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Open research questions in Prostate Cancer Treatment and Research

62 unresolved questions extracted from the limitations and future-work sections of 451 Prostate Cancer Treatment and Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The PRIMARY scoring system, using the intraprostatic PSMA-pattern was developed and tested using [ 68 Ga]Ga-PSMA-11 and proposed to be universal across PSMA-ligands, however no data on [ 18 F]PSMA-1007 for biopsy guidance exists.

    Prospective evaluation of the PRIMARY score using [18F]PSMA-1007 PET/MRI in second-line prostate biopsies after negative MRI · 2026 · DOI

  • Although intraductal carcinoma of the prostate and cribriform architecture are associated with genomic instability and poor prognosis, their value as surrogate markers of BRCA1/2 alterations remains uncertain.

    BRCA Testing in Prostate Cancer: A Histopathologist’s Perspective · 2026 · DOI

  • The mechanisms by which prostate cancer (PCa) cells survive Enzalutamide therapy are poorly understood, but androgen receptor (AR) and non-AR mediated mechanisms have been reported.

    Abstract B004: Analysis of proteomic changes in enzalutamide-resistant prostate cancer cells and identification of potential therapeutic targets for drug repurposing · 2026 · DOI

  • 5{beta}-dihydrotestosterone (5{beta}-DHT) is a naturally occurring testosterone metabolite generally considered androgenically inactive because it binds wild-type AR weakly, yet its activity against clinically relevant AR mutants has not been systematically evaluated.

    5β-Dihydrotestosterone reveals a mutant androgen receptor vulnerability in prostate cancer · 2026 · DOI

  • Advancements in immunology and the mechanisms of tumor immune evasion have positioned immuno- therapy as a revolutionary treatment approach across oncology, as seen in melanoma, renal cell carcinoma, breast cancer, and lung cancer.[54] These outcomes sparked interest in immunotherapy for metastatic prostate cancer. In this review, we will focus on immune checkpoint inhibitors (ICIs). Programmed death (PD) inhibitors, such as nivolumab and pembro- lizumab, enable immune targeting of tumor cells. Following an immune response, the immune system downregulates itself via cytotoxic T-lymphocyte–asso- ciated protein 4 (CTLA-4). CTLA4 inhibitors like ipili- mumab perpetuate the immune response to target tumor cells.[55] In 2011, the FDA first approved ipili- mumab for advanced melanoma, as it demonstrated improved OS.[56] Immunotherapy in metastatic castration- resistant prostate cancer (mCRPC) Despite the success in other tumor types, trials assess- ing the efficacy of immunotherapy in prostate cancer have not been compelling. In 2014, Kwon et al[57] found no difference in OS in patients with mCRPC who pro- gressed after chemotherapy and received ipilimumab, although they noted a slight benefit in PFS. These results were largely replicated in 2016 in chemotherapy-naive mCRPC, although with slightly improved PFS and PSA response rates.[58] For pembrolizumab, the phase 1b KEYNOTE-028 trial showed initial promise against mCRPC.[59] Of the 23 patients who received pembrolizumab, 4 had partial responses (objective response rate [ORR] 17.4%, 95% CI, 5.0%–38.8%). Pembrolizumab resulted in a mean duration of response of 13.5 months and increased median PFS and OS in heavily pretreated programmed death ligand 1 (PD-L1)-positive mCRPC. The subse- quent phase II KEYNOTE-199 trial evaluated pembroli- zumab in mCRPC with prior docetaxel and one or h t t p : / / c r e a t i v e c o m m o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / l D o w n o a d e d f r o m h t t p s : / / i n n o v a t i o n s o u r n a s - j i l j l p o . k g m e r i d a n . c o m a t i 2 0 2 6 - 0 7 - 0 6 i v a O p e n A c c e s s . i T h s w o r k i s p u b l i s h e d u n d e r - - a C C B Y N C N D 4 - . 0 I n t e r n a t i o n a l i L c e n s e .

    Emerging Therapeutic Strategies in Metastatic Hormone-Sensitive Prostate Cancer · 2026 · DOI

  • These observations highlight GPER1’s potential as a promising chemopreventive target and warrants studies to test GPER1 agonists for PCa chemoprevention in humans.

    Abstract P105: GPER1 (G-protein Coupled Estrogen Receptor 1): A Molecular Target for Prostate Cancer Chemoprevention · 2026 · DOI

  • For abiraterone, the mechanism of hepatic injury remains incompletely defined, but available evidence suggests that it may relate both to CYP17 inhibition and to hepatic metabolism through cytochrome P450 pathways, particularly CYP3A4 and CYP2D6, with possible formation of toxic or immunogenic intermediates[30-32].

    Exploring the relationship between potential hepatotoxicity and novel hormonal therapies in prostate cancer: a systematic review and meta-analysis · 2026 · DOI

  • Furthermore, optimized criteria for response assessment using 177Lu-PSMA SPECT/CT remain elusive. However, direct head-to- head comparisons between 177Lu-PSMA SPECT/CT and CT/BS are lacking, limiting our ability to position SPECT/CT within the broader imaging landscape.

