Evan Y. Yu

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

BACKGROUNDnFirst-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.nnnMETHODSnFor 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.nnnFINDINGSnBetween 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.nnnINTERPRETATIONnAtezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.nnnFUNDINGnF Hoffmann-La Roche, Genentech.

Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle‐invasive bladder cancer

Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle‐invasive bladder cancer despite the lack of Level I evidence in this setting.

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

Background:Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel.Methods:We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel.Results:Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2–9.1), 4.0 (3.2–4.8), 4.1 (2.9–5.4) and 2.8 (2.5–3.2) months; median duration of enzalutamide was 9.1 (7.3–not reached), 4.7 (3.7–7.7), 5.4 (3.8–8.4) and 3.9 (3.0–4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7–16.5). 12-month OS was 78% (59–100%), 64% (45–90%), 77% (61–97%) and 51% (41–62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide.Conclusions:The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

Challenges and Recommendations for Early Identification of Metastatic Disease in Prostate Cancer

Prostate cancer is often associated with metastases to bone and/or soft tissue. The progression to metastatic castrate-resistant prostate cancer is a seminal event in disease progression affecting treatment decisions. A multidisciplinary group was convened to review the currently available imaging guidelines for metastatic disease in prostate cancer and found no consensus on eligibility criteria, type of imaging modality, and the frequency of scanning for detecting metastatic disease. The aim of this review was to present the recommendations from the group to identify optimal strategies for early identification of metastases in patients with prostate cancer.

A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer

PurposeKX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC).MethodsWe treated 31 patients with oral KX2-391 (40xa0mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50xa0% success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin].ResultsThe trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24xa0weeks was 8xa0%, and median PFS was 18.6xa0weeks. The PSA response rate (≥30xa0% decline) was 10xa0%, and median PPFS was 5.0xa0weeks. Additionally, 18xa0% of men with unfavorable (≥5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32xa0% for uNTx, 21xa0% for CTx, 10xa0% for BAP, and 25xa0% for osteocalcin. In pharmacokinetic studies, median Cmax was 61 (range 16–129) ng/mL, and median AUC was 156 (35–348) ngxa0h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and constipation.ConclusionKX2-391 dosed at 40xa0mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a Cmax of ≥142xa0ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.

Persistent androgen receptor addiction in castration-resistant prostate cancer

It is now understood that persistent activation of the androgen receptor (AR) signaling pathway often underlies the development of castration-resistant prostate cancer (CRPC). This realization led to renewed interest in targeting the AR and ultimately to the development of the potent next-generation AR-directed agents abiraterone and enzalutamide. While these drugs prolong survival in men with CRPC, they are unfortunately not curative. Perhaps not surprisingly, evidence points to persistent AR signaling as one of the key drivers by which resistances to these agents develops. In this context, activation of the AR signaling program can occur through a number of molecular adaptations, including alterations leading to persistent canonical AR signaling (e.g., AR amplification/overexpression, elucidations/concentration of intratumoral androgens), activation of the AR program via feedback pathways (e.g., AKT/mTOR/Pi3K, HER2/Neu), and activation of the AR program via mutation or substitution (e.g., AR ligand binding domain mutation; AR splice variants; glucocorticoid receptor signaling). This review will provide an overview of the more clinical relevant (i.e., druggable) pathways that have been implicated in the emergence of drug resistance in men with CRPC and highlight some of the ongoing efforts towards developing therapeutics to impair these mechanisms.

Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer

Objectives. To compare pathologic outcomes after treatment with gemcitabine and cisplatin (GC) versus methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) in the neoadjuvant setting. Methods. Data was retrospectively collected on 178 patients with T2-T4 bladder cancer who underwent radical cystectomy between 2003 and 2011. Outcomes of interest included those with complete response (pT0) and any response (≤pT1). Odds ratios were calculated using multivariate logistic regression. Results. Compared to those who did not receive neoadjuvant chemotherapy, there were more patients with complete response (28% versus 9%, OR 3.11 (95% CI: 1.45–6.64), P = 0.03) and any response (52% versus 25%, OR 3.23 (95% CI: 1.21–8.64), P = 0.01). Seventy-two patients received GC (n = 41) or MVAC (n = 31). CR was achieved in 29% and 22% of GC and MVAC patients, respectively (multivariate OR 0.39, 95% CI 0.10–1.58). Any response (≤pT1) was achieved in 56% of GC and 45% of MVAC patients (multivariate OR 0.45, 95% CI 0.12–1.71). Conclusions. We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of patients with muscle invasive urothelial cancer (MIBC). Our findings support the use of GC as an alternative regimen in the neoadjuvant setting.

Clinical Correlates of Benefit From Radium-223 Therapy in Metastatic Castration Resistant Prostate Cancer

We sought to identify potential clinical variables associated with outcomes after radium‐223 therapy in routine practice.

Relationships Between Times to Testosterone and Prostate-Specific Antigen Rises During the First Off-Treatment Interval of Intermittent Androgen Deprivation are Prognostic for Castration Resistance in Men With Nonmetastatic Prostate Cancer

BACKGROUNDnIntermittent androgen deprivation (IAD) represents an alternative to continuous AD with quality-of-life benefit and no evidence of inferior overall survival for nonmetastatic prostate cancer. Early markers of prognosis for men treated with IAD have not been described.nnnPATIENTS AND METHODSnMen with nonmetastatic prostate cancer were treated with 9 months of leuprolide and flutamide followed by a variable off-treatment interval; AD was resumed when prostate specific antigen (PSA) reached a prespecified value (1 ng/mL, radical prostatectomy; 4 ng/mL, intact prostate). Cycles were repeated until castration resistance (marking the advent of castration-resistant prostate cancer [CRPC]), defined as 2 PSA rises with testosterone (T) ≤ 50 ng/dL. Kinetics and relationships of PSA and T levels were evaluated, with a focus on times to rise in each level, during the first off-treatment interval. Associations with CRPC and prostate cancer mortality were estimated using Cox proportional hazards models controlling for age and Gleason score.nnnRESULTSnEach 30-day increase in time to PSA rise was associated with a 21% reduction in the risk of developing CRPC (95% CI, 3%-36%; P = .02). Longer time (≥ 60 days) to PSA rise after rise to T > 50 ng/dL was associated with a 71% reduction in the risk of developing CRPC (95% CI, 92% reduction to 2% inflation; P = .05). Time to first T > 50 ng/dL and PSA doubling time were not prognostic for progression to CRPC. No time interval was prognostic for prostate cancer mortality.nnnCONCLUSIONnDuring the first off-treatment interval of IAD, longer times to PSA rise overall and after T > 50 ng/dL were associated with reduced risk of developing CRPC.

Targeting intratumoral androgens: statins and beyond

While initially effective, androgen deprivation therapy (ADT) is not curative, and nearly all men with advanced prostate cancer will eventually progress to the more resistant, and ultimately lethal form of the disease, so called castration-resistant prostate cancer (CRPC). The maintenance of androgens within the prostate cancer microenvironment likely represents one of the key mechanisms by which this transition from hormone-sensitive to CRPC occurs. This can be accomplished either through intratumoral androgen biosynthesis or the active transport of androgens and androgenic precursors into the tumor microenvironment. More recently, preclinical and clinical data supported therapeutic strategies that seek to target these two mechanisms, either through the use of drugs that impair androgen biosynthesis (e.g. inhibiting the steroidogenic enzymes CYP17 and AKR1C3 with abiraterone and indomethacin, respectively) or drugs that inhibit the SLCO transporters responsible for importing androgens (e.g. statins).