Bothersome Hot Flashes Following Neoadjuvant Androgen Deprivation Therapy and Stereotactic Body Radiotherapy for Localized Prostate Cancer.

BACKGROUND: Androgen deprivation therapy (ADT) improves local cancer control in unfavorable localized prostate cancer treated with radiotherapy. ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and stereotactic body radiotherapy (SBRT) as well as its relationship with testosterone recovery. METHODS: Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a of the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (one, three, six, nine, 12, 18, 24, and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. RESULTS: From 2007 to 2010, 122 localized prostate cancer patients (nine low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (three to six months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were Black and 27% were obese. Seventy-seven percent of patients received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline (2%) nine months post-SBRT with a cumulative incidence of 52.4%. The median baseline EPIC-26 hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline (92) by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083, p<0.01). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. CONCLUSION: Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.

Impact of neoadjuvant relugolix on patient-reported sexual function and bother.

Introduction: Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in combination with radiation therapy in the treatment of unfavorable prostate cancer. It has been shown to achieve rapid and profound testosterone suppression. As a result, these very low testosterone levels may impact both sexual functioning and perceptions. This prospective study sought to assess neoadjuvant relugolix-induced sexual dysfunction prior to stereotactic body radiation therapy (SBRT). Methods: Between March 2021 and September 2023, 87 patients with localized prostate cancer were treated with neoadjuvant relugolix followed by SBRT per an institutional protocol. Sexual function and bother were assessed via the sexual domain of the validated Expanded Prostate Index Composite (EPIC-26) survey. Responses were collected for each patient at pre-treatment baseline and after several months of relugolix. A Utilization of Sexual Medications/Devices questionnaire was administered at the same time points to assess erectile aid usage. Results: The median age was 72 years and 43% of patients were non-white. The median baseline Sexual Health Inventory for Men (SHIM) score was 13 and 41.7% of patients utilized sexual aids prior to relugolix. Patients initiated relugolix at a median of 4.5 months (2-14 months) prior to SBRT. 95% and 87% of patients achieved effective castration (≤ 50 ng/dL) and profound castration (< 20 ng/dl) at SBRT initiation, respectively. Ability to have an erection, ability to reach orgasm, quality of erections, frequency of erections, and overall sexual function significantly declined following relugolix. There was a non- significant increase in sexual bother. Discussion: In concordance with known side effects of androgen deprivation therapy (ADT), neoadjuvant relugolix was associated with a significant decline in self-reported sexual function. However, patients indicated only a minimal and non-significant increase in bother. Future investigations should compare outcomes while on relugolix directly to GnRH agonist-induced sexual dysfunction.

Renal cell carcinoma histologic subtypes exhibit distinct transcriptional profiles.

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1+/TMBhi/MSIhi). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.

Early biochemical outcomes following neoadjuvant/adjuvant relugolix with stereotactic body radiation therapy for intermediate to high risk prostate cancer.

Introduction: Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy. Prostate SBRT offers an abbreviated treatment course with comparable efficacy to conventionally fractionated radiotherapy. Relugolix is a new oral GnRH receptor antagonist which achieves rapid, sustained testosterone suppression. This prospective study sought to evaluate early testosterone suppression and PSA response following relugolix and SBRT for intermediate to high prostate cancer. Methods: Relugolix was initiated at least 2 months prior to SBRT. Interventions to improve adherence were not utilized. PSA and total testosterone levels were obtained prior to and 1-4 months post SBRT. Profound castration was defined as serum testosterone ≤ 20 ng/dL. Early PSA nadir was defined as the lowest PSA value within 4 months of completion of SBRT. Per prior trials, we examined the percentage of patients who achieved PSA level of ≤ 0.5 ng/mL and ≤ 0.2 ng/mL during the first 4 months post SBRT. Results: Between July 2021 and January 2023, 52 men were treated at Georgetown with relugolix (4-6 months) and SBRT (36.25-40 Gy in 5 fractions) per an institutional protocol (IRB 12-1775). Median age was 71 years. 26.9% of patients were African American and 28.8% were obese (BMI ≥30 kg/m2). The median pretreatment PSA was 9.1 ng/ml. 67% of patients were ≥ Grade Group 3. 44 patients were intermediate- and 8 were high-risk. Patients initiated relugolix at a median of 3.6 months prior to SBRT with a median duration of 6.2 total months. 92.3% of patients achieved profound castration during relugolix treatment. Poor drug adherence was observed in 2 patients. A third patient chose to discontinue relugolix due to side effects. By post-SBRT month 4, 87.2% and 74.4% of patients achieved PSA levels ≤ 0.5 ng/ml and ≤ 0.2 ng/ml, respectively. Discussion: Relugolix combined with SBRT allows for high rates of profound castration with low early PSA nadirs. We observed a 96% testosterone suppresion rate without the utilization of scheduled cues/reminders. This finding supports the notion that patients with localized prostate cancer can consistently and successfully follow an oral ADT protocol without daily reminders. Given relugolix's potential benefits over injectable GnRH receptor agonists, its usage may be preferred in specific patient populations (fear of needles, prior cardiovascular events). Future studies should focus on boundaries to adherence in specific underserved populations.

Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292).

BACKGROUND: Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. PATIENTS AND METHODS: This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy. RESULTS: From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kß Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance. PATIENTS AND METHODS: In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kß inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate. RESULTS: Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug-drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2-71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%. CONCLUSIONS: Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.

Patients' preferences for delaying metastatic castration-resistant prostate cancer: Combining health state and treatment valuation.

PURPOSE: Men with castration-resistant prostate cancer (CRPC) experience disease progression at different rates. The purpose of this study was to quantify the strength of patient preferences for delaying prostate cancer progression utilizing a discrete choice experiment (DCE) and valuing 3 health states in the continuum of CRPC. PATIENTS AND METHODS: Men with CRPC, recruited from US patient panels, completed a cross-sectional web-based survey. The survey consisted of vignette-based time trade-off and a DCE designed to quantify patients' willingness to pay to delay metastatic CRPC. Three health states were presented: (1) living with non-metastatic castration-resistant prostate cancer (nmCRPC) (2) living with metastatic CRPC (mCRPC) before chemotherapy, and (3) living with mCRPC either on or after chemotherapy. The DCE consisted of 15 hypothetical choices with attributes characterizing CRPC (pain, fatigue, out of pocket cost, dosing, and time until cancer metastasizes). Patients' willingness to pay for changes in each attribute were derived. RESULTS: A total of 176 patients with CRPC were surveyed (mean age: 64.2 years; 74% nmCRPC). Patients valued the nmCRPC health state (0.865) significantly higher than mCRPC before chemotherapy (0.743) or mCRPC on or after chemotherapy (0.476), both P < 0.001. In the DCE, patient treatment valuation was most affected by increasing the number of months until cancer metastasized; patients were willing to pay an additional $682 per month to delay time to metastases from 6 to 24 months (95% Confidence Interval: $387-$977) and additional $1,041 per month to delay time to metastasis to 48 months (95% Confidence Interval: $591-$1,490). CONCLUSIONS: The results of this study demonstrated men with CRPC place significant value on delaying metastases. This study represents the first time 2 stated preference methods, time trade-off and DCE, were used together to understand patients' preferences and valuation of health states in CRPC.

Cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer.

OBJECTIVE: To evaluate the safety and efficacy of cabozantinib combined with docetaxel. PATIENTS AND METHODS: This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m2 every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. RESULTS: A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). CONCLUSION: Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

BACKGROUND: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma. METHODS: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999. FINDINGS: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths. INTERPRETATION: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies. FUNDING: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.

An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer.

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm.

Rationale for Involved Field Stereotactic Body Radiation Therapy-Enhanced Intermittent Androgen Deprivation Therapy in Hormone-Sensitive Nodal Oligo-Recurrent Prostate Cancer Following Prostate Stereotactic Body Radiation Therapy.

Lymph node recurrent prostate cancer is a common clinical scenario that is likely to increase significantly with the widespread adoption of novel positron emission tomography (PET) agents. Despite increasing evidence that localized therapy is disease modifying, most men with lymph node recurrent prostate cancer receive only systemic therapy with androgen deprivation therapy (ADT). For men who receive localized therapy the intent is often to delay receipt of systemic therapy. Little evidence exists on the optimal combination of local and systemic therapy in this patient population. In this hypothesis generating review, we will outline the rationale and propose a framework for combining involved field SBRT with risk adapted intermittent ADT for hormone sensitive nodal recurrent prostate cancer. In patients with a limited number of nodal metastases, involved field stereotactic body radiation therapy (SBRT) may have a role in eliminating castrate-resistant clones and possibly prolonging the response to intermittent ADT. We hypothesize that in a small percentage of patients, such a treatment approach may lead to long term remission or cure.

