Synthetic Lethality by Co-Inhibition of Androgen Receptor and Polyadenosine Diphosphate-Ribose in Metastatic Prostate Cancer.

Androgen receptor pathway inhibitors (ARPI) and polyadenosine diphosphate-ribose inhibitors (PARPi) are part of the standard of care in patients with metastatic castration-resistant prostate cancer (mCRPC). There is biological evidence that the association of ARPI and PARPi could have a synergistic effect; therefore, several ongoing clinical trials are investigating the efficacy of this combination with preliminary results that are not perfectly concordant in identifying patients who can obtain the most benefit from this therapeutic option. The purpose of this review is to describe the PARPi mechanisms of action and to analyze the biological mechanisms behind the interplay between the androgen receptor and the PARPi system to better understand the rationale of the ARPI + PARPi combinations. Furthermore, we will summarize the preliminary results of the ongoing studies on these combinations, trying to understand in which patients to apply. Finally, we will discuss the clinical implications of this combination and its possible future perspectives.

Baseline chest X-ray in coronavirus disease 19 (COVID-19) patients: association with clinical and laboratory data.

PURPOSE: To assess the reliability of CXR and to describe CXR findings and clinical and laboratory characteristics associated with positive and negative CXR. METHODS: Retrospective two-center study on consecutive patients admitted to the emergency department of two north-western Italian hospitals in March 2020 with clinical suspicion of COVID-19 confirmed by RT-PCR and who underwent CXR within 24 h of the swab execution. 260 patients (61% male, 62.8 ± 15.8 year) were enrolled. CXRs were rated as positive (CXR+) or negative (CXR-), and features reported included presence and distribution of airspace opacities, pleural effusion and reduction in lung volumes. Clinical and laboratory data were collected. Statistical analysis was performed with nonparametric tests, binary logistic regression (BLR) and ROC curve analysis. RESULTS: Sensitivity of CXR was 61.1% (95%CI 55-67%) with a typical presence of bilateral (62.3%) airspace opacification, more often with a lower zone (88.7%) and peripheral (43.4%) distribution. At univariate analysis, several factors were found to differ significantly between CXR+ and CXR-. The BLR confirmed as significant predictors only lactate dehydrogenase (LDH), C-reactive protein (CRP) and interval between the onset of symptoms and the execution of CXR. The ROC curve procedure determined that CRX+ was associated with LDH > 500 UI/L (AUC = 0.878), CRP > 30 mg/L (AUC = 0.830) and interval between the onset of symptoms and the execution of CXR > 4 days (AUC = 0.75). The presence of two out of three of the above-mentioned predictors resulted in CXR+ in 92.5% of cases, whereas their absence in 7.4%. CONCLUSION: CXR has a low sensitivity. LDH, CRP and interval between the onset of symptoms and the execution of CXR are major predictors for a positive CXR.

Navigating the ICI Combination Treatment Journey: Patterns of Response and Progression to First-Line ICI-Based Combination Treatment in Metastatic Renal Cell Carcinoma.

The use of immune checkpoint inhibitors (ICIs) in combination with tyrosine kinase inhibitors or other ICIs has significantly improved the prognosis for patients with mccRCC. This marks a major milestone in the treatment of mccRCC. Nonetheless, most patients will discontinue first-line therapy. In this narrative review, we analyze the different patterns of treatment discontinuation in the four pivotal phase III trials that have shown an improvement in overall survival in mccRCC first-line therapy, starting from 1 January 2017 to 1 June 2023. We highlight the different discontinuation scenarios and their influences on subsequent treatment options, aiming to provide more data to clinicians to navigate a complex decision-making process through a narrative review approach. We have identified several causes for discontinuations for patients treated with ICI-based combinations, such as interruption for drug-related adverse events, ICI treatment completion, treatment discontinuation due to complete response or maximum clinical benefit, or due to progression (pseudoprogression, systemic progression, and oligoprogression); for each case, an extensive analysis of the trials and current medical review has been conducted.

Hormonal Agents in Localized and Advanced Prostate Cancer: Current Use and Future Perspectives.

