Researchers searched PubMed/MEDLINE, the Web of Science Core Collection and Cochrane CENTRAL from database inception through 20 August 2026. The review included phase III randomized trials evaluating abiraterone, enzalutamide, apalutamide or darolutamide, regardless of whether the studies reported fracture outcomes. Twenty-two trials met the eligibility criteria. Thirteen trials, involving 13,712 participants, contributed data for all-grade fracture-related adverse events, while eight trials, involving 9,254 participants, contributed data for grade 3 or higher events.

Risk ratios were pooled with random-effects models using restricted maximum-likelihood estimation and a Hartung–Knapp adjustment. For all-grade fracture-related adverse events, the pooled risk ratio was 2.13 (95% confidence interval, 1.74–2.60), with statistical heterogeneity of 45.8% and a 95% prediction interval of 1.23–3.68. For grade 3 or higher events, the pooled risk ratio was 2.64 (95% confidence interval, 1.73–4.02), with heterogeneity of 11.8%. The corresponding pooled cumulative risk differences were 4.93 percentage points for all-grade events and 1.71 percentage points for grade 3 or higher events, although the abstract cautions that these estimates require caution because observation periods and baseline fracture risks differed among trials.

Exploratory analyses suggested possible differences among the four agents, but no interaction was observed by prostate cancer disease state. These subgroup findings were based on indirect comparisons and were imprecise in several groups. The direction of the associations remained statistically stable in sensitivity and rare-event analyses, but differences in fracture definitions and treatment exposure across trials remained unresolved. The findings therefore describe associations with adverse events as reported in randomized trials, rather than establishing a uniform fracture risk for every individual receiving an ARPI-containing regimen.

Subject of Research: Reported fracture adverse-event risks with androgen receptor pathway inhibitor-containing therapies for prostate cancer

Article Title: Evaluation of bone fracture risk among men with prostate cancer treated with androgen receptor pathway inhibitor-containing therapies: a systematic review and meta-analysis

Article References: Zhu, J., Zhang, A., Jing, W., & Zhang, F. (2026). Evaluation of bone fracture risk among men with prostate cancer treated with androgen receptor pathway inhibitor-containing therapies: a systematic review and meta-analysis. BMC Cancer. https://doi.org/10.1186/s12885-026-16982-4

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16982-4

Keywords: prostate cancer, androgen receptor pathway inhibitors, fracture risk, adverse events, systematic review, meta-analysis, randomized trials, abiraterone, enzalutamide, apalutamide, darolutamide, Evaluation

The research team, led by Taketo Kawai of the National Center for Global Health and Medicine together with colleagues from Astellas Pharma Inc., mined the Medical Data Vision database, one of Japan’s largest hospital-based administrative data resources covering approximately 30 percent of the nation’s Diagnosis Procedure Combination hospitals. Their goal was to move beyond the carefully selected populations of phase 3 clinical trials and measure how modern prostate cancer therapies actually perform in routine clinical practice, where patients are older, carry more comorbidities, and are managed under the constraints of a universal health insurance system.

The therapeutic landscape they examined has shifted dramatically over the past decade. For most of modern oncology history, advanced prostate cancer was treated with androgen-deprivation therapy, or ADT, which suppresses the testosterone that fuels tumor growth, often supplemented by older nonsteroidal antiandrogens such as bicalutamide and flutamide. Beginning in 2018, however, Japan approved a wave of androgen receptor signaling inhibitors—abiraterone, followed by enzalutamide and apalutamide in 2020, and darolutamide combined with docetaxel chemotherapy in 2023—that block the androgen receptor pathway more aggressively. Phase 3 trials had already shown these agents extend overall survival when added to ADT, but Japanese guidelines stop short of telling physicians which specific inhibitor to choose.

