PSA doubling time 4.65 months as an optimal cut-off of Japanese nonmetastatic castration-resistant prostate cancer.

A multicenter study of nonmetastatic castration-resistant prostate cancer (nmCRPC) was conducted to identify the optimal cut-off value of prostate-specific antigen (PSA) doubling time (PSADT) that correlated with the prognosis in Japanese nmCRPC. Of the 515 patients diagnosed and treated for nmCRPC at 25 participating Japanese Urological Oncology Group centers, 450 patients with complete clinical information were included. The prognostic values of clinical factors were evaluated with respect to prostate specific antigen progression-free (PFS), cancer-specific survival (CSS), and overall survival (OS). The optimal cutoff value of PSADT was identified using survival tree analysis by Python. The Median PSA and PSADT at diagnosis of nmCRPC were 3.3 ng/ml, and 5.2 months, respectively. Patients treated with novel hormonal therapy (NHT) showed significantly longer PFS (HR: hazard ratio 0.38, p < 0.0001) and PFS2 (HR 0.45, p < 0.0001) than those treated with vintage nonsteroidal antiandrogen agent (Vintage). The survival tree identified 4.65 months as the most prognostic PSADT cutoff point. Among the clinical and pathological factors PSADT of < 4.65 months remained an independent prognostic factor for OS (HR 2.96, p = 0.0003) and CSS (HR 3.66, p < 0.0001). Current data represented optimal cut-off of PSADT 4.65 months for a Japanese nmCRPC.

Facile synthesis of elastin nanogels encapsulated decursin for castrated resistance prostate cancer therapy.

Nanogels offer hope for precise drug delivery, while addressing drug delivery hurdles is vital for effective prostate cancer (PCa) management. We developed an injectable elastin nanogels (ENG) for efficient drug delivery system to overcome castration-resistant prostate cancer (CRPC) by delivering Decursin, a small molecule inhibitor that blocks Wnt/ßcatenin pathways for PCa. The ENG exhibited favourable characteristics such as biocompatibility, flexibility, and low toxicity. In this study, size, shape, surface charge, chemical composition, thermal stability, and other properties of ENG were used to confirm the successful synthesis and incorporation of Decursin (DEC) into elastin nanogels (ENG) for prostate cancer therapy. In vitro studies demonstrated sustained release of DEC from the ENG over 120 h, with a pH-dependent release pattern. DU145 cell line induces moderate cytotoxicity of DEC-ENG indicates that nanomedicine has an impact on cell viability and helps strike a balance between therapeutics efficacy and safety while the EPR effect enables targeted drug delivery to prostate tumor sites compared to free DEC. Morphological analysis further supported the effectiveness of DEC-ENG in inducing cell death. Overall, these findings highlight the promising role of ENG-encapsulated decursin as a targeted drug delivery system for CRPC.

Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Poly(ADP-ribose) polymerase inhibitors (PARPi) are a novel option to treat patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib plus abiraterone acetate and prednisone (AAP) is indicated for BRCA1/2 mutation-positive mCRPC. Niraparib plus AAP demonstrated safety and efficacy in the phase 3 MAGNITUDE trial (NCT03748641). In the absence of head-to-head studies comparing PARPi regimens, the feasibility of conducting indirect treatment comparisons (ITC) to inform decisions for patients with first-line BRCA1/2 mutation-positive mCRPC has been explored. METHODS: A systematic literature review was conducted to identify evidence from randomized controlled trials on relevant comparators to inform the feasibility of conducting ITCs via network meta-analysis (NMA) or population-adjusted indirect comparisons (PAIC). Feasibility was assessed based on network connectivity, data availability in the BRCA1/2 mutation-positive population, and degree of within- and between-study heterogeneity or bias. RESULTS: NMAs between niraparib plus AAP and other PARPi regimens (olaparib monotherapy, olaparib plus AAP, and talazoparib plus enzalutamide) were inappropriate due to the disconnected network, differences in trial populations related to effect modifiers, or imbalances within BRCA1/2 mutation-positive subgroups. The latter issue, coupled with the lack of a common comparator (except for olaparib plus AAP), also rendered anchored PAICs infeasible. Unanchored PAICs were either inappropriate due to lack of population overlap (vs. olaparib monotherapy) or were restricted by unmeasured confounders and small sample size (vs. olaparib plus AAP). PAIC versus talazoparib plus enzalutamide was not possible due to lack of published arm-level baseline characteristics and sufficient efficacy outcome data in the relevant population. CONCLUSION: The current randomized controlled trial evidence network does not permit robust comparisons between niraparib plus AAP and other PARPi regimens for patients with 1L BRCA-positive mCRPC. Decision-makers should scrutinize any ITC results in light of their limitations. Real-world evidence combined with clinical experience should inform treatment recommendations in this indication.