Prostate cancer (PC) is generally a hormone-dependent tumor. Androgen deprivation therapy ( has been the standard of care in metastatic disease for more than 80 years. Subsequent studies have highlighted the efficacy of ADT even in earlier disease settings such as in localized disease or in the case of biochemical recurrence (BCR). Improved knowledge of PC biology and ADT resistance mechanisms have led to the development of novel generation androgen receptor pathway inhibitors (ARPI). Initially used only in patients who became resistant to ADT, ARPI have subsequently shown to be effective when used in patients with metastatic hormone-naive disease and in recent years their effectiveness has also been evaluated in localized disease and in case of BCR. The objective of this review is to describe the current role of agents interfering with the androgen receptor in different stages of PC and to point out future perspectives.

Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis.

BACKGROUND: Radium 223 (Ra-223) was approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) patients with bone-only disease, following demonstration of significant improvement in overall survival (OS). To date, there are no validated prognostic factors useful in predicting outcome of mCRPC patients treated with Ra-223. Our retrospective study aims to evaluate the prognostic role of treatment discontinuation due to adverse events in mCRPC patients treated with Ra-223, and to identify which factors correlate with the toxicity onset. METHODS: We performed a retrospective analysis of all consecutive mCRPC patients treated with Ra-223 from September 2013 to December 2019 at our institute. Patients were divided in 2 groups according to the reason of Ra-223 therapy discontinuation: toxicity versus other causes. Outcome measures were progression-free survival (PFS) and OS. RESULTS: In the overall population (75 patients) median PFS and OS were 5.46 months and 11.15 months respectively. Patients who discontinued treatment due to toxicity had a lower median PFS (3.49 vs 5.89 months, HR: 1.88, 95% CI: 1.14-3.12, p = 0.014) and OS (8.59 vs 14.7 months HR: 3.33, 95% CI: 1.85-6.01, p < 0.001) than patients who discontinued therapy due to other causes. The risk of Ra-223 discontinuation due to toxicity correlates with the number of previous treatments (p = 0.002), previous chemotherapy treatment (p = 0.039), baseline LDH (p = 0.012), Hb (p = 0.021) and platelet-to-lymphocyte ratio (p = 0.024). CONCLUSIONS: Discontinuation due to toxicity is associated with worse outcomes in mCRPC patients treated with Ra-223. To reduce the risk of developing toxicities that may compromise treatment efficacy, Ra-223 should be used early in mCRPC patients.

Therapeutic sequencing in advanced renal cell carcinoma: How to choose considering clinical and biological factors.

In the last fifteen years a better understanding of the biological processes promoting tumour growth and progression led to an impressive revolution in metastatic renal cell carcinoma (mRCC) treatment landscape. Angiogenesis plays a critical role in the pathogenesis of RCC. These biological evidences led to targeted therapies interfering with vascular endothelial growth factor and mammalian target of rapamycin pathway. Another big step in the RCC therapeutic landscape was recently made because of the understanding of the interplay between angiogenesis and immune cells. Dual immune checkpoint inhibitors (ICIs) and ICIs plus tyrosine kinase inhibitors (TKI) combinations have been approved considering overall survival benefit compared to targeted therapies as first line treatment. We summarize the activity and the biological rationale of ICIs combinations as mRCC first line therapy. Additionally, we review the clinical and biological criteria useful to guide clinicians in the choice of treatment sequencing focusing on ICIs combinations resistance mechanisms.

How to Improve the Quality of Life of Patients with Prostate Cancer Treated with Hormone Therapy?