Total cost of care for castration-resistant prostate cancer in a commercially insured population and a medicare supplemental insured population.

Background: The total cost of healthcare for patients with castration-resistant prostate cancer (CRPC) is an important component for assessing value of treatment options. The need for real-world evidence has increased with the introduction of oral targeted therapies for metastatic and nonmetastatic disease. In this study, we examined patient healthcare costs during periods of nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC).Methods: This retrospective cohort study captured data from claims in the Truven Health MarketScan Commercial and Medicare Supplemental (Medigap) databases (1/1/2012-12/31/2016). Male patients (≥18 years) with ≥1 prostate cancer diagnosis, a subsequent metastatic diagnosis, and prescription claim for an mCRPC-indicated therapy (index date) were included. Patients were considered to have nmCRPC during the 12-month period prior to mCRPC if they had ≥1 claim for androgen deprivation therapy. Unadjusted all-cause healthcare resource utilization (HRU) and associated costs in 2016 USD per patient per year (PPPY) were determined for nmCRPC and mCRPC periods.Results: Patients included from the Commercial database (N = 449) had an average age of 59.4 ± 4.5 (standard deviation) years and a mean Quan Charlson Comorbidity Index (QCI) score of 2.8 ± 1.6. Among patients included from the Medigap database (N = 1,173), the mean age was 78.6 ± 7.2 years and mean QCI score was 3.3 ± 2.0. Across all healthcare resource types, HRU was approximately 1.5-2.5 times greater after a diagnosis of metastasis for both study populations. For commercially insured patients, total all-cause healthcare costs increased 6.2-fold from the nmCRPC to mCRPC periods ($29,192 to $182,156 PPPY). Likewise, among Medigap patients, total all-cause healthcare costs increased 5.1-fold from the nmCRPC to mCRPC periods ($27,549 to $139,847).Conclusions: In this study, the cost of care during 2012-2016 was substantially higher for mCRPC than nmCRPC, underscoring the value of interventions that may delay progression to metastases in high-risk individuals.

Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921.

Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] ≥ 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA > 10 ng/mL plus biopsy GS > 6. Patients with PSA ≤ 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided α = .05. Results Nine hundred sixty-one eligible intent-to-treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.

Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study.

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 µg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 µg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR.

Assessment of Real-World Central Nervous System Events in Patients with Advanced Prostate Cancer Using Abiraterone Acetate, Bicalutamide, Enzalutamide, or Chemotherapy.

BACKGROUND: Central nervous system (CNS) events are frequently reported among patients with advanced prostate cancer as a consequence of the treatments used in this patient population. OBJECTIVE: To assess the incidence of CNS events in patients with advanced prostate cancer who initiated treatment with abiraterone acetate, bicalutamide, enzalutamide, or chemotherapy. METHODS: The Truven Health MarketScan Research databases were used to retrospectively identify patients with prostate cancer who initiated treatment with abiraterone acetate, enzalutamide, bicalutamide, or chemotherapy after September 1, 2012 (ie, the index date). The chemotherapy agents included cabazitaxel, docetaxel, mitoxantrone hydrochloride, and estramustine, and were used as monotherapy or as combination therapy. Patients were followed until December 31, 2014, the end of exposure to treatment, or until loss to follow-up. Kaplan-Meier rates and adjusted Cox proportional hazard models were used to compare the incidence of CNS events between the abiraterone acetate cohort and the other cohorts. A sensitivity analysis of patients with a diagnosis of metastasis was also conducted. RESULTS: A total of 1067 patients receiving abiraterone acetate, 5524 receiving bicalutamide, 592 receiving enzalutamide, and 256 receiving chemotherapy were identified. After 12 months, patients who received abiraterone acetate were less likely to have a CNS event than patients who received enzalutamide (39.5% vs 46.0%, respectively; P = .0036) or chemotherapy (39.5% vs 51.1%, respectively; P = .0277), and were more likely to have a CNS event than patients who received bicalutamide (39.5% vs 34.2%, respectively; P = .0397). After multivariate adjustment, at 12 months, patients who initiated abiraterone acetate treatment had 20% (P = .0388) reduction in the risk for a CNS event compared with patients who initiated enzalutamide; 8% (P = .3622) versus bicalutamide; and 27% (P = .0456) versus chemotherapy. The sensitivity analysis yielded similar results. CONCLUSION: The results of this large observational study suggest that among patients with metastatic prostate cancer, treatment with abiraterone acetate is associated with a significantly lower likelihood of having a CNS event compared with treatment with enzalutamide or chemotherapy, but not with bicalutamide, even when controlling for metastatic disease.

