Comment on: "Comparative neurological safety of novel hormonal therapies in advanced prostate cancer: a Bayesian network meta-analysis of randomized trials".

LONG-TERM OUTCOME FOR MEN WITH ANDROGEN INDEPENDENT PROSTATE CANCER TREATED WITH KETOCONAZOLE AND HYDROCORTISONE

Background:Orally administrated agents play a key role in the management of prostate cancer, providing a convenient and cost-effective treatment option for patients. However, they are also associated with adherence issues which can compromise therapeutic outcomes. This scoping review identifies and summarizes data on adherence to oral hormonal therapy in advanced prostate cancer and discusses associated factors and strategies for improving adherence.Methods:PubMed (inception to 27 January 2022) and conference databases (2020–2021) were searched to identify English language reports of real-world and clinical trial data on adherence to oral hormonal therapy in prostate cancer using the key search terms ‘prostate cancer’ AND ‘adherence’ AND ‘oral therapy’ OR respective aliases.Results:Most adherence outcome data were based on the use of androgen receptor pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Self-reported and observer-reported adherence data were used. The most common observer-reported measure, medication possession ratio, showed that the vast majority of patients were in possession of their medication, although proportion of days covered and persistence rates were considerably lower, raising the question whether patients were consistently receiving their treatment. Study follow-up for adherence was generally around 6 months up to 1 year. Studies also indicate that persistence may drop further with longer follow-up, especially in the non-mCRPC setting, which may be a concern when years of therapy are required.Conclusions:Oral hormonal therapy plays an important role in the treatment of advanced prostate cancer. Data on adherence to oral hormonal therapies in prostate cancer were generally of low quality, with high heterogeneity and inconsistent reporting across studies. Short study follow-up for adherence and focus on medication possession rates may further limit relevance of available data, especially in settings that require long-term treatment. Additional research is required to comprehensively assess adherence.

Objectives To analyze the short-term curative effect and side reaction of Intensity Modulated Radiation Therapy (IMRT) combined with endocrine therapy for advanced prostate cancer. Methods The clinical data of 42 patients with advanced prostate cancer treated by IMRT combined with endocrine therapy were analyzed retrospectively. The regimen of radiotherapy was taken as follow: 1.8~2.0 Gy per fraction, once a day, five times a week, the DT was 64~78 Gy, and the average radiation dose was 70.4 Gy. The regimen of endocrine therapy was taken as follow: maximum androgen blockade. It was castration combined with anti androgen treatment of bicalutamide at the same time. There were 28 patients whom were castrated by operation before radiation therapy, and 14 patients were castrated by goserelin or leuprorelin. Results All patients had finished the radiation therapy. The serum PSA of 36 patients was decreased to below 1 ng/mL 6 months after the therapy. The frequency of urination, dysuria, tenesmus and other symptoms had been improved after radiation therapy. The incidence rate of 3 levels of acute gastrointestinal side reaction was 33.3% (14 cases), 9.5% (4 cases), and 4.8% (2 cases) respectively.The incidence rate of 2 levels of acute urinary system side reaction was 38.1% (16 cases) and 9.5% (4 cases) respectively. Conclusions The curative effect of IMRT combined with endocrine therapy for advanced prostate cancer is satisfied, and the incidence rate of the side reaction is low. It is an effective way for prostate cancer. Key words: Prostatic Neoplasms; Radiotherapy; Endocrine Therapy

89Zr-MSTP2109A, A Novel Antibody Based Radiotracer to Evaluate and Guide the Clinical Translation of Antibody-Drug Conjugates Targeting STEAP1

