Is There a Place for De-escalating Therapy in Patients with Metastatic Hormone-sensitive Prostate Cancer?

Although intermittent androgen deprivation therapy was often recommended for metastatic hormone-sensitive cancer therapy in the past, we do not know whether its use can be extrapolated to combination therapy. Trials evaluating intermittent therapy are necessary as this strategy could improve patient quality of life and reduce adverse events and costs.

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.

Treatment options in first-line metastatic renal carcinoma: A meta-analysis of 2556 patients treated with immune checkpoint inhibitors-based combinations in randomised controlled trials.

BACKGROUND & AIMS: The average five-year survival of metastatic renal cell carcinoma (mRCC) is 71%. However, there is significant variability in patient prognosis. Immune checkpoint inhibitors (ICIs) have been introduced into the treatment landscape of mRCC. This meta-analysis aimed to estimate progression-free and overall survival probabilities and identify possible outcome predictors of mRCC patients treated with ICI combination as first-line treatment. METHODS: Studies comparing the combination of ICI combinations versus standard of therapy for first-line treatment of advanced renal-cell carcinoma were searched in MEDLINE, CANCERLIT, the Cochrane Controlled Trials Register, and the Cochrane Library from inception through September 2023. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using the DerSimonian and Laird methods. RESULTS: Six studies met the inclusion criteria. Globally, 5121 patients were included in this meta-analysis: 2556 patients treated with immune checkpoint inhibitors and 2565 with sunitinib as control. The ICI combination was associated with improved PFS (hazard ratio (HR) 0.68; 95 % confidence interval (CI), 0.56-0.81, p < 0.0001). Furthermore, ICI combination was also associated with OS improvement (HR 0.85; 95 % CI, 0.78-0.92, p = 0.001). There is no statistical increase in adverse events. CONCLUSIONS: Our findings show that PFS and OS are statistically increased in mRCC with ICI combination treatment by 32% and 15%, respectively.

Prognostic and Predictive Role of SPOP Mutations in Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: Mutations in the speckle-type POZ (SPOP) gene are frequently identified in prostate cancer (PC); yet, prognostic implications for affected patients remain unclear. Limited consensus exists regarding tailored treatments for SPOP-mutant (SPOPmut) PC. OBJECTIVE: To elucidate the prognostic and predictive significance of SPOP mutations across distinct PC stages and treatments. EVIDENCE ACQUISITION: A systematic literature search of PubMed, Embase, and Scopus was conducted up to January 29, 2024. The meta-analysis included studies comparing survival outcomes between SPOPmut and SPOP wild-type (SPOPwt) PC. EVIDENCE SYNTHESIS: From 669 records, 26 studies (including five abstracts) were analyzed. A meta-analysis of metastasis-free survival in localized (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.59-0.88; p < 0.01) and overall survival (OS) in metastatic PC (HR: 0.64, 95% CI: 0.53-0.76; p < 0.01) showed a favorable prognosis for patients with SPOPmut PC. In metastatic settings, SPOP mutations correlated with improved progression-free survival (PFS) and OS in patients undergoing androgen deprivation therapy ± androgen receptor signaling inhibitor (HR: 0.51, 95% CI: 0.35-0.76, p < 0.01, and HR: 0.60, 95% CI:0.46-0.79, p < 0.01, respectively). In metastatic castration-resistant PC, only abiraterone provided improved PFS and OS to patients with SPOP mutations compared with patients with SPOPwt, but data were limited. SPOP mutations did not correlate with improved PFS (p = 0.80) or OS (p = 0.27) for docetaxel. CONCLUSIONS: Patients with SPOPmut PC seem to exhibit superior oncological outcomes compared with patients with SPOPwt. Tailored risk stratification and treatment approaches should be explored in such patients. PATIENT SUMMARY: Speckle-type POZ (SPOP) mutations could be a favorable prognostic factor in patients with prostate cancer (PC) and may also predict better progression-free and overall survival than treatment with hormonal agents. Therefore, less intensified treatments omitting chemotherapy for patients with SPOP-mutant PC should be explored in clinical trials.

EORTC 2238 "De-Escalate": a pragmatic trial to revisit intermittent androgen deprivation therapy in the era of new androgen receptor pathway inhibitors.

