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Simple Summary: Radiolabeled choline and PSMA PET have been largely tested in the initial staging of prostate cancer and for biochemical recurrence. Moreover, diverse data are now available about their role in the evaluation of response to local and systematic therapies, and their predictive impact on the prognosis, before and after therapy. Therefore, in the present systematic review, we aimed to describe the available data, to summarize the current evidence in these settings of disease. The aims of this systematic review were to (1) assess the utility of PSMA-PET and choline-PET in the assessment of response to systemic and local therapy, and to (2) determine the value of both tracers for the prediction of response to therapy and survival outcomes in prostate cancer. We performed a systematic literature search in PubMed/Scopus/Google Scholar/Cochrane/EMBASE databases (between January 2010 and October 2021) accordingly. The quality of the included studies was evaluated following the "Quality Assessment of Prognostic Accuracy Studies" tool (QUAPAS-2). We selected 40 articles: 23 articles discussed the use of PET imaging with [68Ga]PSMA-11 (16 articles/1123 patients) or [11C]/[18F]Choline (7 articles/356 patients) for the prediction of response to radiotherapy (RT) and survival outcomes. Seven articles (three with [68Ga]PSMA-11, three with [11C]Choline, one with [18F]Choline) assessed the role of PET imaging in the evaluation of response to docetaxel (as neoadjuvant therapy in one study, as first-line therapy in five studies, and as a palliative regimen in one study). Seven papers with radiolabeled [18F]Choline PET/CT (n = 121 patients) and three with [68Ga]PSMA-11 PET (n = 87 patients) were selected before and after enzalutamide/abiraterone acetate. Finally, [18F]Choline and [68Ga]PSMA-11 PET/CT as gatekeepers for the treatment of metastatic prostate cancer with Radium-223 were assessed in three papers. In conclusion, in patients undergoing RT, radiolabeled choline and [68Ga]PSMA-11 have an important prognostic role. In the case of systemic therapies, the role of such new-generation imaging techniques is still controversial without sufficient data, thus requiring additional in this scenario. [ABSTRACT FROM AUTHOR]

Simple Summary: The efficacy of abiraterone plus prednisolone (ABI) against nonmetastatic castration-resistant prostate cancer (CRPC) remains unclear. To evaluate enzalutamide and ABI as the first-line treatment for CRPC, we conducted the randomized controlled trial including both metastatic and nonmetastatic CRPC. As a sub-analysis, we focused on nonmetastatic CRPC in this study. ABI and enzalutamide had similar efficacy and safety profiles in patients with nonmetastatic CRPC. Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22–2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35–1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19–2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is a very common disease in men. Nowadays several life-prolonging therapies are available, also efficient in the metastatic setting. However, it is important to choose the best approach for each patient, and in this context molecular biomarkers are fundamental. Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain correlates with worse outcomes. This study investigates correlation between PSA response endpoints, plasma DNA analysis and progression free/overall survival, underling the importance of a multimodal approach to early predict outcome. Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate ctDNA fraction and AR CN from plasma samples. We divided patients into high and low ctDNA level and in AR gain and AR normal. Results: 220 baseline samples were collected from mCRPC treated with abiraterone (n = 140) or enzalutamide (n = 80). A lower rate of PSA decline ≥ 50% was observed in patients with high ctDNA (p = 0.017) and AR gain (p = 0.0003). Combining ctDNA fraction and AR CN, we found a different median PSA progression-free survival (PFS) among four groups: (1) low ctDNA/AR normal, (2) high ctDNA/AR normal, (3) low ctDNA/AR gain, and (4) high ctDNA/AR gain (11.4 vs. 5.0 vs. 4.8 vs. 3.7 months, p < 0.0001). In a multivariable analysis, high ctDNA, AR gain, PSA DT, PSA DT velocity remained independent predictors of PSA PFS. Conclusions: Elevated ctDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abiraterone or enzalutamide. [ABSTRACT FROM AUTHOR]

Simple Summary: In the present study, we sought to determine whether a commonly used oral drug to treat adult-onset diabetes, metformin, which has a longstanding clinical history and known safety and tolerability profile, can improve the anti-cancer effects of two well-established oral agents currently in use to treat advanced prostate cancer, abiraterone and enzalutamide. We used androgen-sensitive cell culture models of human prostate cancer to test our hypothesis. We found that metformin and the oral anti-prostate cancer agents together are more effective in inhibiting prostate cancer cell growth and inducing prostate cancer cell death than when used alone. We identified new pathways by which the enhanced anti-cancer effects occur with the combination treatments. The present work suggests that incorporating metformin with abiraterone or enzalutamide may improve treatment outcomes in hormone sensitive prostate cancer. We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC. [ABSTRACT FROM AUTHOR]

