Search Results (172)

Background/Objectives: High-risk prostate cancer is a biologically heterogeneous group of tumors carrying a substantial risk of progression to lethal, castration-resistant disease. Although androgen deprivation therapy (ADT) remains the therapeutic backbone, nearly all advanced disease eventually progresses to castration-resistant prostate cancer (CRPC) through Darwinian clonal evolution under sustained therapeutic pressure. This narrative review reframes high-risk prostate cancer management as an effort to reprogram the evolutionary trajectory and delay castration resistance, addressing current risk stratification, androgen receptor (AR)-dependent and AR-independent mechanisms of resistance, and multidisciplinary strategies that modify selective pressure. Methods: A narrative review of the literature was conducted, including peer-reviewed studies, pivotal phase III trial reports, and current clinical practice guidelines indexed in PubMed, Scopus, and Web of Science up to 2026. Sources on high-risk and castration-resistant prostate cancer, the biology of treatment resistance, and multidisciplinary treatment intensification were selected and synthesized. Results: Treatment intensification has been extended to high-risk biochemical recurrence (EMBARK), directed by biomarkers in PTEN-deficient disease (CAPItello-281), and moved earlier through prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PSMAfore, PSMAddition). In localized disease, effective AR-pathway intensification with abiraterone (STAMPEDE) contrasts with the failure of chemotherapy (PEACE-2) and enzalutamide (ENZARAD). Emerging therapies targeting lineage plasticity exploit its dynamic and potentially reversible biology, raising the prospect of reversing established resistance rather than merely delaying it. CAPItello-281 and PSMAddition have immature overall survival data and are not yet standard of care. Conclusions: Coordinated multidisciplinary care, matched to the disease stage and molecular context, offers a realistic path to delay castration resistance and improve survival. Full article

Preclinical models play a critical role in the development of PSMA-targeted radiopharmaceuticals for prostate cancer. However, many existing models have practical limitations, including slow tumor growth, low engraftment rates, and restricted availability, and all human PSMA-positive lines are confined to immunodeficient hosts. We developed and characterized a novel PSMA-expressing transgenic cell line, CT26-PSMA, as a practical tool for preclinical screening of PSMA-targeting agents. The CT26-PSMA cell line was established by stable transfection of the murine colon carcinoma CT26 cell line with human PSMA using the Sleeping Beauty transposon system. PSMA expression was confirmed by RT-qPCR (reverse transcription quantitative polymerase chain reaction), flow cytometry, and radioligand saturation binding on intact cells. Two [⁶⁸Ga]Ga-labeled radioconjugates—the well-established PSMA-617 and a newly synthesized conjugate (Conjugate-1)—were used to validate the functionality of the model through in vitro binding, uptake and internalization studies, and through ex vivo biodistribution in CT26-PSMA tumor-bearing athymic male nu/nu mice. The CT26-PSMA cell line demonstrated high and stable PSMA expression, with approximately 95% of cells expressing the biomarker and no measurable loss over 16 passages in antibiotic-free medium. Saturation binding gave a receptor density of ∼3.5 × 10⁶ sites per cell, approximately four-fold higher than that of LNCaP cells (∼0.8 × 10⁶), with dissociation constants that were indistinguishable between the two radioconjugates and between the two cell lines (K_d 9.0–11.6 nM). Subcutaneous tumors reached ~300 mm³ within 8–10 days of inoculation, with a take rate of 10/10 versus 1/10 for LNCaP (Fisher’s exact test, p = 1.2 × 10⁻⁴). Both radiotracers showed saturable, 2-PMPA-blockable binding and uptake in CT26-PSMA cells, confirming the functional activity of the recombinant receptor. Biodistribution studies revealed accumulation of both conjugates in CT26-PSMA tumors, with generally comparable tumor-to-background profiles. The CT26-PSMA cell line represents a robust, rapid, and reproducible platform for preclinical evaluation of PSMA-targeting radiopharmaceuticals, and its murine BALB/c origin permits engraftment in immunocompetent or minimally immunosuppressed hosts, whereas existing human PSMA-positive lines do not. It is intended as a screening platform rather than as a model of prostate cancer biology. The validation data obtained with [⁶⁸Ga]Ga-labelled conjugates confirm the suitability of this cell line for future studies of PSMA-directed compounds. Full article