Prostate cancer (PC) is a hormone-sensitive tumor. Androgen deprivation therapy (ADT) is the cornerstone of systemic therapy for patients with intermediate or high-risk localized, recurrent, and metastatic prostate cancer. Although generally well tolerated, ADT can lead to short- and long-term adverse events that can worsen the quality of life of patients with PC. In the last decade, the introduction of novel generation androgen receptor pathway inhibitors (ARPI) has resulted in an improvement in the prognosis of patients with metastatic PC when used in combination with ADT. The use of ARPI in increasingly early stages of the disease determines a longer exposure of patients to these treatments. Although ARPIs are normally well-tolerated drugs, they generally cause an increase in toxicity compared to ADT alone, being able to worsen some adverse events already induced by ADT or leading to the development of specific side effects. Although there are no specific treatments for all the adverse events induced by hormonal therapies, it is essential to know the possible toxicities induced by the different treatments and to start procedures to prevent and/or recognize and consequently treat them early in order to not compromise the quality of life of the patients with PC. The aim of this review is to describe the adverse events induced by hormonal therapies. We will first describe the side effects induced by both ADT and ARPI and then the specific adverse events of the different ARPIs. Furthermore, we will try to highlight the possible therapeutic options to prevent or mitigate the toxicity induced by hormone therapies in order to improve the quality of life of the patients with PC.

Fluoro-edenite non-neoplastic diseases in Biancavilla (Sicily, Italy): pleural plaques and/or pneumoconiosis?

BACKGROUND: A mesothelioma cluster in Biancavilla (Sicily, Italy), drew attention to fluoro-edenite, a fibre classified by International Agency for Research on Cancer as carcinogenic to humans. Significant excesses in mortality and morbidity were observed for respiratory diseases and a significant excess of pneumoconiosis hospitalizations was reported. OBJECTIVE: Aim of this study is to assess the characters of the lung damage in Biancavilla residents hospitalized with pneumoconiosis or asbestosis diagnoses. METHODOLOGY: Medical records, available radiographs and computed tomography scans were collected. The obtained imaging was reviewed by a panel of three specialists and focused on pleural and parenchymal abnormalities. Cases with an ILO-BIT or ICOERD score equal or greater than 2 were considered positive for a pneumoconiosis-like damage, cases with a score lower than 2 or insufficient quality of imaging were considered inconclusive. If no pneumoconiotic aspects were present the cases were classified as negative. RESULTS: Out of 38 cases, diagnostic imaging for 25 cases were found. Ten cases out of 25 showed asbestosis-like features, nine subjects were considered negative. In six patients' results were inconclusive. CONCLUSIONS: Asbestosis-like features were substantiated in Biancavilla residents without known occupational exposure to asbestos. Further studies to estimate population respiratory health are required. Experimental studies on the fibrogenic potential of fluoro-edenite are needed.

Metastatic Urothelial Carcinoma: Have We Take the Road to the Personalized Medicine?

Urothelial cancer is a lethal malignancy characterized by a wide diffusion in Western countries due to a larger exposure to known risk factors, such as aromatic amines, tobacco smoke and benzene [...].

New emerging targets in advanced urothelial carcinoma: Is it the primetime for personalized medicine?

In recent years the introduction of immunotherapy has importantly changed the treatment landscape of advanced urothelial carcinoma. Several immune checkpoint inhibitors are now the standard of care as maintenance treatment after disease control with platinum-based first-line chemotherapy (avelumab), in subsequent lines (pembrolizumab) or as upfront therapy in platinum-ineligible patients (atezolizumab or pembrolizumab). Moreover, personalized therapy based on tumor molecular features has been developed. Namely, the increasing knowledge of the pathogenesis and molecular pathways underlying cancer development and progression is leading the introduction of target therapies such as the recently approved fibroblastic growth factor receptor (FGFR) inhibitor erdafitinib or the anti-nectin 4 antibody drug-conjugated enfortumab vedotin. Consequently, clinicians face new challenges, such as the choice of the best therapeutic sequence for each patient. The aim of this review is focusing on the emerging treatment options in metastatic urothelial carcinoma and discussing clinical features for choosing therapeutic sequencing.

Prognostic factors in metastatic castration resistant prostate cancer patients treated with radium-223: a retrospective study.