Synthesis of curcumin derivatives targeting androgen receptor for castration-resistant prostate cancer therapy.

In this work, a series of curcumin derivatives (1a-1h, 2a-2g, and 3a-3c) were synthesized for the suppression of castration-resistant prostate cancer cells. All synthesized compounds were characterized by 1H NMR, 13C NMR, HRMS, and melting point. The in vitro cytotoxicity study shows that compounds 1a, 1e, 1f, 1h, 2g, 3a, and 3c display similar or enhanced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9, other synthesized compounds display reduced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9. Molecular docking simulation was performed to study the binding affinity and probable binding modes of the synthesized compounds with androgen receptor. The results show that all synthesized compounds exhibit higher cdocker interaction energies as compared to ASC-J9. Compounds 1h, 2g, and 3c not only show strong cytotoxicity against 22Rv1 and C4-2 cells but also exhibit high binding affinity with androgen receptor. In androgen receptor suppression study, compounds 1f and 2g show similar androgen receptor suppression effect as compared to ASC-J9 on C4-2 cells, compound 3c displays significantly enhanced AR suppression effect as compared to ASC-J9, 1f and 2g. Compounds 1a, 1e, 1f, 1h, 2g, 3a and 3c prepared in this work have significant potential for castration-resistant prostate cancer therapy.

Intra-individual Dose Escalation of Abiraterone According to Its Plasma Exposure in Patients with Progressive Metastatic Castration-Resistant Prostate Cancer: Results of the OPTIMABI Trial.

BACKGROUND AND OBJECTIVE: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. METHODS: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22-26 h). RESULTS: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis. CONCLUSION: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).

Understanding the molecular regulators of neuroendocrine prostate cancer.

Worldwide, prostate cancer (PCa) remains a leading cause of death in men. Histologically, the majority of PCa cases are classified as adenocarcinomas, which are mainly composed of androgen receptor-positive luminal cells. PCa is initially driven by the androgen receptor axis, where androgen-mediated activation of the receptor is one of the primary culprits for disease progression. Therefore, in advanced stage PCa, patients are generally treated with androgen deprivation therapies alone or in combination with androgen receptor pathway inhibitors. However, after an initial decrease, the cancer recurs for majority patients. At this stage, cancer is known as castration-resistant prostate cancer (CRPC). Majority of CRPC tumors still depend on androgen receptor axis for its progression to metastasis. However, in around 20-30% of cases, CRPC progresses via an androgen receptor-independent pathway and is often presented as neuroendocrine cancer (NE). This NE phenotype is highly aggressive with poor overall survival as compared to CRPC adenocarcinoma. NE cancers are resistant to standard taxane chemotherapies, which are often used to treat metastatic disease. Pathologically and morphologically, NE cancers are highly diverse and often co-exist with adenocarcinoma. Due to the lack of proper biomarkers, it is often difficult to make an early diagnosis of this lethal disease. Moreover, increased tumor heterogeneity and admixtures of adeno and NE subtypes in the same tumor make early detection of NE tumors very difficult. With the advancement of our knowledge and sequencing technology, we are now able to better understand the molecular mediators of this transformation pathway. This current study will give an update on how various molecular regulators are involved in these lineage transformation processes and what challenges we are still facing to detect and treat this cancer.

Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy.

BACKGROUND: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC. METHODS: We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system. FINDINGS: Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression. INTERPRETATION: The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. FUNDING: The funding details can be found in the Acknowledgements section.

Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen-targeted therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

Real-world economic burden associated with disease progression from metastatic castration-sensitive to castration-resistant prostate cancer on treatment in the United States.

