Clinical outcomes of volume of disease on patients receiving enzalutamide versus abiraterone acetate plus prednisone as first-line therapy for metastatic castration-resistant prostate cancer.

Background: Androgen receptor signaling inhibitors (ARSis) abiraterone acetate (AA) plus prednisone and enzalutamide (Enza), are currently the most administered first-line treatments for metastatic castration-resistant prostate cancer (mCRPC). AA and Enza have shown similar overall survival (OS) benefits and there is no consensus upon the best option for mCRPC first-line treatment. Volume of disease may represent a useful biomarker to predict response to therapy in such patients. Objectives: In this study, we seek to evaluate the impact of volume of disease on patients treated with first-line AA versus Enza for mCRPC. Design and methods: We retrospectively evaluated a cohort of consecutive patients with mCRPC categorized by volume of disease [high volume (HV) or low volume (LV) per E3805 criteria] at ARSi onset and treatment type (AA or Enza), assessing OS and radiographic progression-free survival (rPFS), from therapy start, as co-primary endpoints. Results: Of the 420 patients selected, 170 (40.5%) had LV and received AA (LV/AA), 76 (18.1%) LV and had Enza (LV/Enza), 124 (29.5%) HV and were given AA (HV/AA), and 50 (11.9%) HV and received Enza (HV/Enza). Among patients with LV, OS was significantly longer when treated with Enza [57.2 months; 95% confidence interval (CI): 52.1-62.2 months] versus AA (51.6 months; 95% CI, 42.6-60.6 months; p = 0.003). Consistently, those with LV receiving Enza showed increased rPFS (40.3 months; 95 CI, 25.0-55.7 months) than those having AA (22.0 months; 95% CI, 18.1-26.0 months; p = 0.004). No significant difference in OS or rPFS was observed in those with HV treated with AA versus Enza (p = 0.51 and p = 0.73, respectively). In multivariate analysis of patients with LV, treatment with Enza was independently associated with better prognosis than AA. Conclusion: Within the intrinsic limitations of a retrospective design and small population, our report suggests that volume of disease could be a useful predictive biomarker for patients starting first-line ARSi for mCRPC.

Time of metastatic disease presentation and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC).

BACKGROUND: Currently, there is no universally accepted prognostic classification for patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT). Subgroup analyses demonstrated that pts with low volume (LV), per CHAARTED trial definition, mHSPC, and those who relapse after prior local therapy (PLT) have longer overall survival (OS) compared to high volume (HV) and de-novo (DN), respectively. Using a hospital-based registry, we aimed to assess whether a classification based on time of metastatic disease (PLT vs DN) and disease volume (LV vs HV) are prognostic for mHSPC pts treated with ADT. METHODS: A retrospective cohort of consecutive patients with mHSPC treated with ADT between 1990 and 2013 was selected from the prospectively collected Dana-Farber Cancer Institute database and categorized as DN or PLT and HV or LV, at time of ADT start. Primary and secondary endpoints were OS and time to castration-resistant prostate cancer (CRPC), respectively, which were measured from date of ADT start using Kaplan-Meier method. Multivariable Cox proportional hazards models using known prognostic factors was used. RESULTS: The analytical cohort consisted of 436 patients. The median OS and time to CRPC for PLT/LV were 92.4 (95%CI: 80.4-127.2) and 25.6 (95%CI: 21-35.7) months and 43.2 (95%CI: 37.2-56.4) and 12.2 (95%CI: 9.8-14.8) months for DN/HV, respectively, whereas intermediate values were observed for PLT/HV and DN/LV. A robust gradient for both outcomes was observed (Trend test P < 0.0001) in the four groups. In a multivariable analysis, DN presentation, HV, and cancer-related pain were independent prognostic factors. CONCLUSIONS: In our hospital-based registry, time of metastatic presentation and disease volume were prognostic for mHSPC pts treated with ADT. This simple prognostic classification system can aid patient counseling and future trial design.

Non-clear cell renal cell carcinoma, part 1: histology.

Non-clear cell renal cell carcinomas (RCCs) represent up to 20% of all RCCs. Despite often being clustered as a single entity, these tumors represent a heterogeneous group of diseases with distinct molecular drivers, histologies, and clinical outcomes. Their low incidence and heterogeneity have resulted in a lack of studies that address the optimal strategies for each subtype. This article (the first in a 2-part series) reviews the histology of RCC, whereas the second article reviews current targeted therapies approved for RCC, such as the vascular endothelial growth factor receptor tyrosine kinase inhibitors and the mammalian target of rapamycin inhibitors. Ongoing studies will provide more information regarding the role of these agents in non-clear cell RCC.

Non-clear cell renal cell carcinoma, part 2: therapy.

Non-clear cell renal cell carcinomas (RCCs) represent a heterogeneous group of diseases with distinct molecular drivers, histologies, and clinical outcomes. Their low incidence and heterogeneity have resulted in a lack of studies that address the optimal strategies for each subtype. This article (the second in a 2-part series) reviews the current targeted therapies approved for RCC, such as the vascular endothelial growth factor receptor tyrosine kinase inhibitors and the mammalian target of rapamycin inhibitors. Ongoing studies will provide more information regarding the role of these agents in non-clear cell RCC. Ultimately, enhanced understanding of genetic triggers and the development of more tailored treatments remain imperative to improve outcomes in non-clear cell RCC.

Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer.

IMPORTANCE: Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells. OBJECTIVE: To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. MAIN OUTCOMES AND MEASURES: To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors. RESULTS: In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72). CONCLUSIONS AND RELEVANCE: Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.

Sequencing current therapies in the treatment of metastatic prostate cancer.

The standard treatment for metastatic prostate cancer is androgen deprivation therapy. However, progressive, metastatic disease usually develops, giving rise to metastatic castration-resistant prostate cancer (mCRPC). Great improvements have been made recently in the management of mCRPC, with current approved treatments including chemotherapy, androgen receptor-targeted agents, immunotherapies and radiopharmaceuticals. While the emergence of multiple effective therapies is encouraging, devising a treatment strategy can be difficult and it is becoming increasingly important, and challenging, to identify factors that influence the ideal timing of specific therapies. Considering where to place these agents in the treatment schedule of mCRPC, or whether these agents should be sequenced or combined to derive the optimal benefit for the patient, is not yet clear. Furthermore, cross-resistance may exist between these agents, which may ultimately influence treatment decisions and sequence choices. Preliminary data are emerging regarding the safety and activity for sequential treatment regimens, but there are currently no prospective studies. As prostate cancer is highly heterogeneous clinically, it is likely that no single treatment sequence will be optimal for all patients. However, at present, there are no validated biomarkers to guide individualized treatment for mCRPC. Here we review available data for the different mCRPC treatments, discussing potential sequencing of agents and possible cross-resistance or synergy among the recently approved and emerging therapies.