To capture treatment effects with precision, the investigators constructed two overlapping cohorts. The first, comprising 1,306 men with measurable prostate-specific antigen, or PSA, records, allowed the team to track biochemical responses to therapy. The second, encompassing all 11,737 eligible patients regardless of PSA data availability, enabled broader analyses of how long patients stayed on treatment and whether they survived. The primary endpoint was the proportion of patients achieving a 90 percent or greater reduction in PSA—a blood marker that correlates closely with tumor burden—during the first-line treatment period, with secondary measures including 50 percent PSA reductions, deep responses to 0.2 nanograms per milliliter or below, time to PSA progression, and time to treatment discontinuation.

The results were striking. At three months, cumulative PSA90 response rates reached 91.8 percent for ADT plus enzalutamide, 90.9 percent for ADT plus apalutamide, and 90.7 percent for ADT plus abiraterone, with the newer triplet regimen of darolutamide, docetaxel, and ADT achieving 81.2 percent. By contrast, only 69.3 percent of men on ADT plus older nonsteroidal antiandrogens and 63.2 percent of those on ADT alone had achieved the same threshold. After statistical adjustment for age, comorbidities, metastasis sites, hospital size, and baseline PSA, the advantages of the androgen receptor signaling inhibitors remained highly significant. The pattern held for deeper responses as well: by twelve months, nearly 80 percent of enzalutamide patients had driven PSA to 0.2 nanograms per milliliter or lower, compared with just 30.3 percent on ADT alone.

Equally important, the modern regimens delayed disease progression. Median time to PSA progression stretched to approximately 35 months for enzalutamide, 33.6 months for abiraterone, and 33.4 months for apalutamide, versus 23.8 months for ADT alone and a mere 15.2 months for ADT combined with older antiandrogens. Notably, no statistically significant differences emerged among the androgen receptor signaling inhibitors themselves on any PSA-related endpoint, suggesting that in biochemical terms the newer agents perform comparably. Sensitivity analyses that varied treatment gap definitions, follow-up windows, and baseline PSA measurements confirmed the robustness of these findings.

Treatment duration told a more nuanced story. In the full cohort, men on ADT plus enzalutamide remained on first-line therapy for a median of 32.4 months and those on abiraterone for 28.6 months, while the darolutamide triplet had not yet reached its median. ADT alone lasted a median of 12.9 months and ADT plus older antiandrogens only 10.7 months. Yet apalutamide stood out with a significantly shorter median duration of 19.5 months, despite PSA responses and progression times indistinguishable from its peers. Because the database does not record why patients stop treatment, the authors speculate that tolerability issues, patient and physician preferences, or switching behavior—apalutamide patients more often moved to another inhibitor—likely explain the gap rather than inferior efficacy.

Survival signals reinforced the case for treatment intensification. After adjustment, non-abiraterone inhibitor regimens were associated with significantly lower mortality risk than conventional therapy, with enzalutamide, apalutamide, and the darolutamide triplet each showing reduced risk of in-hospital death compared with ADT alone or ADT plus older antiandrogens. The darolutamide triplet demonstrated the lowest death risk of all, though the authors caution this result is difficult to interpret because the regimen was only approved in 2023, leaving small patient numbers and short follow-up. The analysis also revealed a striking pattern in treatment selection: patients receiving the newer inhibitors were generally younger than those on conventional therapy, hinting that age, comorbidity burden, and even Japan’s cost-sharing caps under the High-Cost Medical Expense Benefit system shape who gets intensified treatment.

The study’s authors are candid about its limitations. The database captures primarily hospital-based care, potentially overrepresenting larger specialized institutions; PSA data were available from only about 10 percent of contributing facilities; reasons for discontinuation, disease severity, imaging results, and pathology details were not recorded; and mortality was limited to in-hospital deaths. Race and ethnicity variables were absent, and retrospective claims analyses are always vulnerable to unmeasured confounding. Still, the consistency of the PSA findings across multiple sensitivity analyses, and their close alignment with prior clinical trial results, lends considerable weight to the conclusions.