BACKGROUND: The advent of next-generation imaging will likely reduce nonmetastatic prostate cancer (PC) prevalence and increase identification of metastatic prostate cancer cases, resulting in two predominant advanced stages in the metastatic setting. There is a need to characterize changes in health care resource utilization (HRU) and costs when metastatic castration-sensitive PC (mCSPC) progresses to metastatic castration-resistant PC (mCRPC) to identify value drivers from current and new treatments. OBJECTIVE: To describe treatment patterns, HRU, and total health care costs among patients with mCSPC, before and after progression to mCRPC. METHODS: Clinical data from the Flatiron Metastatic PC Core Registry (January 1, 2013, to December 1, 2021) and linked claims from Komodo Health (January 1, 2014, to December 1, 2021) were used to identify patients with progression from mCSPC to mCRPC (date of progression was the index date) and subsequently initiated first-line mCRPC therapy on/after January 1, 2017. Treatment patterns and all-cause/PC-related HRU and health care costs were described per-patient-per-month (PPPM), separately for no more than 12 months pre-index (mCSPC disease state) and post-index (mCRPC disease state). Costs (payer's perspective) included those for services/procedures from medical claims and costs from pharmacy claims. Continuous HRU and costs were compared between the mCSPC and mCRPC disease states using Wilcoxon signed rank tests. RESULTS: Among 296 patients with mCSPC progressing to mCRPC (median age 69.0 years, 60.5% White, 15.9% Black), use of systemic therapies with androgen deprivation therapy increased dramatically from 35.1% in the mCSPC disease state to 92.9% in the mCRPC disease state, and use of androgen deprivation therapy monotherapy decreased from 25.7% to 2.4%, respectively. Although 39.2% received none of these therapies in the mCSPC disease state, this proportion decreased to 4.7% after transition to mCRPC. The mean number of days with PC-related outpatient visits increased from 1.57 to 2.16 PPPM in the mCSPC and mCRPC disease states (P < 0.001). From the mCSPC to mCRPC disease states, mean all-cause total health care costs PPPM increased from $4,424 (medical costs: $2,846) to $9,717 (medical costs: $4,654), and mean PC-related total health care costs PPPM increased from $2,859 (medical costs: $1,626) to $8,012 (medical costs: $3,285; all P < 0.001). CONCLUSIONS: In this real-world study of patients with disease progression from mCSPC to mCRPC in US clinical practice, nearly 2-in-3 patients did not receive treatment with additional systemic therapies before progression to castration resistance. Post-progression, mean PC-related total costs increased nearly 3-fold, with a more than 2-fold increase in PC-related medical costs. Use of additional systemic therapies may delay the time and cost associated with disease progression to castration resistance.

Treatment escalation and de-escalation of de-novo metastatic castration-sensitive prostate cancer.

Androgen receptor signaling inhibitors combined with androgen deprivation therapy have become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC), regardless of tumor volume or risk. However, survival of approximately one-third of these patients has not improved, necessitating further treatment escalation. On the other hand, for patients with oligometastatic mCSPC, there is an emerging role for local radiation therapy. Although data remain scarce, it is expected that treatment of both primary tumor as well as metastasis-directed therapy may improve survival outcomes. In these patients, systemic therapy may be de-escalated to intermittent therapy. However, precise risk stratification is necessary for risk-based treatment escalation or de-escalation. In addition to risk stratification based on clinical parameters, research has been conducted to incorporate genomic and/or transcriptomic data into risk stratification. In future, an integrated risk model is expected to precisely stratify patients and guide treatment strategies. Here, we first review the transition of the standard treatment for mCSPC over the last decade and further discuss the newest concept of escalating or de-escalating treatment using a multi-modal approach based on the currently available literature.

[The Association of Docetaxel Side Effects and Introduction of Subsequent Cabazitaxel for Castration-Resistant Prostate Cancer : A Clinical Study].

The administration of cabazitaxel for patients with castration-resistant prostate cancer (CRPC) requires prior docetaxel therapy. Sequential chemotherapy may have to be discontinued due to docetaxelassociated side effects. This study investigated the relationship between treatment outcome of docetaxel and cabazitaxel and their associated side effects. We retrospectively analyzed 69 patients with CRPC who had been administered docetaxel withand without subsequent cabazitaxel at Toyonaka Municipal Hospital from October 2014 to June 2022. Twenty-eight patients (41%) discontinued docetaxel because of side effects, and the median number of docetaxel cycles at discontinuation was 2 (range : 1-11). Fourteen of these patients received no treatment following docetaxel. A comparison of the 28 patients who had discontinued docetaxel due to side effects with 41 patients who had not revealed a significant difference in the total numbers of chemotherapy cycles (2.5 vs 9 ; P＜0.001) and time to treatment failure (56 days vs 301 days ; P＝ 0.001), with a trend toward shorter overall survival from the start of docetaxel treatment (259 days vs 512 days ; P＝0.06). Multivariate analysis identified discontinuation of docetaxel due to side effects (OR＝0.07 ; P＜0.001) and lower hemoglobin (OR＝0.01 ; P＝0.001) as significant factors inhibiting the introduction of cabazitaxel. Reducing the side effects of docetaxel, including early drug switching, may allow more CRPC patients to be reached with cabazitaxel. Consequently, the resulting taxane-based chemotherapy may contribute to an additional survival advantage.