BACKGROUND: Our study aims to identify baseline prognostic factors in metastatic castration resistant prostate cancer (mCRPC) patients treated with radium-223. METHODS: Data about demographics, ECOG performance status, lymph node (LN) involvement, local treatment for prostate cancer, previous systemic treatments, cells blood count, PSA, ALP, albumin, LDH, bone protecting agents use (BPA), analgesic use and survival were collected. Univariable and multivariable analyses were performed. RESULTS: Seventy-five men received radium-223 between September 2013 and December 2019. Median age was 73 years. Thirty-four (45.3%) had ECOG PS 0, 41 (54.7%) PS 1-2. In univariable analysis, LN involvement (HR 1.68, 95% CI 1.01-2.80, P=0.047), absence of local treatment on primary tumor (HR 1.93, 95% CI 1.13-3.29, P=0.016), baseline strong opioidsuse (HR 1.82, 95% CI 1.08-3.06, P=0.024), high platelets to lymphocyte ratio (PLR) (HR 1.91, 95% CI 1.06-3.45, P=0.03), high baseline ALP (HR 1.81, 95% CI 1.10-2.99, P=0.019) and high baseline LDH (HR 3.86,95% CI 2.01-7.41, P<0.001) were significantly associated with worst OS. At multivariable analysis, LN involvement, strong opioids use, baseline ALP, LDH and PLR levels were significantly associated with outcome. CONCLUSIONS: In mCRPC patients treated with Radium-223, baseline ALP, LDH, strong opioid use, PLR, LN involvement and treatment on primary site are associated with different OS.

New Perspectives in the Medical Treatment of Non-Muscle-Invasive Bladder Cancer: Immune Checkpoint Inhibitors and Beyond.

Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette-Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation. The aim of this review is to analyse and describe the clinical activity of new emerging drugs in BCG-unresponsive NMIBC focusing on immunotherapy results.

Interactions between androgen receptor signaling and other molecular pathways in prostate cancer progression: Current and future clinical implications.

In last years several improvements have been made in the management of prostate cancer (PCa). Androgen receptor (AR) is considered the main driver in PCa growth and progression and most drugs are directed against AR pathway. Once PCa spreads outside the prostate, androgen deprivation therapy (ADT) represents the cornerstone of treatment in hormone-sensitive prostate cancer (HSPC). Unfortunately, the response is only transient and most patients eventually develop castration-resistant prostate cancer (CRPC). Most resistance mechanisms depend on maintenance of AR signalling in castration environment. Recent discoveries of multiple growth-promoting and survival pathways in PCa suggest the importance of alternative mechanisms involved in disease progression, such as DNA damage response pathway, PTEN/PI3K/AKT/mTOR pathway, cell cycle pathway, WNT pathway, TMPRSS2/ETS fusion, neuroendocrine pattern and immune system response. In this review, we discuss the interplay between AR signaling and other molecular pathways involved in PCa pathogenesis and their therapeutic implication in advanced disease.

Are tyrosine kinase inhibitors an effective treatment in testicular metastases from kidney cancer? Case report.

Testicular metastases from renal cell carcinoma (RCC) are extremely rare. Tyrosine kinase inhibitors (TKI) are the cornerstone of systemic therapy for metastatic RCC. We report a case of testicular metastasis in a 72-year-old patient with RCC that developed 17 years after nephrectomy and response to TKI treatment, a retrospective literature search on testicular metastases from RCC, and the indirect evidence described in the literature on the efficacy of chemotherapy and target therapy on testicular lesions.

Prognostic role of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with metastatic castration resistant prostate cancer treated with abiraterone or enzalutamide.