Simple Summary: In patients with prostate cancer, the use of new-generation hormonal therapy, added to androgen deprivation therapy, requires careful evaluation of cognitive function. The aim of this systematic review is to describe the evidence about cognitive function in randomized trials testing new-generation hormonal therapy (abiraterone, enzalutamide, apalutamide, darolutamide). For each trial, we assessed the availability of both investigator-assessed cognitive impairment and disorders and patient-reported evaluation of cognitive function. Out of 19 trials, the investigator-based evaluation of cognitive impairment was available in seven (36.8%), while patient-reported evaluation of cognitive function results was presented only in one trial (5.3%). This analysis shows that, despite cognitive deterioration could be relevant in patients with prostate cancer, clinical development of new-generation hormonal drugs has not included a systematic evaluation of cognitive function. In patients with prostate cancer, earlier use and longer duration of new-generation hormonal therapy (NGHT), added to androgen deprivation therapy, requires careful evaluation of cognitive function. The aim of this systematic review is to describe the evidence about cognitive function in all the randomized trials (RCTs) testing NGHT (abiraterone, enzalutamide, apalutamide, darolutamide). We assessed the availability of both investigator-assessed cognitive impairment and disorders and patient-reported evaluation of cognitive function. Nineteen RCTs (17,617 patients) were included. The investigator-based evaluation of cognitive impairment was available in seven RCTs (36.8%). In total, 19/19 RCTs (100%) included patient-reported outcomes (PROs) collection, but PRO tools adopted allowed evaluation of cognitive function in two RCTs (10.5%). Among them, PRO-based cognitive function results were presented only in one RCT (5.3%): in ENZAMET, mean changes from baseline were worse with enzalutamide than with placebo, but deterioration-free survival favored enzalutamide. Despite cognitive deterioration could be relevant, clinical development of NGHT has not included a systematic evaluation of cognitive function. Assessment by investigators is at risk of underreporting, and commonly used PROs do not allow proper cognitive function analysis. Furthermore, the methodology of analysis can jeopardize the interpretation of results. Although direct comparisons are scanty, there could be differences between different NGHTs. [ABSTRACT FROM AUTHOR]

Simple Summary: We report the final results of a multicenter, prospective, 2-arm trial in a real world setting for patients with metastatic castration resistant prostate cancer. A number of 675 patients were allocated by center-based cluster-randomization to arm A with adherence enhancing measures or arm B without adherence enhancing measures. Our study reveals a generally high medication adherence in patients with mCRPC with no clear difference between Arm A and Arm B. Our results confirm the benefit of Abiraterone acetate plus Prednisolone in terms of effectiveness and quality of life in a real world setting. Residual androgen production causes tumor progression in metastatic, castration-resistant prostate cancer (mCRPC) patients. Abiraterone acetate (AA), a prodrug of abiraterone, is an oral CYP-17 inhibitor that blocks androgen production. It was hypothesized that adherence-enhancing measures (AEM) might be beneficial for mCRPC patients receiving abiraterone acetate plus prednisone (AA + P). This multicenter, prospective, 2-arm trial allocated mCRPC patients who were progressive after docetaxel-based chemotherapy or asymptomatic/mildly symptomatic after failure of an androgen deprivation therapy to Arm A (with AEM) or Arm B (without AEM) by center-based cluster-randomization. The primary objective was to assess the influence of AEM on discontinuation rates and medication adherence in mCRPC patients treated with AA + P. A total of 360 patients were allocated to Arm A, and 315 patients to Arm B. At month 3, the rate of treatment discontinuation, not due to disease progression or the start of new cancer therapy, was low in both arms (A: 9.0% vs. B: 7.3%, OR = 1.230). Few patients had a medium/low Morisky Medication Adherence Scale (MMAS-4) score (A: 6.4% vs. B: 9.1%, OR = 0.685). The results obtained did not suggest any clear adherence difference between Arm A and Arm B. In patients with mCRPC taking AA + P medication, adherence seemed to be generally high. [ABSTRACT FROM AUTHOR]

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase 3 trials have been conducted in this setting, no direct comparison is currently available among the different strategies. Inadequate power, absence of preplanning and small sample size frequently affect the subgroup analyses according to disease volume or patient's risk. The choice between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide, apalutamide or radiotherapy to the primary tumor remains challenging. Factors that are related to the tumor, patient or drug side effects, currently guide these clinical decisions. This comprehensive review aims to indirectly compare the phase 3 trials in the mHSPC setting, in order to extrapolate data useful for treatment selection, providing also perspectives on future biomarkers. [ABSTRACT FROM AUTHOR]