Management Of Advanced Prostate Cancer Research Articles

Management of advanced prostate cancer in the Asia‐Pacific region: Summary of the Asia‐Pacific Advanced Prostate Cancer Consensus Conference 2023

Management of advanced prostate cancer in the Asia‐Pacific region: Summary of the Asia‐Pacific Advanced Prostate Cancer Consensus Conference 2023

Clinical Management of Advanced Prostate Cancer: Where Does Radiopharmaceutical Therapy Fit in the Treatment Algorithm?

Most men with newly appreciated metastatic prostate cancer are optimally treated with a backbone consisting of androgen receptor-directed therapy with or without taxane chemotherapy. Despite improvements in disease outcomes, prostate cancer remains an extremely heterogeneous disease with variable mechanisms of therapeutic resistance. As a result, it remains a leading cause of cancer-related death in men. Radiopharmaceutical therapy has emerged as an alternative, non-androgen receptor-directed treatment modality for metastatic castration-resistant prostate cancer that impacts patient survival and represents a potentially more personalized approach. In this review, we aim to outline the current treatment landscape for metastatic prostate cancer with a focus on radiopharmaceutical therapy, specifically 177Lu-PSMA-617. In addition, we illustrate various clinical challenges with 177Lu-PSMA-617 treatment to date and explore investigative efforts to leverage radiopharmaceutical therapies as part of combination regimens or earlier in the treatment algorithm to further improve patient outcomes. Finally, we introduce ongoing studies of alternative radiopharmaceutical therapies in metastatic prostate cancer that may be incorporated into the treatment algorithm pending further study.

Nuclear receptor NURR1 functions to promote stemness and epithelial-mesenchymal transition in prostate cancer via its targeting of Wnt/β-catenin signaling pathway

Dysregulated activation of Wnt/β-catenin signaling pathway is a frequent or common event during advanced progression of multiple cancers. With this signaling activation, it enhances their tumorigenic growth and facilitates metastasis and therapy resistance. Advances show that this signaling pathway can play dual regulatory roles in the control of cellular processes epithelial-mesenchymal transition (EMT) and cancer stemness in cancer progression. Aberrant activation of Wnt/β-catenin signaling pathway is shown to be common in prostate cancer and also castration-resistant prostate cancer (CRPC). However, the transcriptional regulators of this pathway in prostate cancer are still not well characterized. NURR1 (NR4A2) is an orphan nuclear receptor and plays an important role in the development of dopaminergic neurons. Previously, we have shown that NURR1 exhibits an upregulation in isolated prostate cancer stem-like cells (PCSCs) and a xenograft model of CRPC. In this study, we further confirmed that NURR1 exhibited an upregulation in prostate cancer and also enhanced expression in prostate cancer cell lines. Functional and molecular analyses showed that NURR1 could act to promote both in vitro (cancer stemness and EMT) and also in vivo oncogenic growth of prostate cancer cells (metastasis and castration resistance) via its direct transactivation of CTNNB1 (β-catenin) and activation of β-catenin to mediate the activation of Wnt/β-catenin signaling pathway. Moreover, we also demonstrated that NURR1 activity in prostate cancer cells could be modulated by small molecules, implicating that NURR1 could be a potential therapeutic target for advanced prostate cancer management.

Toxicity-benefit analysis of advanced prostate cancer trials using weighted toxicity scoring.