[A Case of Metastatic Prostate Cancer with Neuroendocrine Differentiation with Long-Term Survival after Multidisciplinary Therapy].

A 74-year-old man visited the urology clinic with the chief complaint of urinary retention in December 2014. Serum level of initial prostate specific antigen (PSA) was 50 ng/ml and he was diagnosed with Gleason Score 4＋4 prostate adenocarcinoma with regional lymphadenopathy (cT3aN1M0). PSA level had declined after the treatment with combined androgen blockade. In November 2018, he was diagnosed with castration resistant prostate cancer (CRPC) as local progression was detected by computed tomography (CT) while PSA level did not increase. Since local symptoms worsened, resulting in repeated hematuria after the treatment with enzalutamide, palliative radiation therapy to the prostate (45 Gy) was performed. Five months later, follow-up CT showed multiple metastasis in bilateral lung and left testicle. Serum level of neuron-specific enolase (NSE) was 24.4 ng/ml without an elevated in serum PSA level. He received rebiopsy of the prostate, but no malignant findings were observed. Consequently, bilateral orchiectomy was performed for diagnosis of left testicular tumor. Pathological examination revealed metastasis of neuroendocrine prostate cancer (NEPC). Chemotherapy using cisplatin and irinotecan was administered after orchiectomy. Complete response of lung lesions was achieved and serum level of NSE decreased within normal range. No recurrence has been confirmed for 4 years after the completion of chemotherapy.

Appropriate definition of non-metastatic castration-resistant prostate cancer (nmCRPC) and optimal timing of androgen receptor signaling inhibitor (ARSI).

BACKGROUND: Defined by rising PSA levels under androgen deprivation therapy (ADT) despite no visible metastases on conventional imaging, non-metastatic castration-resistant prostate cancer (nmCRPC) represents a complex clinical challenge. A significant subset of these patients rapidly develops metastatic disease, negatively impacting survival. We examined the difference in prognosis of nmCRPC patients according to the timing of therapeutic interventions with androgen receptor signaling inhibitor (ARSI). METHODS: We examined 102 nmCRPC patients treated with ARSI. We divided patients according to their PSA levels when ARSI was administered: Cohort A (PSA 0.5-2.0 ng/mL), Cohort B (PSA 2.0-4.0 ng/mL), and Cohort C (PSA > 4.0 ng/mL). Utilizing the Kaplan-Meier method for survival analysis, our analytical starting point was the moment when PSA levels exceeded 0.5 ng/mL post-ADT nadir, ensuring a fair comparison and minimizing lead-time bias. RESULTS: After excluding 5 patients whose PSA nadir after ADT > 0.5 ng/mL, patient distribution across Cohort A, Cohort B, and Cohort C was 32, 24, and 41 patients, respectively. Kaplan-Meier survival analysis highlighted a 2-year metastasis-free survival rate of 97% for Cohort A, 87% for Cohort B, and 73% for Cohort C. A marked statistical difference emerged when comparing Cohort A with Cohorts B and C, with a p-value of 0.043. CONCLUSION: The timely initiation of ARSI is paramount in nmCRPC management. Our findings strongly advocate for consideration of ARSI administration in nmCRPC patients before their PSA levels exceed 2.0 ng/mL. Our results indicated a PSA threshold of 1.0 ng/mL for nmCRPC definition which is more reasonable to administer ARSI without delay.

Natural History of Nonmetastatic Prostate Cancer Managed With Watchful Waiting.

Importance: It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with adverse consequences. Objective: To report transitions to androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC), death from PCa, or death from other causes in men treated with a WW strategy. Design, Setting, and Participants: This nationwide, population-based cohort study included men with nonmetastatic PCa diagnosed since 2007 and registered in the National Prostate Cancer Register of Sweden with WW as the primary treatment strategy and with life expectancy less than 10 years. Life expectancy was calculated based on age, the Charlson Comorbidity Index (CCI), and a drug comorbidity index. Observed state transition models complemented observed data to extend follow-up to more than 20 years. Analyses were performed between 2022 and 2023. Exposure: Nonmetastatic PCa. Main Outcomes and Measures: Transitions to ADT, CRPC, death from PCa, and death from other causes were measured using state transition modeling. Results: The sample included 5234 men (median [IQR] age at diagnosis, 81 [79-84] years). After 5 years, 954 men with low-risk PCa (66.2%) and 740 with high-risk PCa (36.1%) were still alive and not receiving ADT. At 10 years, the corresponding proportions were 25.5% (n = 367) and 10.4% (n = 213), respectively. After 10 years, 59 men with low-risk PCa (4.1%) and 221 with high-risk PCa (10.8%) had transitioned to CRPC. Ten years after diagnosis, 1330 deaths in the low-risk group (92.3%) and 1724 in the high-risk group (84.1%) were from causes other than PCa. Conclusions and Relevance: These findings suggest that the WW management strategy is appropriate for minimizing adverse consequences of PCa in men with a baseline life expectancy of less than 10 years.