For the roughly 96,000 Japanese men diagnosed with prostate cancer each year, the message is clear and consequential. Adding a modern androgen receptor signaling inhibitor to hormone deprivation produces faster, deeper PSA declines, delays progression by more than a year, extends time on effective therapy, and appears to improve survival compared with the older standard of care. But the equally important lesson may be that drug choice within this class is not merely a biochemical decision. Adverse event profiles, patient background, financial considerations, and the preferences of patients and their physicians all shape whether a treatment is sustained. As the authors conclude, these real-world factors deserve careful weight when clinicians and patients choose among therapies that, on paper, look remarkably alike.

Subject of Research: Real-world effectiveness of androgen receptor signaling inhibitors as first-line therapy for metastatic castration-sensitive prostate cancer in Japan

Article Title: Real-World Longitudinal Treatment Outcomes for Patients with Metastatic Castration-Sensitive Prostate Cancer in Japan

Article References: Kawai, T., Kiyonaga, F., Uno, S., Shibata, H., & Saito, A. (2026). Real-World Longitudinal Treatment Outcomes for Patients with Metastatic Castration-Sensitive Prostate Cancer in Japan. Advances in Therapy. https://doi.org/10.1007/s12325-026-03759-1

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03759-1

Keywords: prostate cancer, metastatic castration-sensitive prostate cancer, androgen deprivation therapy, androgen receptor signaling inhibitors, enzalutamide, apalutamide, abiraterone, darolutamide, PSA response, real-world evidence, Japan, treatment outcomes

The research, led by Zihao Deng, Lifang He, and colleagues under corresponding author Yukun Cui at the Cancer Hospital of Shantou University Medical College, tackles a phenomenon known as lineage plasticity. This is the capacity of cancer cells to shed their original identity and adopt alternative cell states when pressured by therapy, a behavior increasingly recognized as a major driver of treatment resistance in prostate cancer and other tumors. In the androgen receptor-low or androgen receptor-null state, prostate cancer cells build extensive epigenetic barriers: their chromatin, the packaged form of DNA inside the nucleus, becomes inaccessible, and the three-dimensional architecture of the genome locks into a repressive topology that keeps the androgen receptor gene and its regulatory elements silenced. How that locking-in happens, and whether it can be reversed, has remained poorly understood.

KIF11, also known as kinesin family member 11, is best known as a mitotic kinesin, a motor protein that drives spindle assembly during cell division and has long been pursued as a chemotherapy target. Existing KIF11 inhibitors tend to work at cytotoxic doses that halt division in any rapidly proliferating cell. The Shantou team took a different angle. Combining public transcriptomic and epigenomic datasets with their own RNA sequencing, ATAC-seq chromatin accessibility profiling, RNA interference, low-dose pharmacological inhibition with the KIF11 inhibitor ispinesib, chromatin immunoprecipitation, chromosome conformation capture, DNA methylation assays, and reporter and therapeutic-response experiments, they asked what happens to prostate cancer cells when KIF11 activity is reduced gently rather than destroyed completely.

The answer surprised them. In androgen receptor-low and androgen receptor-null prostate cancer models, including PC3 and DU145 cells, either RNAi-mediated depletion or low-dose pharmacological inhibition of KIF11 activated androgen receptor-associated transcriptional programs. The cells began, in effect, to remember who they were supposed to be. Chromatin accessibility increased at androgen receptor regulatory regions, and the team measured higher occupancy of FOXA1 and GRHL2, two pioneering transcription factors that act as gatekeepers of the androgen receptor enhancer, at that key regulatory element. At the same time, the co-activator EP300 and the transcription elongation factor SUPT5H showed increased occupancy at androgen receptor regulatory elements, signaling that the locus was not merely open but actively engaged in productive transcription.