Background/Objectives: Because human prostate cancer (PCa) typically exhibits slow tumor growth, establishing reliable PCa tumor models is often time-consuming and unpredictable, thereby limiting the efficiency of preclinical theranostic research. To overcome this limitation, this study employed a non-viral PiggyBac transposon system to introduce triple-reporter genes into PSMA-expressing C4-2 cells, generating orthotopic and subcutaneous xenograft models that allow noninvasive, real-time monitoring of PCa progression and treatment response. Methods: Reporter-engineered C4-2 3R cells were generated by co-transfecting constructs encoding the reporter cassette and PB transposase, followed by enrichment through fluorescence microscopy and fluorescence-activated cell sorting (FACS) and implantation orthotopically or subcutaneously into mice. Tumor growth and treatment response to a single 2 Gy X-ray dose followed by 14.8 MBq of ¹⁷⁷Lu-PSMA-617, or to each monotherapy, were monitored weekly using an IVIS imaging system. Imaging findings were validated by tumor dissection and hematoxylin and eosin (H&E) staining, while PSMA expression was assessed by Western blotting and ¹⁸F-PSMA-1007 PET/CT. Results: C4-2 3R cells stably expressed the triple reporter genes (mRFP, luc2, and HSV1-tk), generating detectable orthotopic bioluminescence within one week and persisting for at least five weeks. In contrast, subcutaneous implantation generated only transient luc2 signals with no tumor formation. X-ray exposure did not increase total PSMA levels but induced the redistribution of PSMA to the cell membrane. Combined external beam radiotherapy (EBRT) and ¹⁷⁷Lu-PSMA-617 treatment produced higher ¹⁸F-PSMA-1007 uptake and stronger tumor suppression, with minimal residual tumor mass, as compared to single-treatment or control groups. Conclusions: This preliminary investigation suggests that the C4-2 3R model provides a practical and trackable tool for investigating slow-growing PCa tumors and evaluating PSMA-targeted therapies, either alone or in combination with EBRT. Full article

Objectives: Eligibility for Lutetium-177 labeled prostate-specific membrane antigen ([¹⁷⁷Lu]Lu-PSMA) radioligand therapy depends on PSMA PET/CT interpretation and may vary across observers and centres. We aimed to identify imaging and clinical correlates of VISION-like PSMA PET-defined eligibility and to compare exploratory clinical, PET-based, and combined models. Materials and Methods: Seventy-six consecutive patients with de novo metastatic prostate cancer undergoing PSMA PET/CT were retrospectively assessed for [¹⁷⁷Lu]Lu-PSMA eligibility. Candidacy was determined by consensus of two nuclear medicine physicians using VISION-like criteria. Three stepwise logistic regression models used clinical variables, PSMA PET/CT variables, or both, and were internally validated with bootstrap out-of-bag predictions. Results: Forty-three patients (56.6%) met VISION-like criteria for RLT. Internally validated area under the curve (AUC) values were 0.731, 0.817, and 0.829 for the clinical, PSMA PET/CT, and combined models. PET-defined candidacy was associated with higher PSMA-positive lesion count, greater PET-derived tumour burden, and higher mean standardised uptake value (SUVmean). Clinically, CHAARTED low-volume disease and prior docetaxel exposure were linked to lower probability, whereas disease state at imaging was not significant. In the combined multivariable model, SUVmean was independently associated with higher candidacy (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.04–1.42; p = 0.015), whereas prior docetaxel showed the opposite association (OR: 0.10, 95% CI: 0.0129–0.776; p = 0.028). Conclusions: PSMA-positive lesion count and SUVmean were the most reproducible determinants of VISION-like eligibility. Prior docetaxel exposure was associated with lower candidacy in the combined model, although the exposed subgroup was small and the confidence interval wide. Whether systemic therapy modifies PSMA expression, and with it access to subsequent PSMA-targeted lines, requires paired imaging before and after treatment in the same patients. Full article