    Prognostic value of interim post-treatment SPECT/CT following lutetium-177 (177Lu)-PSMA therapy in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis · 2026 · DOI

  • Within each basket, PFS superiority was identified for the pancreas, prostate, and "Other" baskets, whereas the breast and kidney baskets were inconclusive.

    Addition of Metastasis-Directed Therapy to Standard of Care for Oligometastatic Solid Tumors: Primary Analysis of All Tumor-Histology Baskets of the Phase II Randomized EXTEND Trial · 2026 · DOI

  • Conclusions: From this review, although still based on limited literature evidence and mostly derived from retrospective and small SCPC sub-cohorts,18F-FDG PET/CT currently appears as the most reliable tracer for SCPC, aiding tumor detection and prognostication when PSMA/choline imaging fails.

    The Role of PET Tracers in Small-Cell Prostate Cancer (SCPC): An Overview in Clinical and Preclinical Settings · 2026 · DOI

  • This case suggests that darolutamide plus ADT, administered as a tailored perioperative intensified systemic strategy, may induce a rapid and profound PSA response and may be associated with pCR in selected patients with very high-risk LAPC, while further investigation is warranted.

    Pathological complete response to perioperative treatment with darolutamide plus ADT in locally advanced prostate cancer without PTEN or RB1 loss: a case report · 2026 · DOI

  • • FOXA1 is a good addition to immunohistochemical panels used for the diagnosis of prostate cancer, especially when the morphology is poorly differentiated or there is a suspicion of small cell/neuroendocrine differentiation. It is recommended to use a combination of the marker panel (FOXA1, NKX3.1, PSA, and NE markers (e.g., synaptophysin and chromogranin), to enhance the accuracy of diagnosis and decrease the risk of misclassification of tumour origin. • • Large-scale, prospective studies are recommended to confirm the use of FOXA1 as a diagnostic and perhaps prognostic biomarker in other populations including with relation to clinical outcome, such as survival and treatment response. • Further studies using molecular techniques to probe the role of FOXA1 in mechanism of tumor progression, and lineage plasticity in prostate cancer should be promoted to elucidate its biological importance in prostate cancer evolution. In order to achieve a uniform immunohistochemical scoring system and to increase interobserver agreement in the diagnostic routine, 5. It is recommended that the scoring systems for FOXA1 immunohistochemistry be standardized.

    Histopathological and Immunohistochemical Evaluation of FOXA1 as a Robust Diagnostic Marker in Prostate Cancer · 2026 · DOI

  • Overall, PDT benefits appear confined to low-volume dis- ease, and its added value with intensified systemic therapy remains unclear. In clinical practice, MDT should complement, not replace, systemic therapy, and its optimal integration—including timing and dura- tion—remains to be established.

    Primary site- and metastasis-directed therapies in patients with metastatic prostate cancer: A narrative review · 2026 · DOI

  • In addition, although specificity for local lesions was relatively low in the present study, it may be limited by the small sample size in this subgroup (false positive = 2, true negative = 1), while the high sensitivity remains clini- cally meaningful.

    Diagnostic impact of interpretation criteria for [18F]PSMA-1007 PET/CT: Prospective comparison with CT and bone scan · 2026 · DOI

  • The 15 participants that were not available for the gen- eration of the 6th month data in the ADT group (Fig. 1) were excluded from further analyses. Undoubtedly, this approach may have influenced the study outcome. The Nnabugwu et al. African Journal of Urology (2026) 32:38 need for assistance by some participants to complete the study questionnaires could have influenced their responses. It is also possible that the absence of random- ization may have influenced the nature of the partici- pants in the subgroups. The small number of participants in the GnRHa subgroup increases the risk of overfitting in the multivariate analysis. The use of Ugandan health value set for Nigerians may also have affected the derived utilities.

    Quantifying the short-term gains in health-related quality of life from androgen deprivation therapy in metastatic hormone-naïve prostate cancer · 2026 · DOI

  • The observed differences between groups should be interpreted in the context of a non-randomized design, as treatment allocation was influenced by the temporal implementation of SBRT and clinical decision-making, introducing potential selection bias, an inherent limitation of observational comparative studies (23, 28, 29). Additionally, differences in baseline characteristics, dosimetric parameters, and organ-at-risk constraints between MHRT and UHRT may have contributed to the observed toxicity patterns, and residual confounding related to treatment planning cannot be excluded. Follow-up duration differed significantly between groups due to the sequential implementation of ultra-hypofractionated radiotherapy within institutional practice. Therefore, late toxicity outcomes in the UHRT cohort, particularly erectile dysfunction, should be interpreted with caution, as the shorter median follow-up duration may underestimate the true incidence of delayed adverse events that typically develop over longer observation periods. Toxicity assessment was based on clinician-reported outcomes using CTCAE criteria rather than validated patient-reported out- come measures (PROMs), which may underestimate subjective symptoms such as urinary or sexual dysfunction and represents a potential source of measurement bias. Future studies incorporating PROMs are warranted to provide a more comprehensive assess- ment of treatment-related toxicity. Furthermore, longer follow-up is required to fully characterize early late toxicity and long-term oncologic outcomes, as demon- strated in extended analyses of randomized hypofractionation trials (30). Finally, the association observed between the NCCN risk group and early late toxicity should be interpreted with caution. The large effect estimates and wide confidence intervals likely reflect sparse data and a limited number of events in the reference category, which may result in model instability and overestimation of effect size. Therefore, these findings should be considered indicative of the direction of association rather than precise estimates. The higher frequency of erectile dysfunction observed in the moderately hypofractionated group compared with the SBRT group should be interpreted with caution, as the magnitude of this difference exceeds that reported in randomized trials such as PACE-B (11), where SBRT demonstrated a comparable toxicity profile. This finding may reflect residual confounding or differences in baseline characteristics and outcome assessment inherent to the study design and should therefore be considered exploratory.