The landscape of treating metastatic prostate cancer has evolved with the addition of Androgen Receptor pathway inhibitor (ARPI) to Androgen Deprivation Therapy (ADT), significantly improving survival rates. However, prolonged use of these therapies introduces notable side effects, prompting a need to revisit intermittent treatment duration. The EORTC 2238 De-Escalate trial is a pragmatic trial seeking to reassess the role of intermittent therapy in patients undergoing maximal androgen blockade (MAB) for metastatic hormone naïve prostate cancer (mHNPC), i.e., the combination of ADT with an ARPI, with the aims of reducing side effects, enhancing Quality of Life (QoL) and optimizing resource usage, while maintaining oncological benefits.

Activity of Lutetium-177 Prostate-specific Membrane Antigen and Determinants of Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Cabazitaxel: The PACAP Study.

BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.

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.

TEAM Study: Upfront Docetaxel Treatment in Patients With Metastatic Hormone-Sensitive Prostate Cancer: A Real-World, Multicenter, Retrospective Analysis.

BACKGROUND: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) dramatically changed. PEACE-1 and ARASENS trials established triplet therapy efficacy. Identifying prognostic factors supporting treatment choice is pivotal. METHODS: TEAM is an observational, retrospective study to evaluate prognostic role of variables in mHSPC patients receiving upfront docetaxel in 11 Italian centers. Outcome measures were progression-free survival (PFS) and overall-survival (OS). RESULTS: From September 2014 to December 2020, 147 patients were included. Median PFS and OS were 11.6 and 37.4 months. At univariate analysis, PFS-related variables were Gleason Score (GS) (P = .001), opioid use (P = .004), bone metastases number (P < .001), baseline PSA (P = .006), Hb (P < .001), ALP (P < .001) and LDH (P = .002), time between ADT and docetaxel start (P = .018), 3-month PSA (P < .001) and ALP (P < .001), and number of docetaxel cycles (P < .001). OS-related variables were PSA at diagnosis (P = .024), primary tumor treatment (P = .022), baseline pain (P = .015), opioid use (P < .001), bone metastases number (P < . 001), baseline Hb (P < .001), ALP (P < .001) and LDH (P = .001), NLR ratio (P = .039), 3-month PSA (P < .001) and ALP (P < .001) and docetaxel cycles number (P < .001). At multivariate analysis, independent prognostic variables were GS, opioid use, baseline LDH and time between ADT and docetaxel initiation for PFS, and baseline Hb and LDH for OS. CONCLUSION: Patients receiving upfront docetaxel with high GS, high disease burden, pain or opioid use, baseline unfavorable laboratory values had worse outcomes. Patients had greater docetaxel benefit when initiated early after ADT start. These parameters could be taken into account when selecting candidates for triplet therapy.

Safety profile of darolutamide versus placebo: a systematic review and meta-analysis.

BACKGROUND: Darolutamide is an androgen receptor pathway inhibitor (ARPI) used in patients with prostate cancer (PC). In pivotal trials, it has demonstrated a favorable toxicity profile. There are no head-to-head comparison studies between the different ARPIs, but the efficacy of these drugs seems to be similar making the toxicity profile a key element for treatment selection. METHODS: We conducted a systematic review of all clinical trials assessing treatment with darolutamide for patients with PC using placebo as the control using the PubMed/Medline and Cochrane library databases. We also performed a meta-analysis to compare the safety of darolutamide versus placebo evaluating adverse events (AE) leading to treatment discontinuation and the rate of the AE reported as "AE of interest" in the ARAMIS trial. The comparison among darolutamide and the placebo group in terms of safety and tolerability was performed using odds ratio (OR) as meta-analytic outcome. RESULTS: We identified three articles comprising 2902 patients for the systematic review and meta-analysis (1652 treated with darolutamide and 1250 with placebo). Darolutamide did not increase AE leading to treatment discontinuation compared to placebo (pooled OR: 1.176, 95% CI 0.918-1.507, p = 0.633). Regarding the "AE of interest" there was no difference between darolutamide and placebo in terms of asthenia, cardiac arrhythmia, cardiac disorder, coronary artery disorder, depression mood disorder, falls, fatigue, heart failure, hot flushes, hypertension, mental-impairment disorder, rash, seizure and weight loss. The only "AE of interest" with a statistically significant difference in favor of placebo was bone fractures (pooled OR: 1.523, 95% CI 1.081-2.146). CONCLUSIONS: In our systematic review and meta-analysis, darolutamide showed a toxicity profile comparable to placebo with the exception of bone fractures. In the absence of head-to-head comparison studies between the different ARPIs, the results of our research suggest a preferred use of darolutamide in the approved settings.

Neuro-Gastro-Cannabinology: A Novel Paradigm for Regulating Mood and Digestive Health.