110 Background: The weighted toxicity score (WTS) is a metric suitable for comparing the toxicity burden in experimental versus control arms of randomized controlled trials (RCTs). When compared against clinical endpoints, the WTS can be used to evaluate the cost versus benefit of anti-cancer agents. This study sought to apply the WTS to prostate cancer (PC) clinical trials. Methods: Select phase 3 PC RCTs with reported adverse event (AE) data were compiled. The WTS was computed for each trial arm and compared to reported hazard ratios (HRs) of primary and/or secondary endpoints (i.e., overall survival (OS) and progression-free survival (PFS)). Average WTSs for the experimental versus control arms were used to calculate the toxicity differential between treatment arms. Average HRs for OS and PFS were used to compare efficacy. Results: Sixteen RCTs were analyzed (investigational agents: androgen-receptor signaling inhibitors (ARSi) [n = 4], poly (ADP-ribose) polymerase inhibitors (PARPi) monotherapy [n = 3], ARSi + PARPi as well as ARSi + ARSi combination therapies [n = 3 each], and triple therapy [n=3]). The median number of distinct reported AEs across all studies was 18 (range, 9-61). Overall, toxicity and efficacy were greater among experimental than control arms (6.62 versus 4.00 median WTS; median HR for OS 0.71, median HR for PFS 0.61). The triple therapy studies observed the lowest increase in toxicity by adding an ARSi to control therapy (10.4%), associated with 52% lower risk of progression, and 29% lower risk of death. Comparably, the ARSi + PARPi trials noted the highest increase in toxicity (79.7%), with 32% lower risk of progression and 12% lower risk of death. The PARPi monotherapy, ARSi monotherapy, and ARSi + ARSi combination therapy studies reported increased toxicity due to experimental therapy in descending order (Table). Conclusions: The WTS enables toxicity versus benefit assessment for anti-cancer regimens. Clinical application of this metric may facilitate individualized treatment planning in advanced PC management. [Table: see text]

Integrated analysis identifies GABRB3 as a biomarker in prostate cancer

BackgroundTreatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer.MethodsWe genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer.ResultsAfter multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer.ConclusionOur results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted.

Addressing controversial areas in the management of advanced prostate cancer in Canada Areas of consensus and controversy from the third Canadian consensus forum.

The management of prostate cancer (PCa) is rapidly evolving. Treatment and diagnostic options grow annually, however, high-level evidence for the use of new therapeutics and diagnostics is lacking. In November 2022, the Genitourinary Research Consortium held its 3rd Canadian Consensus Forum (CCF3) to provide guidance on key controversial areas for management of PCa. A steering committee of eight multidisciplinary physicians identified topics for discussion and adapted questions from the Advanced Prostate Cancer Consensus Conference 2022 for CCF3. Questions focused on management of metastatic castration-sensitive prostate cancer (mCSPC); use of novel imaging, germline testing, and genomic profiling; and areas of non-consensus from CCF2. Fifty-eight questions were voted on during a live forum, with threshold for "consensus agreement" set at 75%. The voting panel consisted of 26 physicians: 13 urologists/uro-oncologists, nine medical oncologists, and four radiation oncologists. Consensus was reached for 32 of 58 questions (one ad-hoc). Consensus was seen in the use of local treatment, to not use metastasis-directed therapy for low-volume mCSPC, and to use triplet therapy for synchronous high-volume mCSPC (low prostate-specific antigen). Consensus was also reached on sufficiency of conventional imaging to manage disease, use of germline testing and genomic profiling for metastatic disease, and poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA-positive prostate cancer. CCF3 identified consensus agreement and provides guidance on >30 practice scenarios related to management of PCa and nine areas of controversy, which represent opportunities for research and education to improve patient care. Consensus initiatives provide valuable guidance on areas of controversy as clinicians await high-level evidence.

Personalized dietary management of advanced prostate cancer using nutrigenomics: a case report

While there are emerging reports in the scientific literature on potential associations between cholesterol/lipids and prostate cancer, information on the dietary management of these cancer patients is currently lacking. We report on a 57-year-old white Australian male diagnosed with advanced prostate cancer who had personalized dietary management in preparation for and following his medical treatment: radiation and radical prostatectomy. Dietary recommendations were based on his blood results and nutrigenomic tests which showed a history of and genetic predisposition to dyslipidemia. Nutritional analysis also confirmed the need for dietary modification of his fat intake. Eighteen months post medical and dietary intervention his PSA level was reported at 0.1 ug/L and all blood lipid levels were within reference ranges. At two years there was no detectable disease recurrence and androgen deprivation therapy (ADT) was not required. Personalized dietary recommendations could be a clinically beneficial addition to the multidisciplinary management of prostate cancer patients.