Glioblastoma multiforme (GBM) is the most common brain tumor in the adult population, and it is characterized by poor prognosis; thus, new treatment strategies are strongly needed. Precision medicine is a rapidly growing field in oncology that identifies specific molecular features of tumor cells and allows theranostic strategies (combining diagnosis and therapy). In nuclear medicine, prostate-specific membrane antigen (PSMA) represents an interesting molecular target in theranostics, considering its involvement in the neoangiogenesis of many kinds of tumors, including GBM. In this narrative review, we performed a web-based literature search to explore the current evidence regarding PSMA-targeted nuclear medicine theranostics in GBM, highlighting diagnostic applications, therapeutic potential, and future clinical perspectives. Full article

PSMA PET/CT imaging biomarkers are increasingly investigated as predictors of response and survival outcomes following [¹⁷⁷Lu]Lu-PSMA radioligand therapy in prostate cancer. This review summarizes the current evidence and clinical relevance of these biomarkers. As [¹⁷⁷Lu]Lu-PSMA radioligand therapy is increasingly being introduced into earlier treatment lines of prostate cancer management, the identification of reliable imaging biomarkers for response prediction and outcome assessment is becoming increasingly important. Quantitative PSMA PET/CT parameters such as whole-body (WB) mean standardized uptake value (SUV_mean), WB PSMA-positive tumor volume, and tumor load, as well as qualitative features including disease distribution and phenotype (e.g., visceral metastases and FDG-avid, PSMA-negative discordant lesions), have been associated with treatment response, progression-free survival, and overall survival. However, the clinical utility of these imaging biomarkers is limited by heterogeneous study designs, small cohorts, and a lack of standardization in image acquisition, quantification, and cutoff definitions. This review critically appraises available data on baseline PSMA PET/CT-based prognostic and potentially predictive biomarkers for RLT and identifies the methodological barriers that must be addressed before these biomarkers can be implemented in clinical practice. Full article

Lutetium-177-PSMA-617 (Lu-PSMA) radioligand therapy (RLT) is established in metastatic castration-resistant prostate cancer (mCRPC), with regulatory approvals based on the VISION and TheraP trials. Subsequent trials have extended the evidence to taxane-naive mCRPC (PSMAfore) and demonstrated that combining Lu-PSMA with enzalutamide yields a significant overall survival benefit over enzalutamide alone (ENZA-p). However, higher and more homogeneous PSMA expression in treatment-naive disease, combined with lower tumor burden and preserved bone marrow reserve, provides a biological rationale for deploying RLT earlier in the disease course. In metastatic hormone-sensitive prostate cancer (mHSPC), the Phase III PSMAddition trial reported improved radiographic progression-free survival when Lu-PSMA was added to standard androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitor (ARPI), and the Phase II UpFrontPSMA trial demonstrated enhanced biochemical responses with Lu-PSMA induction before docetaxel. In oligometastatic and oligorecurrent disease, the BULLSEYE and LUNAR trials have shown progression-free survival benefits, raising the possibility of deferring androgen deprivation therapy and its associated morbidity. Meanwhile, next-generation radionuclides, including actinium-225 (WARMTH) and the dual beta-Auger emitter terbium-161 (VIOLET), are entering clinical development to address the radiobiological limitations of Lutetium-177. This review synthesizes the evidence for PSMA-targeted radioligand therapy across the prostate cancer disease continuum and discusses patient selection, treatment sequencing, and the access and cost-effectiveness considerations that will shape adoption in earlier disease settings. Full article