Objective To explore clinical efficacy, complications and quality of life of the radiotherapy combined with endocrine therapy for advanced prostate cancer. Methods From April 2012 to April 2014, 86 cases of advanced prostate cancer patients in our hospital were selected as the research object. According to the different treatment methods, all patients were randomly divided into observation group (43 cases) and control group (43 cases), the control group was treated with three-dimensional conformal radiation treatment, observation group received radiotherapy combined with endocrine treatment.Clinical efficacy after treatment, complications and quality of life were compared between the two groups. Results The observation group after complete remission accounting for 37.21%(16/43), the total effective 62.79% (27/43) was significantly higher than the control group 16.28% (7/43), 34.88% (15/43)(P<0.05). Two group of patients had complications after treatment, but the total complication rate of observation group was significantly lower than the control group (P<0.05). The indexes of the two groups before treatment patients with expanded prostate cancer index composite(EPIC) had no significant difference, after treatment of each index of two groups of patients with EPIC decreased significantly, and the observation group decreased more significantly than the control group (P<0.05). Serum PSA and maximum urinary flow rate of two groups of patients before treatment were no significant difference between the two groups after treatment, PSA was significantly lower than before treatment, and the maximum urine flow rate compared with before treatment were significantly increased, but the observation group improved significantly better than the control group (P<0.05). Conclusions Radiotherapy combined with endocrine therapy has some advantages on the clinical efficacy of advanced prostate cancer, complications reduction, and improvement of survival quality, and effectively reduces the level of serum PSA and improves maximum urinary flow rate. Key words: Prostatic Neoplasms; Radiotherapy; Quality of Life

Novel hormonal agents (NHAs), including enzalutamide, abiraterone acetate, apalutamide, and darolutamide, have improved survival in advanced prostate cancer (PCa). However, their potential neurological adverse effects (AEs)-notably cognitive impairment, seizures, and falls-raise safety concerns, particularly in older adults. This study aimed to compare the neurological safety profiles of NHAs in men with advanced PCa using a Bayesian network meta-analysis (NMA). We conducted a systematic review and Bayesian NMA following PRISMA-NMA guidelines. Comprehensive searches of PubMed, EMBASE, and Web of Science were completed through May 21, 2025. Eligible randomized controlled trials (RCTs) compared NHAs plus androgen deprivation therapy (ADT) with placebo, ADT, or other NHAs. Neurological AEs of interest included cognitive impairment, falls, and seizures. Bayesian random-effects models were used to calculate risk ratios (RRs) with 95% credible intervals (CrIs). Treatments were ranked using surface under the cumulative ranking curve (SUCRA) values. Twenty-five RCTs with over 19,000 patients were included. No treatments showed a statistically significant increased risk of neurological AEs. Enzalutamide had the highest estimated risk for cognitive impairment (RR 3.88; 95% CrI, 0.697-22.1) and seizures (RR 13.8; 95% CrI, 0.983-1.07 × 103), although not statistically significant. Darolutamide and nonsteroidal antiandrogens exhibited the most favorable neurological safety profiles across outcomes based on SUCRA rankings. Although no NHA significantly increased neurological AEs, enzalutamide showed the highest estimated risk, while darolutamide and NSAAs ranked best for neurological safety. Darolutamide may be preferred in elderly patients, highlighting the need for further long-term safety data.

The aim of this study was to investigate the feasibility and safety of high-intensity focused ultrasound (HIFU) combined with (+) low-dose external beam radiotherapy (LRT) as supplemental therapy for advanced prostate cancer (PCa) following hormonal therapy (HT). Our definition of HIFU+LRT refers to treating primary tumour lesions with HIFU in place of reduced field boost irradiation to the prostate, while retaining four-field box irradiation to the pelvis in conventional-dose external beam radiotherapy (CRT). We performed a prospective, controlled and non-randomized study on 120 patients with advanced PCa after HT who received HIFU, CRT, HIFU+LRT and HT alone, respectively. CT/MR imaging showed the primary tumours and pelvic lymph node metastases visibly shrank or even disappeared after HIFU+LRT treatment. There were significant differences among four groups with regard to overall survival (OS) and disease-specific survival (DSS) curves (P = 0.018 and 0.015). Further comparison between each pair of groups suggested that the long-term DSS of the HIFU+LRT group was higher than those of the other three groups, but there was no significant difference between the HIFU+LRT group and the CRT group. Multivariable Cox's proportional hazard model showed that both HIFU+LRT and CRT were independently associated with DSS (P = 0.001 and 0.035) and had protective effects with regard to the risk of death. Compared with CRT, HIFU+LRT significantly decreased incidences of radiation-related late gastrointestinal (GI) and genitourinary (GU) toxicity grade ≥ II. In conclusion, long-term survival of patients with advanced PCa benefited from strengthening local control of primary tumour and regional lymph node metastases after HT. As an alternative to CRT, HIFU+LRT showed good efficacy and better safety.