Loss of PDE4D7 expression promotes androgen independence, neuroendocrine differentiation and alterations in DNA repair: implications for therapeutic strategies

BackgroundAndrogen signalling remains the seminal therapeutic approach for the management of advanced prostate cancer. However, most tumours eventually shift towards an aggressive phenotype, characterised by androgen independence and treatment resistance. The cyclic adenosine monophosphate (cAMP) pathway plays a crucial role in regulating various cellular processes, with the phosphodiesterase PDE4D7 being a vital modulator of cAMP signalling in prostate cancer cells.MethodsUsing shRNA-mediated PDE4D7 knockdown in LNCaP cells and downstream analysis via RNA sequencing and phenotypic assays, we replicate clinical observations that diminished PDE4D7 expression promotes an aggressive prostate cancer phenotype.ResultsOur study provides evidence that loss of PDE4D7 expression represents a pivotal switch driving the transition from an androgen-sensitive state to hormone unresponsiveness and neuroendocrine differentiation. In addition, we demonstrate that PDE4D7 loss affects DNA repair pathways, conferring resistance to poly ADP ribose polymerase (PARP) inhibitors.ConclusionReinstating PDE4D7 expression sensitises prostate cancer cells to anti-androgens, DNA damage response inhibitors, and cytotoxic therapies. These findings provide significant insight into the regulatory role of PDE4D7 in the development of lethal prostate cancer and the potential of its modulation as a novel therapeutic strategy.

Unleashing novel horizons in advanced prostate cancer treatment: investigating the potential of prostate specific membrane antigen-targeted nanomedicine-based combination therapy.

Prostate cancer (PCa) is a prevalent malignancy with increasing incidence in middle-aged and older men. Despite various treatment options, advanced metastatic PCa remains challenging with poor prognosis and limited effective therapies. Nanomedicine, with its targeted drug delivery capabilities, has emerged as a promising approach to enhance treatment efficacy and reduce adverse effects. Prostate-specific membrane antigen (PSMA) stands as one of the most distinctive and highly selective biomarkers for PCa, exhibiting robust expression in PCa cells. In this review, we explore the applications of PSMA-targeted nanomedicines in advanced PCa management. Our primary objective is to bridge the gap between cutting-edge nanomedicine research and clinical practice, making it accessible to the medical community. We discuss mainstream treatment strategies for advanced PCa, including chemotherapy, radiotherapy, and immunotherapy, in the context of PSMA-targeted nanomedicines. Additionally, we elucidate novel treatment concepts such as photodynamic and photothermal therapies, along with nano-theragnostics. We present the content in a clear and accessible manner, appealing to general physicians, including those with limited backgrounds in biochemistry and bioengineering. The review emphasizes the potential benefits of PSMA-targeted nanomedicines in enhancing treatment efficiency and improving patient outcomes. While the use of PSMA-targeted nano-drug delivery has demonstrated promising results, further investigation is required to comprehend the precise mechanisms of action, pharmacotoxicity, and long-term outcomes. By meticulous optimization of the combination of nanomedicines and PSMA ligands, a novel horizon of PSMA-targeted nanomedicine-based combination therapy could bring renewed hope for patients with advanced PCa.

Neferine Targets the Oncogenic Characteristics of Androgen-Dependent Prostate Cancer Cells via Inducing Reactive Oxygen Species.

Castration resistance poses a significant challenge in the management of advanced prostate cancer (PCa), with androgen deprivation therapy (ADT) or chemotherapy being the primary treatment options. However, these approaches often lead to significant side effects and the development of therapeutic resistance. Therefore, it is crucial to explore novel treatment options that can efficiently target PCa, improve patient survival, and enhance their quality of life. Neferine (Nef), a bioactive compound derived from plants, has emerged as a promising candidate for cancer treatment due to its ability to induce apoptosis, autophagy, and cell cycle arrest. In this study, we investigated the potential anticancer effects of Nef in androgen receptor (AR)-positive LNCaP and VCaP cells, representative models of androgen-dependent PCa. Our findings demonstrate that Nef effectively inhibits cell growth, proliferation, and the tumorigenic potential of androgen-dependent PCa cells. Furthermore, Nef treatment resulted in the excessive production of reactive oxygen species (ROS), leading to the activation of key markers of autophagy and apoptosis. These results suggest that Nef has the potential to target the oncogenic characteristics of androgen-dependent PCa cells by exploiting the potency of ROS and inducing autophagy and apoptosis in AR-positive PCa cells. These findings shed light on the therapeutic potential of Nef as a novel treatment option with reduced side effects for androgen-dependent prostate cancer. Further investigations are warranted to assess its efficacy and safety in preclinical and clinical settings.

Immunogenomic profiles associated with response to life-prolonging agents in prostate cancer.