Background: Despite the therapeutic advances made in castration-sensitive prostate cancer, progression to castration-resistant disease is inevitable. Lutetium-177 vipivotide tetraxetan (¹⁷⁷Lu-PSMA-617) is a novel radioligand approved for use in metastatic castration-resistant prostate cancer (mCRPC). With promising efficacy, it is not without numerous potential side effects, namely cytopenias, which are often a reason for early discontinuation of ¹⁷⁷Lu-PSMA-617. We sought to describe the incidence of cytopenias associated with permanent discontinuation of ¹⁷⁷Lu-PSMA-617 at our institution. Methods: We conducted a retrospective review of patients who received ¹⁷⁷Lu-PSMA-617at the University of Virginia Comprehensive Cancer Center from 2018 to 2025. From this we assessed for the incidence of toxicities resulting in permanent discontinuation of ¹⁷⁷Lu-PSMA-617, which we refer to as dose-limiting toxicities. Descriptive statistics were used to summarize characteristics of the study population. Median overall survival from time of initiation of ¹⁷⁷Lu-PSMA-617 was estimated using a Kaplan–Meier curve. Results: Of the patients who received ¹⁷⁷Lu-PSMA-617 (n = 64), grade 3 or greater anemia occurred in 36% (n = 23), thrombocytopenia in 3% (n = 2), leukopenia in 3% (n = 2), neutropenia in 0% (n = 0), and lymphopenia in 33% (n = 21). In our cohort, 10.9% (n = 7) developed toxicities necessitating permanent discontinuation. Of these, 9.3% (n = 6) were attributable to cytopenias. Those cytopenias consisted of anemias in 100% (n = 6) of cases, leukopenia in 83% (n = 5), thrombocytopenia in 67% (n = 4), lymphopenia in 100% (n = 6), and neutropenia in 33% (n = 2). Aside from cytopenias, the remaining 1.6% (n = 1) of dose-limiting toxicities were attributable to renal injury. In the VISION trial, the ¹⁷⁷Lu-PSMA-617 treatment arm reported dose-limiting toxicities necessitating permanent discontinuation in 11.9% of participants, but did not report if these were attributable to cytopenia or other toxicities. Notably, 2 patients developed grade 5 pancytopenia and 1 patient developed grade 5 bone marrow failure in the VISION ¹⁷⁷Lu-PSMA-617 treatment arm. Compared to the VISION ¹⁷⁷Lu-PSMA-617 treatment arm, our cohort differed in the distribution of organ metastases, younger median age of patients, and a higher portion of those with ECOG 2 functional status. From the time of ¹⁷⁷Lu-PSMA-617 initiation, median overall survival was estimated to be 18.5 months, compared to 15.3 months in the VISION ¹⁷⁷Lu-PSMA-617 treatment arm. Conclusions: In our real-world analysis, 85% of dose-limiting toxicities necessitating ¹⁷⁷Lu-PSMA-617 discontinuation were attributed to cytopenias. Though a direct comparison cannot be made with the VISION ¹⁷⁷Lu-PSMA-617 treatment arm in terms of dose-limiting toxicity attributable specifically to cytopenias, they reported total dose-limiting toxicity to a similar degree, and cytopenias were the most common causes of grade 3 or greater toxicities. Therefore, it is important to recognize the ubiquity of these adverse events as well as the role that they play in therapy-limiting toxicity. Full article

Prostate-specific membrane antigen (PSMA) has become a central molecular target in prostate cancer because it enables both high-performance imaging and targeted radioligand therapy. PSMA positron emission tomography/computed tomography (PET/CT) is now used across several clinical settings, including primary staging of higher-risk localized disease, localization of biochemical recurrence, salvage radiotherapy planning, and assessment of oligometastatic disease. In metastatic castration-resistant prostate cancer, PSMA-targeted radioligand therapy (RLT), particularly lutetium-177-labeled PSMA-617, has established therapeutic value and is moving into earlier disease states. From an applied science perspective, the clinical performance of PSMA theranostics depends not only on target expression and trial efficacy, but also on radiopharmaceutical design, radionuclide selection, radiochemical quality, PET acquisition and reconstruction, standardized reporting, dosimetry, and quantitative response assessment. This narrative review summarizes the biological, radiochemical, and technical foundations of PSMA theranostics, the clinical evidence supporting PSMA PET/CT in key disease states, and the pivotal data for PSMA-targeted RLT. It also discusses imaging-based treatment eligibility, dosimetry, post-therapy imaging, Response Evaluation Criteria in PSMA Imaging, and next-generation beta- and alpha-emitting platforms. PSMA theranostics should be understood as an integrated clinical and technological platform that links molecular imaging, treatment selection, radionuclide delivery, and longitudinal response assessment across the prostate cancer care pathway. Full article