The mechanism went deeper than transcription factor recruitment. Using chromosome conformation capture techniques, the researchers showed that KIF11 inhibition reduced DNA methylation at CTCF motifs, the DNA sequences recognized by the CCCTC-binding factor, an architectural protein that anchors loops in the genome. With methylation lifted, CTCF occupancy rose, and the physical communication between enhancers and the androgen receptor promoter strengthened. In other words, KIF11 inhibition did not simply sprinkle activating marks on the genome; it rebuilt the three-dimensional wiring of the androgen receptor locus, constructing enhancer-promoter loops that bring distant regulatory elements into direct contact with the gene they control.

That topological resetting proved remarkably stable. Once the enhancer-promoter architecture was established, it locked in a sustained androgen receptor transcriptional program and created a feed-forward reinforcement circuit in which the reactivated pathway maintained its own expression. Functionally, this drove what the authors describe as a lineage return: androgen-insensitive, androgen receptor-low or null prostate cancer cells transitioned back into an androgen receptor-responsive transcriptional state. The change was not cosmetic. With the androgen receptor machinery restored, the cells regained the very dependency that antiandrogen drugs exploit.

The therapeutic consequences were tested across multiple model systems. In cell-line experiments, patient-derived castration-resistant prostate cancer organoids, and xenograft models in mice, low-dose KIF11 inhibition combined with enzalutamide or apalutamide produced robust growth suppression in tumors that would normally ignore these drugs. Crucially, the KIF11 inhibition used in these experiments was deliberately kept at low, non-cytotoxic doses, avoiding the broad toxicity that would come with hitting every dividing cell. The strategy is therefore conceptually distinct from conventional chemotherapy: rather than killing cancer cells directly, the treatment reprograms their regulatory architecture so that a second, well-tolerated class of drugs can work again.

The findings carry significant implications for how lineage plasticity-driven resistance might be overcome in the clinic. If a subset of patients with androgen receptor-low or null disease could be identified, perhaps through biopsy-based profiling of KIF11 levels, CTCF methylation status, or androgen receptor locus topology, they might become candidates for a re-sensitization strategy in which short-term KIF11 inhibition converts their tumors into androgen receptor-dependent ones before initiating or resuming antiandrogen therapy. The authors note that Y. Cui and Z. Deng have filed a patent application related to the findings, suggesting momentum toward translational development. At the same time, the work remains at the preclinical stage, and questions about dosing windows, patient selection, and safety in humans will need to be addressed in future studies.

Scientifically, the study adds an important dimension to a growing body of work showing that cancer is as much a disease of genome architecture as of genome sequence. The idea that inhibiting a mitotic motor protein could demethylate CTCF sites, reopen chromatin, reorganize enhancer-promoter loops, and ultimately restore a whole lineage identity illustrates how deeply intertwined cell division machinery, epigenetics, and three-dimensional genome organization really are. For patients with castration-resistant prostate cancer whose tumors have gone androgen-receptor silent, the research offers a conceptually elegant possibility: the door that cancer slammed shut can, with the right molecular key, be opened again, and the treatments already on the shelf may once more find their target.

Subject of Research: KIF11 inhibition as a lineage-remodeling strategy to restore androgen receptor signaling and antiandrogen sensitivity in castration-resistant prostate cancer

Article Title: KIF11 inhibition remodels lineage state and sensitizes castration-resistant prostate cancer to antiandrogen therapy via enhancer–promoter looping

Article References: Deng, Z., He, L., Li, J., She, S., Luo, X., Lin, J., Qi, Z., Zhuang, Y., Gao, X., Chi, Z., Xu, Z., Ji, Y., Liu, J., Lin, S. L., & Cui, Y. (2026). KIF11 inhibition remodels lineage state and sensitizes castration-resistant prostate cancer to antiandrogen therapy via enhancer–promoter looping. Molecular Cancer. https://doi.org/10.1186/s12943-026-02792-6

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02792-6

Keywords: KIF11, castration-resistant prostate cancer, androgen receptor, lineage plasticity, enhancer-promoter looping, CTCF, epigenetics, enzalutamide, apalutamide, FOXA1, patient-derived organoids, drug resistance