Prostate cancer is the most commonly diagnosed cancer but the management of advanced prostate cancer remains a therapeutic challenge, despite the survival benefits imparted by several therapeutic discoveries targeting different molecular pathways. The mechanisms of resistance to androgen deprivation and tumour progression to lethal metastatic variants are often regulated by androgen receptor (AR) bypass mechanisms and/or neuroendocrine differentiation. Moreover, recent data also suggested the involvement of adaptive and innate infiltrated immune cells in prostate tumour progression. Improvements in cancer genome analyses contributed to a better understanding of antitumour immunity and provided solutions for targeting highly cancer-specific neoantigens generated from somatic mutations in individual patients. In this review, we investigated the current knowledge on the interplay between cancer development and the complex mechanisms of immune regulation. Particularly, we focused on the role of tumour immune microenvironment, generally characterised by strong barriers for immunotherapy, and we discuss the rationale for the potential application of single agent and combination immune-targeting strategies that could lead to improved outcomes. Careful selection based on clinical and genomic factors may allow identification of patients who could benefit from this treatment approach in multiple settings (from localised to advanced prostate tumour) and in different histological subtypes (from adenocarcinoma to neuroendocrine prostate cancer).

Hierarchical Phosphorylation of HOXB13 by mTOR Dictates Its Activity and Oncogenic Function in Prostate Cancer.

Control of HOXB13 transcriptional activity via its direct phosphorylation by the mTOR kinase is a potential therapeutic avenue for the management of advanced prostate cancer.

Efficacy of Degarelix in the Neoadjuvant Setting in Managing Locally Advanced Prostate Cancer.

Background Prostate cancer holds a substantial presence in the global cancer landscape, and a considerable proportion of diagnoses occur at late stages, particularly in India. Management of locally advanced prostate cancer necessitates a multimodal treatment strategy. A critical part of this strategy is neoadjuvant androgen deprivation therapy, typically administered via luteinizing hormone-releasing hormone (LHRH) analogs. This study explores the potential of an alternative approach: neoadjuvant therapy with degarelix, an LHRH antagonist, and its impact on perioperative and postoperative outcomes in patients undergoing radical prostatectomy for locally advanced or high-risk prostate cancer. Methodology We conducted a retrospective, non-randomized clinical study at Apollo Hospitals in Chennai, India. Patients diagnosed with locally advanced or high-risk prostate cancer who underwent radical prostatectomy were included. Participants were patients treated with neoadjuvant degarelix and subsequent radical prostatectomy between March 2020 and June 2022. We excluded patients receiving radical radiotherapy, those switching from LHRH agonists to antagonists, and those contraindicated for androgen deprivation therapy due to existing comorbidities. For comparison, we selected a group from the institutional database who received conventional treatment (i.e., without neoadjuvant therapy). Results The study compared two groups, each with 32 patients. The groups had no significant difference in total operative duration and console times. The postoperative pathological assessment showed significantly lower margin positivity rates and notable pathological downstaging in the group receiving neoadjuvant degarelix compared to the control group. The incidence of node positivity, prostate-specific antigen levels at three months postoperative, and number of pads used per day at one month did not differ significantly between the two groups. Conclusions Our study suggests that neoadjuvant degarelix could notably enhance patient outcomes in locally advanced prostate cancer management. The benefits include improved symptom control, significant reductions in margin positivity rates, and facilitated surgical procedures. Neoadjuvant degarelix therapy could potentially enhance the feasibility of the surgical intervention in locally advanced prostate cancer management, thus suggesting a promising pathway for improved patient care.

A new tumorgraft panel to accelerate precision medicine in prostate cancer.

