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.

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.

Impact of Neuroendocrine Differentiation (NED) on Enzalutamide and Abiraterone Efficacy in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Retrospective Analysis.

Neuroendocrine differentiation (NED) represents a possible androgen receptor pathway inhibitors (ARPI) resistance mechanism in metastatic castration resistance prostate cancer (mCRPC). As mCRPC with NED has been excluded from clinical trials evaluating ARPI efficacy, this study investigates the prognostic impact of NED in mCRPC patients treated with ARPIs. Methods: We retrospectively analyzed 327 mCRPC patient data treated with Enzalutamide or Abiraterone in the first and second or successive lines of treatment. NED was assessed using prostate biopsy samples through immunohistochemical staining. Results: NED was confirmed in 32/327 (9.8%) mCRPC patients. In the overall population, mCRPC with NED showed worse PFS (4.38 vs. 11.48 months HR 2.505 [1.71-3.68] p < 0.05), disease control rate (DCR), and PSA response. In the first line setting, mCRPC with NED demonstrated worse PFS (8.5 vs. 14.9 months HR 2.13 [1.18-3.88], p < 0.05). Similarly, in the second or successive lines, mCRPC with NED showed worse PFS (4.0 vs. 7.5 months HR 2.43 [1.45-4.05] p < 0.05), DCR, PSA response and OS (12.53 vs. 18.03 months HR 1.86 [1.12-3.10] p < 0.05). The adverse impact of NED on PFS was consistence across all subgroups; we also noted a trend of worse PFS in patients with high vs. low NED. Conclusions: In our study, mCRPC with NED treated with Enzalutamide or Abiraterone showed worse clinical outcomes. NED assessment should be considered to optimize treatment decisions in the mCRPC setting.

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.

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.

Efficacy and safety of lurasidone in schizophrenia: pooled analysis of European results from double-blind, placebo-controlled 6-week studies.

The objective of this study is to confirm the efficacy and safety of lurasidone in the acute treatment of schizophrenia in European patients. Data were pooled from three studies of patients randomized to 6 weeks of double-blind, placebo-controlled, fixed-dose (40/80 mg and 120/160 mg) lurasidone. The primary efficacy endpoint was a week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score and secondary endpoints included the Clinical Global Impression, Severity scale (CGI-S). In total 328 safety patients were enrolled; 72.6% were completers. Endpoint change was significantly greater in patients treated with 40-80 mg/d and 120-160 mg/d compared to placebo on the PANSS total score ( P < 0.001) and the CGI-Severity score ( P < 0.001) for all comparisons. For PANSS total scores, endpoint effect sizes for lurasidone 40-80 mg/d and 120-160 mg/d were 0.68 to 0.77, respectively. Adverse events with a frequency ≥5% (and were greater than for combined lurasidone) were insomnia (11.7%), akathisia (11.3%), headache (7.4%), Parkinsonism (6.5%) and nausea (5.7%). Median changes (in mg/dL) at endpoint were minimal for total cholesterol (-8.0); triglycerides (-8.5) and glucose (-2.0) and in mean weight (-0.2 kg). In European patients with schizophrenia, short-term treatment with lurasidone in doses of 40-160 mg/d was generally safe, well-tolerated and effective with minimal effects on weight and metabolic parameters.

Pre-polysomnographic assessment using the Pittsburgh Sleep Quality Index questionnaire is not useful in identifying people at higher risk for obstructive sleep apnea.

BACKGROUND: Polysomnography remains the diagnostic gold standard for obstructive sleep apnea syndrome (OSAS), but it is time consuming and requires dedicated personnel and setting. It may be more useful to plan a polysomnogram based on a preliminary screening. OBJECTIVE: To verify whether a questionnaire of general quality of sleep, the Pittsburgh Sleep Quality Index (PSQI), could outperform a dedicated questionnaire (Epworth Sleep Scale: ESS) in targeting OSAS patients in an at risk population. METHODS: 254 consecutive subjects attending the outpatient clinic for respiratory diseases were clinically evaluated for sleep apnea and referred to a 12 channel night-time polysomnography. All patients were administered the ESS and the PSQI before the procedure. The correlation between the Apnoea/Hypopnoea Index (AHI) and the global score of the PSQI was calculated; Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), Diagnostic accuracy and the area under the receiver operating characteristic curve (AUC) were calculated. ESS performance was used as a control reference. RESULTS: The mean age was 65.8 (standard deviation: 12.1) and the study group was 68.4% male. The mean BMI was 38.5; SD 7.7. Prevalence of OSAS in the study population was 55.5%; OSAS was severe in 60.5% of OSAS patients. ESS was significantly, but weakly, correlated with the AHI (AHI vs ESS: R = 0.308; p < 0.001), whereas PSQI was not (R = 0.037; p = 0.581). Both PSQI and ESS, however, performed unsatisfactorily: sensitivity 37.8% and 69.7%; Specificity 76.1% and 31.0%; Diagnostic Accuracy 57.5% and 49.8%; PPV 60% and 48.7%; NPV 56.3% and 52.2%; AUC 0.589 and 0.509, respectively. CONCLUSIONS: The PSQI score is not helpful in the pre-polysomnographic assessment of people with suspected OSAS. Further studies are required to provide reliable pre-clinical instruments targeting patients amenable to polysomnography.