Metastatic Castration-Resistant Prostate Cancer: Advances in Treatment and Symptom Management.

OPINION STATEMENT: The management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape and biology underpinning this form of prostate cancer. The implementation of various therapeutic agents has improved overall survival but despite the promising advances in therapeutic options, mCRPC remains incurable. The focus of treatment should be not only to improve survival but also to preserve the patient's quality of life (QoL) and ameliorate cancer-related symptoms such as pain. The choice and sequence of therapy for mCRPC patients are complex and influenced by various factors, such as side effects, disease burden, treatment history, comorbidities, patient preference and, more recently, the presence of actionable genomic alterations or biomarkers. Docetaxel is the first-line treatment for chemo-naïve patients with good performance status and those who have yet to progress on docetaxel in the castration-sensitive setting. Novel androgen agents (NHAs), such as abiraterone and enzalutamide, are effective treatment options that are utilized as second-line options. These medications can be considered upfront in frail patients or patients who are NHA naïve. Current guidelines recommend genetic testing in mCRPC for mutations in DNA repair deficiency genes to inform treatment decisions, as for example in breast cancer gene mutation testing. Other potential biomarkers being investigated include phosphatase and tensin homologues and homologous recombination repair genes. Despite a growing number of studies incorporating biomarkers in their trial designs, to date, only olaparib in the PROFOUND study and lutetium-177 in the VISION trial have improved survival. This is an unmet need, and future trials should focus on biomarker-guided treatment strategies. The advent of novel noncytotoxic agents has enhanced targeted drug delivery and improved treatment responses with favourable toxicity profiling. Trials should continue to incorporate and report health-related QoL scores and functional assessments into their trial designs.

The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis.

BACKGROUND: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. METHOD: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. RESULTS: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. CONCLUSION: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. TRIAL REGISTRATION: CRD42023454079.

Plasma microRNA Signature as Companion Diagnostic for Abiraterone Acetate Treatment in Metastatic Castration-Resistant Prostate Cancer: A Pilot Study.

Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug's efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.

Long-Term Pharmacokinetic Follow-Up of Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer.

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.

Multidisciplinary real-world management of metastatic castration-sensitive prostate cancer: A French national study (PROFILE study).

While androgen deprivation therapy (ADT) has been the standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC), recent strategies like intensification of systemic treatment (Rozet et al., 2020) (i.e. adding another treatment to ADT) and radiotherapy have improved overall survival. PROFILE, a national retrospective multicentric real-world study, involved patients with mCSPC recruited by medical oncologists, urologists, and radiation oncologists, and who started treatment between November 2020 and May 2021. Patients by sites were included consecutively. Data were collected from medical records. Primary objectives were to: (1) describe retrospectively the characteristics of whole population of patients with mCSPC as well as subgroups defined by prognostic factors in France at diagnosis; (2) identify current practices for managing mCSPC in a real-life clinical setting. Among the 416 patients with mCSPC included in the PROFILE study, 315 (76%) were synchronous (metastasis at the initial diagnosis) and 101 (24%) were metachronous patients (metastasis diagnosed post-progression). A majority (83% of synchronous and 73% of metachronous patients) received an intensified systemic treatment (ADT plus ARSI [androgen-receptor signaling inhibitors]±chemotherapy±primary tumour radiotherapy±metastasis-directed therapy [MDT]), while only 40% of low-volume patients received prostate radiotherapy. This study depicts the standardization of new therapeutic strategies for patients with mCSPC in France with most of them receiving an intensified treatment, mainly with ADT+ARSI (64% of synchronous intensified patients and 76% of metachronous intensified patients). Most of patients were assessed using conventional imaging (CT scan and/or bone scan). Overall, PROFILE results are in line with French and European guidelines for diagnosis, management, and follow-up of such patients (Rozet et al., 2020; Cornford et al., 2021).