Duration of Treatment in Prostate Cancer Patients Treated with Abiraterone Acetate or Enzalutamide.

BACKGROUND: Abiraterone acetate (AA) and enzalutamide (ENZ) are oral therapies offering survival benefit to metastatic castration-resistant prostate cancer (mCRPC) patients. Despite the availability of multiple treatment options for mCRPC, there is a lack of information on the effect that being initiated on AA or ENZ has on the combined prostate cancer treatment duration. OBJECTIVE: To compare the combined duration of prostate cancer treatments of patients initiated on AA with that of patients initiated on ENZ. METHODS: Truven Health MarketScan Research Databases from March 2012 to December 2014 were used to identify males with prostate cancer initiated on AA or ENZ (index therapy). Baseline characteristics were assessed during the 6 months pre-index. Inverse probability of treatment weights (IPTWs) were used to reduce baseline confounding. Treatment duration spanned from the index date to the earliest of treatment discontinuation (defined as a > 60-day gap in treatment), 24 months post-index, health plan disenrollment, or end of data. Weighted Kaplan-Meier and Cox proportional hazard models were used to compare the combined duration of mCRPC treatments (AA, ENZ, chemotherapy, sipuleucel-T, and radium 223) and any prostate cancer treatments (mCRPC, hormonal, and corticosteroid treatments) between patients initiated on either AA or ENZ. RESULTS: A total of 2,591 patients initiated on AA and 807 patients initiated on ENZ were selected for the study. Patients' characteristics were generally well balanced after IPTW. At 3 months, patients initiated on AA were associated with fewer discontinuations of mCRPC treatments (hazard ratio [HR] = 0.73, P = 0.004) or of any prostate cancer treatments (HR = 0.61, P = 0.002), compared with patients initiated on ENZ. This result was maintained at 6, 9, 12, 18, and 24 months for mCRPC treatments (HR = 0.75, P < 0.001) and for any prostate cancer treatments (HR = 0.69, P < 0.001). Median duration of mCRPC treatments was 4.1 months longer for patients initiated on AA compared with those initiated on ENZ (18.3 vs. 14.2 months, P < 0.001) and similarly, the median duration of any prostate cancer treatment was longer for patients initiated on AA compared with those initiated on ENZ (not reached vs. 22.2 months, P < 0.001). CONCLUSIONS: In this study, patients initiated on AA, compared with those initiated on ENZ, had a longer combined duration of mCRPC or prostate cancer treatments. DISCLOSURES: This research was funded by Janssen Scientific Affairs. Pilon, Emond, and Lefebvre are employees of Analysis Group, a consulting company that has received research grants from Janssen Scientific Affairs. Behl and Ellis are employees of Janssen Scientific Affairs and stockholders in Johnson & Johnson. Dawson is on the speakers bureau for Janssen, Astellas, and Sanofi Aventis. Emond reports grants from Regeneron, Bristol-Myers Squibb, GlaxoSmithKline, Aegerion, Bayer, Novartis, Allergan, Millenium, and Genentech. Pilon reports grants from Novartis, GlaxoSmithKline, Pfizer, and Bayer. Lefebvre reports grants from GlaxoSmithKline, Novartis, Bayer, Medtronic, Noven, and Novo Nordisk. Study concept and design were contributed primarily by Pilon and Lefebvre, along with the other authors. Pilon, Emond, and Lefebre collected the data, and data interpretation was performed by Behl, Lefebvre, and Dawson, along with Pilon, Ellis, and Emond, The manuscript was written by Pilon, Emond, and Lefebvre and revised by Behl, Ellis, and Dawson.

A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma.