The maintenance of homeostasis in the gastrointestinal (GI) tract is ensured by the presence of the endocannabinoid system (ECS), which regulates important physiological activities, such as motility, permeability, fluid secretion, immunity, and visceral pain sensation. Beside its direct effects on the GI system, the ECS in the central nervous system indirectly regulates GI functions, such as food intake and energy balance. Mounting evidence suggests that the ECS may play an important role in modulating central neurotransmission which affects GI functioning. It has also been found that the interaction between the ECS and microbiota affects brain and gut activity in a bidirectional manner, and a number of studies demonstrate that there is a strong relationship between GI dysfunctions and mood disorders. Thus, microbiota can regulate the tone of the ECS. Conversely, changes in intestinal ECS tone may influence microbiota composition. In this mini-review, we propose the concept of neuro-gastro-cannabinology as a novel and alternative paradigm for studying and treating GI disorders that affect mood, as well as mood disorders that imbalance GI physiology. This concept suggests the use of prebiotics or probiotics for improving the tone of the ECS, as well as the use of phytocannabinoids or endocannabinoid-like molecules, such as palmitoylethanolamide, to restore the normal intestinal microbiota. This approach may be effective in ameliorating the negative effects of GI dysfunctions on mood and/or the effects of mood disorders on digestive health.

How Does Environmental and Occupational Exposure Contribute to Carcinogenesis in Genitourinary and Lung Cancers?

Environmental and occupational exposures have been associated with an increased risk of different types of cancers, although the exact mechanisms of higher carcinogenesis risk are not always well understood. Lung cancer is the leading cause of global cancer mortality, and, also, genitourinary neoplasms are among the main causes of cancer-related deaths in Western countries. The purpose of this review is to describe the main environmental and occupational factors that increase the risk of developing lung and genitourinary cancers and to investigate carcinogenesis mechanisms that link these agents to cancer onset. Further objectives are to identify methods for the prevention or the early detection of carcinogenic agents and, therefore, to reduce the risk of developing these cancers or to detect them at earlier stages.

Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study.

INTRODUCTION: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms. METHODS: We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2). RESULTS: This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007). CONCLUSIONS: Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results.

Darolutamide Maintenance in Patients With Metastatic Castration-Resistant Prostate Cancer With Nonprogressive Disease After Taxane Treatment (SAKK 08/16).

PURPOSE: To assess the efficacy and safety of darolutamide maintenance after successful taxane chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Swiss Group for Clinical Cancer Research (SAKK) 08/16 is a randomized phase II study. Patients with mCRPC who received prior androgen-receptor pathway inhibitors (ARPIs) and subsequently had nonprogressive disease on a taxane were randomly assigned to darolutamide 600 mg twice a day or placebo twice a day. The primary end point was radiographic progression-free survival (rPFS) at 12 weeks. Secondary end points were rPFS, event-free survival, overall survival (OS), prostate-specific antigen (PSA) 50% response rate, and adverse events. RESULTS: Overall, 92 patients were recruited by 26 centers. Prior taxane was docetaxel in 93% and cabazitaxel in 7%. Prior ARPI was abiraterone in 60%, enzalutamide in 31%, and both in 9%. rPFS at 12 weeks was significantly improved with darolutamide (64.7% v 52.2%; P = .127). Median rPFS on darolutamide was 5.5 versus 4.5 months on placebo (hazard ratio [HR], 0.54 [95% CI, 0.32 to 0.91]; P = .017), and median event-free survival was 5.4 versus 2.9 months (HR, 0.46 [95% CI, 0.29 to 0.73]; P = .001). PSA 50% response rate was improved (22% v 4%; P = .014). Median OS for darolutamide was 24 versus 21.3 months for placebo (HR, 0.62 [95% CI, 0.3 to 1.26]; P = .181). Treatment-related adverse events were similar in both arms. CONCLUSION: SAKK 08/16 met its primary end point, showing that switch maintenance with darolutamide after prior taxane chemotherapy and at least one ARPI resulted in a statistically significant but clinically modest rPFS prolongation with good tolerability. The median OS with darolutamide maintenance appears promising. Should these findings be confirmed in a larger trial, maintenance treatment could be a novel strategy in managing patients with mCRPC, especially those who responded well to prior ARPI.

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.

Short-Term Safety and Psychosocial Impact of the BNT162b2 mRNA COVID-19 Vaccine in Cancer Patients-An Italian Single-Center Experience.