    Acute and late toxicity in prostate cancer patients treated with moderately vs ultra-hypofractionated radiotherapy · 2026 · DOI

  • While previous findings were limited by the lack of an adequate control group [7], the current comparative analysis supports and strengthens the hypoth- esis that kidney function gradually declines over time as a direct result of 177Lu-PSMA I&T and not as part of disease progression or aging.

    Assessment of nephrotoxicity following lutetium-177 PSMA I&T radioligand therapy: a comparative study with docetaxel chemotherapy · 2026 · DOI

  • The radiation dosimetry estimates and absorbed dose calculations for 89Zr-PSMA-617 require validation in larger patient populations with more diverse body compositions and disease burdens to establish organ-specific absorbed dose thresholds relevant for early biochemical recurrence detection in PSA ≤ 0.2 ng/mL patients.

    Zirconium-89-based PSMA PET/CT with delayed imaging for early detection of biochemical recurrence in prostate cancer patients with PSA ≤ 0.2 ng/mL: A feasibility study · 2026 · DOI

  • The study does not systematically investigate how delayed imaging timepoints (beyond standard 24-48 hour intervals) with 89Zr-PSMA-617 affect lesion detection rates in ultra-low PSA (≤0.2 ng/mL) prostate cancer patients, particularly regarding optimization of imaging windows for kinetic pharmacokinetic analysis.

    Zirconium-89-based PSMA PET/CT with delayed imaging for early detection of biochemical recurrence in prostate cancer patients with PSA ≤ 0.2 ng/mL: A feasibility study · 2026 · DOI

  • The feasibility study with 89Zr-PSMA-617 PET/CT in biochemical recurrence patients with PSA ≤ 0.2 ng/mL lacks comparison of detection sensitivity and specificity against established 68Ga-PSMA tracers ([68Ga]Ga-PSMA-11, [68Ga]Ga-PSMA I&T, [18F]PSMA-1007) in the same patient cohort to establish the clinical advantage of the longer half-life zirconium-89 radioisotope.

    Zirconium-89-based PSMA PET/CT with delayed imaging for early detection of biochemical recurrence in prostate cancer patients with PSA ≤ 0.2 ng/mL: A feasibility study · 2026 · DOI

  • Given many patients were treated with MDT and/or ADT, clinical implication of the findings remains to be elucidated to guide treatment intensification based on findings on 18F-DCFPyL PET.

    Total and anatomically contextualized quantitative <sup>18</sup>F-DCFPyL PET at biochemical recurrence to predict subsequent biochemical progression-free survival in patients with prostate cancer. · 2024 · DOI

  • 33 Background: PSMA PET has been shown to detect more metastasis and alter management at biochemical recurrence (BCR), but it remains to be determined that it changes oncologic outcome.

    Total and anatomically contextualized quantitative <sup>18</sup>F-DCFPyL PET at biochemical recurrence to predict subsequent biochemical progression-free survival in patients with prostate cancer. · 2024 · DOI

  • However, the evidence of the outcome of these treatments is limited and no studies have been conducted comparing biochemical failure (BF) and toxicity associated with surgical treatment and EBRT + high-dose brachytherapy (HDBT) in the region.

    Biochemical failure and toxicity in treatment with brachytherapy and external beam radiotherapy compared with radical prostatectomy in localized prostate cancer · 2022 · DOI

  • CONCLUSIONS: The association between the presence of the TMPRSS2-ERG fusion and the different capability of inflammatory cells to infiltrate malignant structures has not been reported so far.

    Infiltration of Prostate Cancer by CD204+ and CD3+ Cells Correlates with ERG Expression and TMPRSS2-ERG Gene Fusion · 2018 · DOI

  • The absence of ERG expression may reflect populationspecific molecular patterns or archival tissue limitations and warrants further investigation.

    Expression of Phosphatase-Tensin Homolog and Erythroblast Transformation-Specific Related Genes in Prostate Carcinoma Cases Seen at Osun State University Teaching Hospital, Osogbo, Osun State, Nigeria: A 5-Year Retrospective Observational Study · 2026 · DOI

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62 open questions have been extracted from the limitations and future-work passages of 451 Prostate Cancer Treatment and Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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