BACKGROUND: In this trial we assessed the efficacy and tolerability of TRC105, a chimeric monoclonal antibody that targets CD105 (endoglin) in patients with advanced, previously treated urothelial carcinoma (UC). PATIENTS AND METHODS: Patients received TRC105 15 mg/kg every 2 weeks on days 1 and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) at 6 months. Secondary end points included safety, toxicity, and overall survival (OS). CD105 expression was evaluated using immunohistochemistry (IHC) in a separate cohort of 50 UC patients. Biomarker studies included immune subsets, circulating tumor cells (CTCs), circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and osteopontin. RESULTS: Of 13 patients enrolled, 12 were evaluable for OS and PFS. The 3-month PFS probability was 18.2% (median PFS, 1.9 months [95% confidence interval (CI), 1.8-2.1 months). This met the criterion for ending accrual on the basis of the 2-stage design. Median OS was 8.3 months (95% CI, 3.3-17.0 months). IHC for CD105 scores was not associated with T stage (P = .26) or presence of lymph nodes (P = .64). Baseline levels of regulatory T and B cells, CEPs, and changes in CEC level after TRC105 exhibited trends toward an association with PFS or OS. CTCs pre- and post-TRC105 were detected in 4 of 4 patients. CONCLUSION: Although TRC105 was well tolerated, it did not improve 6-month PFS in heavily pretreated patients with advanced UC. CD105 staining was present in 50% of UC tumors at different intensities. Our observations on the pharmacodynamic significance of immune subsets, CECs, and CTCs warrant further study.

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.

Phase II trial of docetaxel, bevacizumab, lenalidomide and prednisone in patients with metastatic castration-resistant prostate cancer.

OBJECTIVE: To determine the safety and clinical efficacy of two anti-angiogenic agents, bevacizumab and lenalidomide, with docetaxel and prednisone. PATIENTS AND METHODS: Eligible patients with metastatic castration-resistant prostate cancer enrolled in this open-label, phase II study of lenalidomide with bevacizumab (15 mg/kg), docetaxel (75 mg/m(2) ) and prednisone (10 mg daily). Docetaxel and bevacizumab were administered on day 1 of a 3-week treatment cycle. To establish safety, lenalidomide dosing in this combination was escalated in a conventional 3 + 3 design (15, 20 and 25 mg daily for 2 weeks followed by 1 week off). Patients received supportive measures including prophylactic pegfilgrastim and enoxaparin. The primary endpoints were safety and clinical efficacy. RESULTS: A total of 63 patients enrolled in this trial. Toxicities were manageable with most common adverse events (AEs) being haematological, and were ascertained by weekly blood counts. Twenty-nine patients (46%) had grade 4 neutropenia, 20 (32%) had grade 3 anaemia and seven (11%) had grade 3 thrombocytopenia. Despite frequent neutropenia, serious infections were rare. Other common non-haematological grade 3 AEs included fatigue (10%) and diarrhoea (10%). Grade 2 AEs in >10% of patients included anorexia, weight loss, constipation, osteonecrosis of the jaw, rash and dyspnoea. Of 61 evaluable patients, 57 (93%), 55 (90%) and 33 (54%) had PSA declines of >30, >50 and >90%, respectively. Of the 29 evaluable patients, 24 (86%) had a confirmed radiographic partial response. The median times to progression and overall survival were 18.2 and 24.6 months, respectively. CONCLUSIONS: With appropriate supportive measures, combination angiogenesis inhibition can be safely administered and potentially provide clinical benefit. These hypothesis-generating data would require randomized trials to confirm the findings.

Sipuleucel-T and immunotherapy in the treatment of prostate cancer.

INTRODUCTION: Immunotherapy represents an emerging modality of treatment utilized in patients with prostate cancer, among various other malignancies. AREAS COVERED: Sipuleucel-T is an autologous active cellular immunotherapy that has demonstrated improved survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The IMPACT trial led to the FDA approval of sipuleucel-T as first-line treatment for men with asymptomatic or minimally symptomatic mCRPC. Additional immunotherapies in cancer have shown promising results in clinical studies. These include ProstVac, which is a poxvirus vaccine targeting prostate-specific antigen, and cell cycle checkpoint inhibitors of cytotoxic T lymphocyte antigen-4 and programmed death-1 (PD-1) and its ligand (PD-L1). The combination of sipuleucel-T with both androgen deprivation therapy and androgen signaling agents has demonstrated robust and augmented immune responses. The responses to immunotherapy are often seen via different parameters compared with other therapies, including increased T-cell activation and antibody response. EXPERT OPINION: The role of immunotherapy in cancer continues to grow and encompass agents with different mechanisms, and ongoing efforts to identify appropriate timing of therapy and patients for use is integral to the management of prostate cancer.