Safety data regarding BNT162b2 in cancer patients (CPs) are scarce. Herein we report the side effects (SEs), the adverse events (AEs), and the patient-reported outcomes (PROs) following BNT162b2 administration in CPs treated at the San Luigi Gonzaga University Hospital. All CPs who agreed to participate in our vaccination campaign received BNT162b2 and were included in the descriptive analysis. An anonymous questionnaire investigating the occurrence of SEs/AEs and PROs was administered to the study population 21 days after the first dose. Pearson's chi-squared test was used to estimate the risk of experiencing SEs/AEs according to selected variables. A total of 997 patients were included in the study: 62.0% had stage IV cancer, and 68.8% were receiving an active treatment, of whom 15.9% were receiving immunotherapy. SEs/AEs were recorded in 37.1% of cases after the first dose and in 48.5% of cases after the second dose. The most common SEs were muscle pain/local rash (27.9% and 28%, after the first and second dose, respectively). Patients older than 70 years showed lower risk of SEs/AEs, while women showed a higher risk. Before receiving the vaccine, 18.2% of patients felt fearful and/or insecure about the vaccination. After the first dose, 57.5% of patients changed their feelings positively. Our data support the short-term safety of BNT162b2 in CPs, regardless of disease stage and concurrent treatments. Overall, the vaccination showed a positive impact on quality of life.

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.

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.

Addition of New Androgen Receptor Pathway Inhibitors to Docetaxel and Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Metanalysis.

In recent years, significant changes have occurred in metastatic hormone-sensitive prostate cancer (mHSPC) management, where docetaxel and new androgen receptor pathway inhibitors (ARPI) have been shown to improve overall survival (OS) compared to androgen deprivation therapy (ADT). Recent data could once again radically change mHSPC treatment. PEACE-1 and ARASENS trials demonstrated a survival benefit of the addition of ARPI to docetaxel and ADT combination (triplet therapy), compared to docetaxel and ADT. With multiple options to choose from, it is crucial to identify the patients who would benefit most from triplet therapy. In this meta-analysis, we evaluated the activity of the triplet therapy versus docetaxel plus ADT in mHSPC. A systematic review of PubMed/Medline, Embase, and the proceedings of major international meetings was performed. Five RCTs fulfilled the inclusion criteria. PEACE-1 and ARASENS studies reported disease-free survival (DFS) and OS. Post hoc analysis of three other trials evaluated the combination of ARPI, docetaxel and ADT. Globally, 2538 patients were included (1270 triplet therapy; 1268 docetaxel + ADT). Triplet therapy was associated with improved OS (hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.66-0.83, p < 0.00001). A statistically significant benefit was shown in high-volume mHSPC patients (HR 0.76; 95% CI 0.59-0.97, p = 0.03) and in patients with de novo metastatic disease (HR 0.73; 95% CI, 0.64-0.82, p < 0.00001). The addition of ARPI to standard therapy was associated with DFS improvement (HR 0.41; 95% CI, 0.35-0.49, p < 0.00001). This metanalysis shows a significant OS benefit from concomitant administration of ARPI, docetaxel and ADT in high volume and de novo mHSPC.

Treatment Landscape for Patients with Castration-Resistant Prostate Cancer: Patient Selection and Unmet Clinical Needs.

Metastatic castration resistant prostate cancer (CRPC) is an inevitably fatal disease. However, in recent years, several treatments have been shown to improve the outcome of CRPC patients both in the non-metastatic (nmCRPC) as well as the metastatic setting (mCRPC). In nmCRPC patients with a PSA doubling time <10 months, the addition of enzalutamide, apalutamide and darolutamide to androgen deprivation therapy (ADT) compared to ADT alone resulted in improved metastases free (MFS) and overall survival (OS). For mCRPC patients, several treatment options have been shown to be effective: two taxane based chemotherapies (docetaxel and cabazitaxel), two androgen-receptor pathway inhibitors (ARPI) (abiraterone and enzalutamide), two radiopharmaceutical agents (radium 223 and 177Lutetium-PSMA-617), one immunotherapy treatment (sipuleucel-T) and two poly ADP-ribose polymerase (PARP) inhibitors (olaparib and rucaparib). Pembrolizumab is US Food and Drug Administration (FDA) approved in all MSI high solid tumors, although a very small proportion of prostate cancer patients harboring this characteristic will benefit. Despite having a broad variety of treatments available, there are still several unmet clinical needs for CRPC. The objective of this review was to describe the therapeutic landscape in CRPC patients, to identify criteria for selecting patients for specific treatments currently available, and to address the current challenges in this setting.