to ADT in a similar patient population (6, 7). The overall survival benefit seen with docetaxel and ADT in the CHAARTED trial (4) was only statistically significant for the highvolume cohort (visceral lesions or 4 bone lesions with 1 beyond vertebral bodies or pelvis). This cemented docetaxel and ADT as the standard of care for high-volume mHSPC, with debate regarding its role in low-volume disease. The combination of AA with ADT versus ADT alone in the LATTITUDE (6) and STAMPEDE trials (7) showed similar overall survival benefit (roughly a 40% relative risk reduction for death for men treated with ADT and AA) to the CHAARTED trial with docetaxel and ADT; yet the benefits seen with STAMPEDE also included patients with high-risk nonmetastatic nodenegative (approximately 28%), nonmetastatic nodepositive (approximately 20%), metastatic (approximately 52%), and recurrent disease (7). Thus, the use of AA has emerged as a new standard of care for mHSPC, regardless of volume of disease. Metastatic hormone-sensitive prostate cancer remains a heterogeneous disease, with the possibility that a subset of patients may exhibit an indolent behavior and potentially benefit from metastasis-directed therapy (8, 9). These patients have been defined by the terms oligometastatic (OM) or “low-volume disease.” There remains no uniform consensus definition for OM (ie, number of lesions or sites of disease). A recent consensus panel had difficulty agreeing to a standard definition, other than including patients with 5 sites of nodal or bony lesions detected on conventional imaging (10). There currently are no completed prospective randomized trials to guide therapy for OM patients after receiving local therapy, yet enthusiasm exists regarding the ability ofmetastasis-directed therapy to achieve local control and delay the need for ADT. For patients with low-volume/OM prostate cancer, we believe that ADT plus the addition of AA is the new standard of care, on the basis of overall survival benefits. Metastasis-directed therapy to nodal recurrence or bony lesions is currently not the standard of care; however, future ongoing prospective trials will clarify its role and determine whether it can improve clinical outcomes above and beyond systemic therapy alone.

Effect of Switching Systemic Treatment After Stereotactic Radiosurgery for Oligoprogressive, Metastatic Renal Cell Carcinoma

Background We assessed the clinical outcomes of patients with oligoprogressive renal cell carcinoma (mRCC) treated with stereotactic radiosurgery (SRS), stratified by changing or continuing systemic treatment. Patients and Methods Ninety‐five consecutive patients with clear cell mRCC who had undergone SRS to the central nervous system (CNS) or spine during systemic treatment were divided into 3 cohorts: those who continued the same systemic therapy (STAY), those who changed systemic treatment after SRS (SWITCH), and patients with progression outside the SRS sites, who also changed systemic treatment (PD‐SYS). The primary outcome was treatment duration after SRS, defined as the interval between SRS and discontinuation of the current systemic therapy for the STAY group and discontinuation of the first subsequent therapy in the SWITCH and PD‐SYS groups. Results Local control with SRS was achieved in 85% of the patients. The most common systemic treatment at SRS included anti–vascular endothelial growth factor (67%), mammalian target of rapamycin (14%), and programmed cell death protein 1 inhibitors (9%). The median treatment duration for the STAY group was 5.2 months (95% confidence interval [CI], 3.5‐6.9) compared with 5.0 months (95% CI, 4.3‐5.7) for the SWITCH group (P = .549) and 3.1 months (95% CI, 1.7‐4.5) for the PD‐SYS group (P = .07, compared with all other patients). No difference in median overall survival was found for the STAY and SWITCH groups (24.2 vs. 27.1 months; P = .381) but was significantly longer than that for the PD‐SYS group (P = .025). Conclusion The decision to continue the same systemic therapy at SRS to treat CNS or spinal lesions did not compromise the clinical outcomes of patients with oligoprogressive mRCC. Micro‐Abstract Stereotactic radiosurgery (SRS) can be used to treat metastatic renal cell carcinoma (mRCC) when progression involves a limited number of metastases. In the present retrospective study of consecutive patients with oligoprogressive mRCC, the decision to continue with the same systemic therapy after SRS did not compromise treatment duration or overall survival. Medical treatment decisions should be individualized according to tolerance of the existing regimen, progressive disease outside sites of SRS, and patient access to subsequent therapies.