Despite the significant advances in the management of advanced prostate cancer (PCa), metastatic PCa is currently considered incurable. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that exemplify each phase of this multistage disease for accurate and rapid evaluation of candidate therapies. Fresh tumor samples along with normal corresponding tissues were obtained directly from patients at surgery. To ensure that the established models reproduce the main features of patient's tumor, both PDX tumors at multiple passages and patient's primary tumors, were processed for histological characteristics. STR profile analyses were also performed to confirm patient identity. Finally, the responses of the PDX models to androgen deprivation, PARP inhibitors and chemotherapy were also evaluated. In this study, we described the development and characterization of 5 new PDX models of PCa. Within this collection, hormone-naïve, androgen-sensitive and castration-resistant (CRPC) primary tumors as well as prostate carcinoma with neuroendocrine differentiation (CRPC-NE) were represented. Interestingly, the comprehensive genomic characterization of the models identified recurrent cancer driver alterations in androgen signaling, DNA repair and PI3K, among others. Results were supported by expression patterns highlighting new potential targets among gene drivers and the metabolic pathway. In addition, in vivo results showed heterogeneity of response to androgen deprivation and chemotherapy, like the responses of patients to these treatments. Importantly, the neuroendocrine model has been shown to be responsive to PARP inhibitor. We have developed a biobank of 5 PDX models from hormone-naïve, androgen-sensitive to CRPC primary tumors and CRPC-NE. Increased copy-number alterations and accumulation of mutations within cancer driver genes as well as the metabolism shift are consistent with the increased resistance mechanisms to treatment. The pharmacological characterization suggested that the CRPC-NE could benefit from the PARP inhibitor treatment. Given the difficulties in developing such models, this relevant panel of PDX models of PCa will provide the scientific community with an additional resource for the further development of PDAC research.

Management of Advanced Prostate Cancer in the Precision Oncology Era.

Prostate cancer (PC) is the second leading cause of cancer death in men in the United States. While diversified and improved treatment options for aggressive PC have improved patient outcomes, metastatic castration-resistant prostate cancer (mCRPC) remains incurable and an area of investigative therapeutic interest. This review will cover the seminal clinical data supporting the indication of new precision oncology-based therapeutics and explore their limitations, present utility, and potential in the treatment of PC. Systemic therapies for high-risk and advanced PC have experienced significant development over the past ten years. Biomarker-driven therapies have brought the field closer to the goal of being able to implement precision oncology therapy for every patient. The tumor agnostic approval of pembrolizumab (a PD-1 inhibitor) marked an important advancement in this direction. There are also several PARP inhibitors indicated for patients with DNA damage repair deficiencies. Additionally, theranostic agents for both imaging and treatment have further revolutionized the treatment landscape for PC and represent another advancement in precision medicine. Radiolabeled prostate-specific membrane antigen (PSMA) PET/CT is rapidly becoming a standard of care for diagnosis, and PSMA-targeted radioligand therapies have gained recent FDA approval for metastatic prostate cancer. These advances in precision-based oncology are detailed in this review.

Novel breakthroughs in advanced prostate cancer management

ABSTRACT Introduction Although PSA screening has been rationalized, prostate cancer continues to have the highest incidence rate in 2021, and alone accounts for 26% of cancer diagnoses in men. A thorough review of the medical literature highlights a vast array of approved and investigational treatments for prostate cancer. Thus, selecting the best treatment option for the appropriate patient at the right time is crucial. Hence, biomarkers help in defining optimal patient stratification, revealing potential processes through which a drug might exert its impact and aid in the tailoring of treatments for efficient personalized medicine. Areas covered This article is a pragmatic review of novel prostate cancer therapies that can help guide clinicians in tackling prostate cancer with the latest treatments. Expert opinion Local radiotherapy has proven to be a game changer for low burden, de novo metastatic prostate cancer. Androgen deprivation therapy continues to be the ultimate treatment. Delaying resistance to these agents will undoubtedly be a breakthrough in the treatment of prostate cancer. When it comes to metastatic castrate-resistant disease, treatment options become narrower. PARP inhibitors and N-terminal domain inhibitors offer new hope and have a synergistic effect, with immunotherapy adding promising agents to the therapeutic arsenal.

Management of patients with advanced prostate cancer—metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022

BackgroundInnovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. ObjectiveTo present the voting results of the APCCC 2022. Design, setting, and participantsThe experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. Outcome measurements and statistical analysisThe panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. Results and limitationsThe voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. ConclusionsThese voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. Patient summaryThe Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. Twitter summaryReport of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. Take-home messageAt APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here.

Outcomes of first subsequent taxane (FST) therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who previously received docetaxel intensification (DI) for metastatic castration-sensitive prostate cancer (mCSPC).