Meeting summary: Workshop conference on endocrine therapy of advanced prostate cancer, airlie house, November 3–4, 1996

Objective To observe the effect of transurethral plasmakinetic resection of prostate （TUPKVP）combined with endocrine therapy on advanced prostate cancer with bladder outlet obstruc-tion. Methods Ten patients diagnosed with advanced prostate cancer with bladder outlet obstruction were treated by TUPKVP combined with endocrine therapy from March 2008 to March 2013. Results Ten patients were successful in operation. Postoperative follow-up of 8 - 68 months,with 5 patients died, the 5 - year survival rate was 50% . IPSS,QOL,postvoid residual volune,Qmax and PSA improved signif-icantly（P 〈 0. 01）. Conclusions TUPKVP combined with endocrine therapy can relive the bladder out-let obstruction symptoms and delay the progress of prostate cancer in patients with advanced prostatic cancer,and improve the quality of the patients’life,the clinical effect is satisfactory. Key words: Advanced prostate cancer; Bladder outlet obstruction; Transurethral plasmakinetic resection of prostate; Endocrine therapy

In a large proportion of advanced prostate cancer patients treated with androgen deprivation therapy, progression of the disease occurs despite low levels of testosterone, termed castration-resistant prostate cancer. This heralds the onset of the lethal form of the disease. Recent investigations into the mechanisms of castration resistance have shown that despite low levels of androgen, the androgen receptor remains active through a variety of mechanisms and thus represents a key treatment target in castration-resistant prostate cancer. Clinical approaches to these patients have rapidly progressed and include antiandrogen withdrawal, sequential antiandrogen use, adrenal androgen production inhibitors, and estrogenic compounds. Multiple efforts are underway to develop additional therapies targeted at this phenomenon. Hormonal therapy in advanced prostate cancer is rapidly evolving to more effectively target disease processes underlying prostate cancer, with multiple promising agents on the horizon.

The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here, we show that enzalutamide- and abiraterone-resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in enzalutamide-resistant cells resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to enzalutamide, abiraterone, and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second-generation androgen receptor-targeted therapies in advanced prostate cancer.