Systemic therapy for metastatic prostate cancer is increasingly defined by upfront intensification and biomarker-guided mechanism switching. This narrative review synthesizes pivotal randomized trials, guideline recommendations, and implementation-focused literature across metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Evidence was organized around decision points at mCSPC diagnosis and at mCRPC transition, while incorporating biological mechanisms of resistance, including AR-axis reactivation, AR splice variants, lineage plasticity, DNA repair–hormone signaling interactions, and PSMA expression heterogeneity. In mCSPC, androgen deprivation therapy plus docetaxel and/or androgen receptor signaling inhibitors (ARSIs) improves survival, with triplet regimens favored for selected chemotherapy-fit patients with aggressive de novo disease. In mCRPC, cross-resistance limits routine ARSI-to-ARSI switching, and randomized data support mechanism-distinct options, including taxanes, PARP-based therapy in homologous recombination repair (HRR)-altered disease, and PSMA-targeted radioligand therapy (RLT) in selected PSMA-positive patients. As RLT moves earlier, PSMA heterogeneity, renal function, bone marrow reserve, and emerging dosimetry-based optimization should inform practical implementation. Ongoing trials are evaluating earlier theranostics, alpha-emitting radioligands, and biomarker-enriched combinations. An implementation-first approach that intensifies treatment when appropriate, tests early and acts on HRR results, uses PSMA PET to guide RLT, and preserves hematologic reserve may maximize access to multiple life-prolonging mechanisms. Full article

Radiopharmacy is a specialized area of hospital pharmacy dedicated to the preparation and appropriate use of radiopharmaceuticals for diagnostic imaging and targeted therapies. While clinical pharmacy activities are well established in many hospital settings, their integration into radiopharmacy remains poorly documented and lacks standardization, particularly in the context of the rapid development of theranostic applications. This descriptive, cross-sectional study aimed to assess current clinical pharmacy practices in radiopharmacy across the HUGOPharm network. Between July and September 2025, an anonymous online questionnaire was distributed to radiopharmacy teams, collecting information on prescription analysis, biological monitoring, interdisciplinary collaboration, and other clinical pharmacy activities. Descriptive statistics were used to analyze responses. All participating centers reported verifying patient identity and key prescription parameters; however, substantial variability in practices was observed. Pharmacotherapeutic analysis was more frequently performed for therapeutic procedures (71%) than for diagnostic procedures (57%). Pre-procedure biological testing was common in therapeutic contexts (86%) but infrequent for diagnostic applications (29%). No center reported conducting structured medication reviews or pharmaceutical consultations. The implementation of radioligand therapies, such as [¹⁷⁷Lu]-PSMA, was associated with enhanced safety checks and increased interdisciplinary collaboration. Overall, clinical pharmacy in radiopharmacy is developing but remains inconsistently implemented. Structured clinical pharmacy activities appear particularly relevant for theranostic procedures and may represent priorities for future practice development to support patient safety and integrated care. Full article

Prostate cancer (PCa) is the most common malignant tumor of the male genitourinary system, and its incidence and mortality have shown a marked global increase in recent years. Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein highly expressed in PCa cells, has emerged as a vital molecular target in the field of PCa precision diagnosis and therapy. In recent years, significant advances have been achieved in PSMA-based molecular imaging, radioligand therapy, and the development of novel targeted drugs. This review aims to summarize and critically discuss recent advances in PSMA-targeted molecular imaging, radioligand therapy, and emerging therapeutic strategies, highlighting their roles in precision diagnosis and personalized treatment of PCa. PSMA positron emission tomography/computed tomography (PET/CT) imaging using radionuclides such as ⁶⁸Ga and ¹⁸F has markedly improved the accuracy of primary tumor staging, localization of recurrent lesions, and therapeutic response assessment. Radioligand therapies, such as ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617, have prolonged survival and demonstrated symptomatic benefits in multiple clinical trials, and are now applied in early disease stages, including chemotherapy-naïve and hormone-sensitive settings. Meanwhile, PSMA-targeted antibodies and antibody–drug conjugates (PSMA-ADCs), as well as bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, are constantly being optimized and show promising clinical potential. Furthermore, PSMA-targeted nanoplatforms enable precise delivery of chemotherapeutic agents, photosensitizers, or imaging probes, achieving integrated diagnosis and therapy with multimodal imaging guidance, and offering new strategies for individualized treatment. Taken together, the evidence summarized in this review highlights PSMA as a pivotal molecular target supporting precision diagnosis and personalized treatment across the continuum of prostate cancer management. Full article