72 Background: The management of advanced prostate cancer continues to rapidly evolve, particularly with earlier use of survival prolonging therapies in mCSPC. Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for pts with mCRPC. However, there is little evidence determining outcomes of taxane chemotherapies as FST in mCRPC pts who received DI in mCSPC. The purpose of this study is to compare outcomes between the survival prolonging taxanes, docetaxel (D) and cabazitaxel (C), as FST after DI. Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 Dec 2020 were reviewed. Pts were considered eligible if they received DI for mCSPC and then received either D or C in mCRPC. Variables of interest were collected from the electronic medical record. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from FST start date. PSA responses were compared using chi-squared test and time-based endpoints were compared using the Kaplan-Meier method. Results: 34 pts were identified: D = 22, C = 12 as FST. 91.2% of pts (D 95.5% vs C 83.3%) received FST in 2nd line mCRPC. Median age at diagnosis (63.1 vs 67.1 yrs, p = 0.236) and median time to CRPC (18.6 vs 14.2 mos, p = 0.079) were similar for D and C, respectively. Median time to FST (24.1 vs 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs 52.7 mos, p = 0.002) were significantly shorter for pts receiving C vs D. PSA responses occurred in 40.9% of pts treated with D compared to 25.0% treated with C (p = 0.645). There was no significant difference in median PFS (2.7 vs 3.5 mos, p = 0.727) or median OS (11.4 vs 8.1 mos, p = 0.132) from time of FST for pts treated with D vs C, respectively. Conclusions: Both D and C demonstrated activity as FST after DI in mCSPC. Pts who received C had shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for C in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with D compared to C. While limited by its retrospective nature and small sample size, this study suggests that D is active as FST despite treatment with DI in mCSPC.

Effects of In-office Dispensing by Single-specialty Urology Practices on Management of Advanced Prostate Cancer.

We examine changes in the volume of patients with advanced prostate cancer and prescriptions for abiraterone and enzalutamide among urology practices with and without in-office dispensing. Using data from the National Council for Prescription Drug Programs, we identified in-office dispensing by single-specialty urology practices from 2011 to 2018. As the greatest growth in implementing dispensing occurred among large groups in 2015, outcomes were measured at the practice level in 2014 (before) and 2016 (after) for dispensing and non-dispensing practices. Outcomes included the volume of men with advanced prostate cancer managed by a practice and prescriptions for abiraterone and/or enzalutamide. Using national Medicare data, generalized linear mixed models were fit to compare the practice-level ratio of each outcome (2016 relative to 2014) adjusting for regional contextual factors. In-office dispensing increased from 1% to 30% of single-specialty urology practices from 2011 to 2018, with 28 practices implementing dispensing in 2015. In 2016 compared to 2014, adjusted changes in the volume of patients with advanced prostate cancer managed by a practice were similar between non-dispensing (0.88, 95% CI 0.81-0.94) and dispensing (0.93, 95% CI 0.76-1.09) practices (P = .60). Prescriptions for abiraterone and/or enzalutamide increased in both non-dispensing (2.00, 95% CI 1.58-2.41) and dispensing (8.99, 95% CI 4.51-13.47) practices (P < .01). In-office dispensing is increasingly common in urology practices. This emerging model is not associated with changes in patient volume but is associated with increased prescriptions for abiraterone and enzalutamide.

Novel hormonal therapies in the management of advanced prostate cancer: extrapolating Asian findings to Southeast Asia

There is a paucity of information on the use of novel hormonal agents in Southeast Asian patients. We reviewed the clinical roles of novel hormonal therapy (NHT), namely abiraterone acetate (AA), enzalutamide, apalutamide and darolutamide, in the management of advanced prostate cancer, and data on its use in Asian patients, in order to extrapolate these findings to the Southeast Asian patient population. There are some differences in the molecular features between the NHTs, which influenced their respective permeabilities through the blood–brain barrier. The Asian sub-analyses of the landmark studies of each NHT were limited. The primary endpoints of the Asian sub-analyses generally reflect the efficacy outcomes of the respective landmark study. Hypertension, fatigue, musculoskeletal disorders, rash, and hot flushes were among the common toxicities observed in Asian patients. Real-world data on AA in the Asian setting is favourable, but data is limited for enzalutamide, apalutamide and darolutamide. Based on the sub-analyses and real-world data, the efficacy and safety of NHTs in the Asian patients showed a similar trend to the respective landmark studies. The lack of clinical trials in the Southeast Asian region hampers the ability to make a robust conclusion on any specific efficacy or safety differences that may be present; clinicians must assume that the broader Asian sub-analyses and real-world data reflects Southeast Asian patients' outcomes.