Loss of TP53 and PTEN activity are frequent genetic events in CRPC that are often associated with poorly differentiated, treatment resistant tumors. Using the Pten/Tp53-null mouse prostate cancer (PCa) model (Pb-Cre; Ptenfl/fl Tp53 fl/fl) and organoid cultures we previously have shown that a high proportion of luminal progenitors are intrinsically resistant to androgen deprivation therapy (ADT). To identify mechanisms of ADT resistance in luminal progenitors, we performed RNAseq analysis of luminal progenitor organoids derived from wild-type(WT) and Pten/Tp53-null mice. Pathway analysis identified key signaling alterations in luminal tumor organoids (AR signaling, lipid metabolism, protein secretion, inflammation etc.) that also have been described in FACS-purified human prostate luminal (CD49flo) fractions. Interestingly, we found no difference in transcriptional profiles from intact and previously castrated tumor organoids, suggesting that Pten/Tp53 null luminal progenitors are intrinsically resistance to ADT. Of note, we observed most significant enrichment of interferon(IFN) signaling in luminal progenitor tumor organoids relative to wild type luminal organoids. In other cancers and contrary to the anti-proliferative IFN signaling, expression of a subset of IFN genes contributes to genotoxic therapy resistance. This subset, referred to as IRDS (IFN-related DNA damage signature), includes a group of unphosphorylated STAT1 (U-STAT1)-driven genes that has a pro-survival function and promotes cancer cell intrinsic drug resistance. We hypothesize that the IRDS contributes to survival of PCa cells following ADT or genotoxic therapies. RT-PCR, immunofluorescence, and western blot analysis of luminal progenitor organoids showed higher U-STAT1 levels in tumor- than WT organoids, whereas pSTAT1 (Y701) was undetectable. Similarly, U-STAT1 was upregulated in Pten/Tp53-null tumor tissue relative to normal prostate. Further, for tumor organoids, ADT resulted in higher U-STAT1 levels. STAT1 depletion in tumor organoids decreased the number of progeny organoids in subsequent passages, suggesting a role in self-renewal for luminal tumor stem cells. Altogether, U-STAT1 regulated signaling has pro-survival function in Pten/Tp53-null advanced PCa. Several PDXs originating from metastatic PCa (LuCaPs 23.1, 96 and 141) express high levels of U-STAT1 dependent IFN signaling. STAT1 depletion significantly reduced self-renewing ability of these PDX derived organoids, consistent with mouse luminal tumor organoids. Interestingly, in LuCaP 141, STAT1 depletion synergized with ADT to inhibit growth ex vivo. These findings suggest that U-STAT1 dependent IFN signaling may contribute to castration resistance. We subsequently analyzed human PCa datasets to determine clinical correlates of IRDS. Analysis of the TCGA primary PCa cohort revealed IRDS as a prognostic marker for progression (n= 500, p&amp;lt;0.05). Further, high IRDS-expressing samples in the CRPC dataset were enriched for low AR signaling (n = 150, r= -0.33, p&amp;lt; 0.05). CRPC patients expressing the highest IRDS levels (n=30 of 150) showed enrichment for genes associated with stem cell features and therapy resistance. Overall, our findings suggest U-STAT1 dependent IRDS expression is correlated with poorly differentiated PCa and may contribute to intrinsic therapy resistance. Citation Format: Supreet Agarwal, Kerry McGowen, Fathi Elloumi, Maggie Cam, Mike Beshiri, Keith Jansson, Eva Corey, Kathleen Kelly. Interferon signaling confers resistance to androgen deprivation therapy in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-050.

5135 Background: Large meta-analyses have documented that maximum androgen blockade (MAB) for advanced prostate cancer confers survival benefits. Also, we and others reported the effectiveness of second-line hormonal therapy for prostate cancer that has relapsed after initial hormone therapy. However, there is little clinical evidence on the effectiveness of this latter treatment strategy. Therefore, in the present study, a multicenter trial in Japan, we performed analyses of clinical outcomes following alternation switching from one non-steroidal antiandrogen to another (i.e., bicalutamide (BCL) to flutamide (FLT) and FLT to BCL) for advanced prostate cancer relapsed after initial MAB therapy. Methods: The study included 232 patients with advanced prostate cancer, who had initially been treated with MAB that included surgical or medical castration combined with non-steroidal antiandrogens. First line regimens included either FLT 375 mg/day or bicalutamide BCL 80 mg/day. If a patient relapsed while on 1st line therapy, we discontinued the antiandrogen and evaluated the patient for antiandrogen withdrawal syndrome (AWS). We then administrated an alternative antiandrogen and evaluated its effect. Results: The incidence of AWS after the initial MAB was 15.5% (BCL) and 12.8% (FLT), respectively. The occurrence of a PSA decrease after antiandrogen withdrawal was one of the prognostic factors. Non-steroidal antiandrogens as alternative therapies for patients who relapsed from initial MAB were effective (PSA decrease >50%) in second-line MAB (FLT 34.2%, BCL 43.6%). A total of 142 of 232 patients (61.2%) showed a PSA decrease in response to an alternative antiandrogen and these responders showed significantly better survival than non- responders, suggesting that responsiveness to second-line therapy predicts increased survival. Conclusions: Following up on MAB with an alternative non-steroidal antiandrogen is effective against advanced prostate cancer that has relapsed after initial MAB. Having even a partial response to second-line MAB treatment was associated with improved survival. Our data support the notion that responders to second-line regimens are androgen-independent but still hormonally sensitive. No significant financial relationships to disclose.

Recent advances in the treatment of prostate cancer

Novel therapies for advanced prostate cancer: have we have widened the goal posts too far?