There is a strong need for nanobodies that target novel cancer-associated antigens to advance radioligand imaging and antibody-based therapeutics. In this study, we investigated whether non-targeted llama immunization using tumor cells, combined with non-targeted phage-display panning of human cell lines, could yield nanobodies specific to Prostate-Specific Membrane Antigen (PSMA). Nanobody selection using both classical three-round PSMA negative–positive panning and single-round panning of cell lines (positive or negative) for PSMA showed clear enrichment for PSMA binders in both strategies. Using shRNA knockdown, flow cytometry, cell-ELISA, immunohistochemistry and structural modeling and docking, we confirmed the PSMA-targeting of selected nanobodies. Two distinct epitopes were predicted to be bound by nanobodies PSMANb9 and A7 (JVZ-007), and this was corroborated by epitope competition assays. These findings support the feasibility of non-targeted immunization and panning strategies for isolating antigen-targeting cancer nanobodies. Full article

Recurrent brain tumors—including high-grade gliomas, brain metastases, and aggressive meningiomas—continue to carry a poor prognosis, with high mortality despite therapeutic advances. The aim of this narrative review is to summarize and critically discuss the current evidence on the role of intra-arterial radioligand therapy (RLT) in the treatment of recurrent brain tumors. RLT, a targeted form of radionuclide therapy, has gained increasing attention for its potential theranostic applications in neuro-oncology. A literature search was conducted using PubMed and Scopus, including clinical studies evaluating intra-arterial radioligand delivery in central nervous system tumors. Recent research has explored intra-arterial administration of radioligands targeting somatostatin receptors and prostate-specific membrane antigen (PSMA). Somatostatin receptors are overexpressed in meningiomas, while PSMA is highly expressed in the neovasculature of glioblastomas and brain metastases; both targets can be addressed using lutetium-177 (¹⁷⁷Lu)- or actinium-225 (²²⁵Ac)-labeled radiopharmaceuticals, traditionally delivered intravenously. Available evidence indicates that the intra-arterial route achieves markedly higher radionuclide uptake on ⁶⁸Ga-PSMA-11 and ⁶⁸Ga-DOTATOC PET, as well as increased absorbed doses in dosimetric models. Dosimetric analyses consistently show greater tracer accumulation compared with intravenous administration, without evidence of significant peri-procedural toxicity. Uptake in healthy brain tissue is minimal, and no relevant differences have been reported in liver or salivary gland accumulation between intra-arterial and intravenous RLT. Although based on heterogeneous and limited data, intra-arterial RLT appears to be a promising therapeutic strategy for recurrent brain tumors. Future research should focus on improving radioligand delivery beyond the blood–brain barrier and enhancing effective tumor targeting. Full article

Prostate cancer is one of the most common malignancies in men, and advanced or metastatic disease remains associated with substantial morbidity and mortality. Therapeutic progress in recent years has been driven by the introduction of targeted treatment strategies, notably poly (ADP-ribose) polymerase (PARP) inhibitors, prostate-specific membrane antigen (PSMA)–directed radioligand therapy (RLT), and androgen receptor pathway inhibitors (ARPIs). This review summarizes evidence from phase II and III clinical trials, meta-analyses, and real-world studies evaluating the efficacy, safety, and clinical integration of olaparib, lutetium (¹⁷⁷Lu) vipivotide tetraxetan, and abiraterone in advanced prostate cancer. Emphasis is placed on the practical clinical application of these agents, including patient selection, treatment sequencing, and combination strategies. PARP inhibition with olaparib has demonstrated clear benefits in metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) mutations, particularly BRCA1/2 alterations. PSMA-directed RLT offers a survival advantage in PSMA-positive mCRPC following AR pathway inhibition, with distinct toxicity considerations that influence patient selection. Abiraterone remains a cornerstone therapy across disease stages and plays an important role both as monotherapy and as a combination partner. Emerging data suggest a potential synergy between PARP inhibitors and AR-targeted agents, while also highlighting the limitations of biomarker-unselected approaches. We conclude that the optimal use of PARP inhibitors, PSMA-targeted RLT, and ARPIs requires a personalized strategy guided by molecular profiling, functional imaging, prior treatment exposure, and safety considerations. This clinically focused overview aims to support evidence-based decision-making in an increasingly complex treatment landscape. Full article