BACKGROUND: Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are markers of systemic inflammation associated with poor outcome in several solid tumors. We retrospectively investigated the prognostic role of PLR and, secondly, NLR in mCRPC patients treated with abiraterone acetate (AA) or Enzalutamide (E), both in pre- and postdocetaxel setting. METHODS: Two hundred twenty-five mCRPC patients treated with AA or E with basal blood count were divided in three groups according to PLR (PLR1<128; PLR2 128-190; PLR>190) and in two groups according to NLR (<3 vs. ≥3). Outcome measures were progression-free survival (PFS) and overall-survival (OS). Univariate and multivariate analyses were performed. RESULTS: One hundred ten patients were in PLR1, 58 in PLR2 and 57 in PLR3. Median OS was 22.0, 20.6 and 21.2 months in PLR1, PLR2 and PLR3 (PLR2 vs. PLR1: HR 0.97, 95%CI 0.62-1.52, P=0.90; PLR3 vs. PLR1: HR 1.37, 95%CI 0.90-2.08, P=0.14). Median PFS was 9.2, 12.7 and 8.5 months in PLR1, PLR2 and PLR3 (PLR2 vs. PLR1: HR 0.87, 95%CI 0.59-1.27, P=0.47; PLR3 vs. PLR1: HR 1.15, 95%CI 0.80-1.66, P=0.45). 142 patients were in NLR<3 and 83 in NLR≥3. Median OS was 26.5 months in NLR<3 and 17.0 months in NLR≥3 (HR 1.75, 95%CI 1.22-2.51, P=0.02). Median PFS was 10.1 months in NLR<3 and 7.6 months in NLR≥3 (HR 1.37, 95%CI 1.00-1.88, P=0.05). CONCLUSIONS: In this retrospective analysis of mCRPC patients treated with AA or E we did not identify a prognostic role of baseline PLR, while we found a significant prognostic role of baseline NLR.

Prognostic role of the duration of response to androgen deprivation therapy in patients with metastatic castration resistant prostate cancer treated with enzalutamide or abiraterone acetate.

BACKGROUND: Our retrospective study aims to evaluate the prognostic role of duration of response to androgen deprivation therapy (ADT) in metastatic castration resistant prostate cancer (mCRPC) patients treated with enzalutamide (E) or abiraterone acetate (AA). MATERIALS AND METHODS: Data about ADT start and duration were available in 255 (82%) of 311 patients treated with AA or E. Patients were divided in three groups according to ADT response (group 1 [G1]: <12 months; group 2 [G2]: 12-36 months; group 3 [G3]: >36 months). Outcome measures were progression-free survival (PFS) and overall survival (OS). RESULTS: Patients with longer ADT response had better OS (median 17.3 months G1, 19.9 months G2, 31.6 months G3; HR G3 vs G1 0.41, 95% CI 0.25-0.64; p = 0.001) and better PFS (median 5.9 months G1, 8.8 months G2, 11.7 months G3; HR G3 vs G1 0.41, 95% CI 0.41-0.27; p < 0001). In docetaxel-naive patients, median OS was 18.8 in G1, 35.2 in G2, and not reached in G3 (HR G3 vs G1 0.33, 95% CI 0.14-0.78; p = 0.038), median PFS was 7 months G1, 9.3 months G2, and 20 months G3 (HR G3 vs G1 0.31, 95% CI 0.15-0.62; p = 0.003). In postdocetaxel patients, median OS was 13.1 months in G1, 17.2 months in G2, and 21.4 months in G3 (HR G3 vs G1 0.52, 95% CI 0.29-0.94; p = 0.082), while median PFS was 5.2 months in G1, 6.8 months in G2, and 8.3 months in G3 (HR G3 vs G1 0.54, 95% CI 0.32-0.91; p = 0.067). CONCLUSIONS: Duration of ADT response is an independent prognostic factor of outcome with AA or E.

Renal cell carcinoma (RCC): fatter is better? A review on the role of obesity in RCC.

Obesity represents a well-known risk factor for renal cell carcinoma development. Several studies evaluated the relationship between obesity and outcome in patients with non-metastatic and metastatic renal cell carcinoma using different parameters such as BMI, visceral fat area and s.c. fat area. These studies suggest that obesity is associated with a better prognosis in renal cell carcinoma patients. This phenomenon is called obesity paradox and it was found in other diseases in which obesity represents an established risk factor such as heart failure, diabetes, atrial fibrillation, hypertension and coronary heart disease. The purpose of this review is to analyze the mechanisms by which obesity increases the risk of renal cell carcinoma development, to describe the evidence available to date about the link obesity-outcome and to evaluate the mechanisms to explain this apparently paradoxical relationship.

Italian survey on the clinical management of non-small cell lung cancer patients during the COVID-19 pandemic: A lesson for the second wave.

This study investigated the clinical management of non small cell lung cancer (NSCLC) patients during the first wave of coronavirus disease 2019 (COVID-19) outbreak in Italy. A 29-questions survey was sent to 95 Italian thoracic oncologists, with 77 % of them declaring significant changes in the outpatients management and treatment. The results of this survey pointed out a significant delay of lung cancer diagnosis along with a relevant reduction of patients' accrual within clinical trials. Telemedicine emerged as a valid support for patient-healthcare interactions. Therapeutic indications followed the guidelines for adjuvant chemotherapy and concurrent chemo-radiation. Clinical indications to first-line therapies were largely confirmed, while major changes regarded the selection of second line treatment options as well as the management of elderly population. This work may represent a valid source of information to improve the clinical management of NSCLC patients during second wave of COVID-19 pandemic.

Bipolar androgen therapy in prostate cancer: Current evidences and future perspectives.

Testosterone suppression by androgen deprivation therapy is the cornerstone of prostate cancer treatment. New-generation hormone therapies improved overall survival in castration-resistant prostate cancer. More recent trials showed a further increase in overall survival when enzalutamide or abiraterone are associated with androgen deprivation therapy in hormone-sensitive disease. However, a higher clonal pressure may lead to the upregulation of alternative pathways for cancer progression and to dedifferentiated diseases that would probably respond poorly to subsequent treatments. In this contest, new strategies that could be able to delay or even revert resistance are needed. The bipolar androgen therapy is an under-investigation treatment that consists in periodical oscillation between castration levels and supraphysiological levels of testosterone in order to prevent the adaptation of prostate cancer cells to a low-androgen environment. This review aims to underline the biological rationale of bipolar androgen therapy and gather evidences from the most recent clinical trials.

Prognostic role of early PSA drop in castration resistant prostate cancer patients treated with abiraterone acetate or enzalutamide.

BACKGROUND: Previous studies demonstrated a predictive value of prostate-specific antigen (PSA) kinetics for treatment outcome. Our retrospective study evaluates the prognostic role of early PSA drop in metastatic castration resistant prostate cancer (mCRPC) patients receiving abiraterone acetate (AA) or enzalutamide (E). METHODS: All mCRPC patients treated with AA or E at the San Luigi Hospital in Orbassano between 2010 and 2018 and at the Ordine Mauriziano Hospital in Turin between 2014 and 2018 were included in this retrospective study. Only patients with an early PSA (measured 28-60 days after the beginning of the treatment) were included in the analysis. Patients were divided in early responders and non-early responders according to early PSA response (drop≥50% from baseline). Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were performed. RESULTS: Of 144 patients with early PSA value, 61 (42.4%) patients received E (docetaxel-naïve 42, post-docetaxel 19) and 83 (57.6%) received AA (docetaxel-naïve 44, post-docetaxel 39). Seventy-five (52.1%) patients achieved early PSA drop. In docetaxel-naïve setting (N.=86), median PFS was 14.9 (with early PSA drop) vs. 8.8 months (without early PSA drop, P=0.001). In post-docetaxel setting (N.=58) median PFS was 11.9 vs. 4.5 months (P<0.001). Globally, median PFS was 14.9 vs. 6.3 months in patients with and without early PSA drop, respectively (P<0.001). In docetaxel-naïve setting, patients with early PSA drop had a median OS of 39.5 vs. 18.8 months (P=0.12). In post-docetaxel setting median OS was 29.6 vs. 10.7 months (P=0.01). Comprehensively, median OS was 31.9 vs. 16.3 (P=0.002) in patients with and without early PSA drop, respectively. At multivariate analysis, early PSA drop confirmed an independent association with PFS (HR 0.21; 95% CI: 0.12-0.38, P<0.001) and OS (HR 0.25; 95% CI: 0.12-0.50, P<0.001). CONCLUSIONS: mCRPC patients treated with AA or E, in docetaxel-naïve or post-docetaxel setting, with early PSA drop had significantly better OS and PFS.