Sacituzumab Govitecan for Second and Subsequent Line Palliative Treatment of Patients with Triple-Negative Breast Cancer: A Polish Real-World Multicenter Cohort Study.

INTRODUCTION: Sacituzumab govitecan (SG) is approved for patients with previously treated metastatic or locally advanced triple-negative breast cancer (TNBC), as per the ASCENT trial results. Real-world studies (RWSs) cover more diverse patients than clinical trials, offering crucial data for healthcare policies. This study aimed to investigate the safety and efficacy of SG in real-world Polish patients with previously treated metastatic TNBC. METHODS: In this ambispective multicenter cohort study, we collected demographic and clinical data. Premedication, adjustments in SG dosage, and treatment regimen adhered to the product's characteristics. RESULTS: We included 79 female patients. The median age at SG initiation was 53 years; 32% of patients were initially diagnosed with a non-TNBC subtype. The median number of previous palliative lines was 2. Seven patients presented with brain metastases. The median overall survival was 10.3 months, and the median progression-free survival (PFS) was 4.4 months. The overall response rate was 35%, with a median time to response of 2 months. SG was discontinued by 70% of patients, primarily due to disease progression (95%). Treatment delays due to adverse events (AEs) occurred in 67% and dose reductions in 25% of patients, with neutropenia being the most common. Grade ≥ 2 AEs included neutropenia (43%), anemia (10.1%), and diarrhea (4%). A longer interval between breast cancer diagnosis and SG initiation or between metastasis diagnosis and SG initiation correlated with improved PFS, likely reflecting the disease's biological aggressiveness rather than treatment efficacy. CONCLUSION: In this RWS, SG demonstrated effectiveness and safety in patients with previously treated metastatic TNBC, consistent with ASCENT trial outcomes. Further research is needed to explore the efficacy of SG in different patient populations and healthcare systems.

Canadian Expert Recommendations on Safety Overview and Toxicity Management Strategies for Sacituzumab Govitecan Based on Use in Metastatic Triple-Negative Breast Cancer.

Sacituzumab Govitecan (SG) is an antibody-drug conjugate (ADC) comprised of an anti-Trop-2 IgG1 molecule conjugated to SN-38, the active metabolite of irinotecan, via a pH-sensitive hydrolysable linker. As a result of recent Canadian funding for SG in advanced hormone receptor (HR)-positive breast cancer and triple-negative breast cancer (TNBC), experience with using SG and managing adverse events (AEs) has grown. This review presents a summary of evidence and adverse event recommendations derived from Canadian experience, with SG use in metastatic TNBC for extrapolation and guidance in all indicated settings. SG is dosed at 10 mg/kg on day 1 and day 8 of a 21-day cycle. Compared to treatment of physicians' choice (TPC) the phase III ASCENT and TROPiCS-02 studies demonstrated favorable survival data in unresectable locally advanced or metastatic TNBC and HR-positive HER2 negative metastatic breast cancer, respectively. The most common AEs were neutropenia, diarrhea, nausea, fatigue, alopecia, and anemia. This review outlines AE management recommendations for SG based on clinical trial protocols and Canadian guidelines, incorporating treatment delay, dose reductions, and the use of prophylactic and supportive medications.

Antibody-drug conjugates (ADCs): a novel therapy for triple-negative breast cancer (TNBC).

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Revolutionizing triple-negative metastatic breast cancer treatment: sacituzumab Govitecan's role in advancing chemotherapy.

Purpose: This review aims to discuss the role and efficacy of Sacituzumab Govitecan in the management of breast cancer. Summary: Breast cancer is the most prevalent type of cancer among women worldwide. This comprehensive review delves into the advancements brought about by Sacituzumab Govitecan in the treatment of metastatic triple-negative breast cancer (TNBC). With a focus on its mode of action, efficacious role, clinical trials, and comparative advantages over conventional chemotherapy, the review highlights the therapy's precision in targeting cancer cells through monoclonal antibodies. Sacituzumab Govitecan's ability to deliver a chemotherapeutic payload specifically to cancer cells with the Trop-2 receptor sets it apart from traditional chemotherapy, minimizing collateral damage and reducing severe side effects. The impact of Sacituzumab Govitecan on improving progression-free survival, tumor response rates, and, significantly, the quality of life for patients is discussed. This article also sheds light on ongoing trials, FDA recognition, and the therapy's potential to transform breast cancer treatment. Conclusion: In conclusion, Sacituzumab Govitecan shows potential as an innovative therapeutic option for breast cancer, particularly in metastatic breast cancer and triple-negative breast cancer, but it warrants additional research.

Novel Antibody-Drug-Conjugates in Routine Clinical Practice for the Treatment of Metastatic Breast Cancer: Adherence, Efficacy and Tolerability - Real-World Data from German Breast Centers.

Introduction: The third-generation antibody-drug conjugates (ADC), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), recently obtained approval for metastatic breast cancer treatment across various subtypes and therapeutic contexts. Materials and Methods: This retrospective, multicentric study evaluated real-world tolerability, feasibility and efficacy in a pre-treated, real-world cohort at three major German breast cancer centers. Results: 125 patients treated with T-DXd or SG from November 2020 to June 2023 were included (T-DXd: 77 patients; SG: 48 patients). The median treatment duration was 6.0 months for T-DXd and 3.5 months for SG therapy, with a median follow-up duration of 10.4 months for T-DXd (95% CI: 8.4-11.6) and 11.8 months for SG (95% CI: 8.0-14.4). Severe neutropenia (CTC ≥ III°) occurred in 33.3% during SG therapy, with a numerical reduction observed following primary, prophylactic use of G-CSF. T-DXd-associated pneumonitis occurred in 8 out of 77 patients (10.4 %). Median progression-free survival (mPFS) was 8.6 months (95% CI: 5.8-12.4) with T-DXd (HER2+: 10.8; HER2-low: 4.7) and 4.9 months (95% CI: 2.8-6.3) with SG (TNBC 4.9; HR+/HER2-: not reached). Median overall survival (OS) was 23.8 months (95% CI: 16.1-not estimable) with T-DXd (HER2+: 27.1; HER2-low: not reached), and 12.4 months (95% CI: 8.7-not estimable) with SG therapy (TNBC: 12.4, HR+/HER2-: not reached). 95.7% of the protocol-specified, therapeutic dose was administered for T-DXd and 89.6% for SG. Conclusion: Overall, this indicates good feasibility, tolerability, and effectiveness of ADC therapies in the real-world setting.

New Advances in Metastatic Urothelial Cancer: A Narrative Review on Recent Developments and Future Perspectives.

The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.

Sacituzumab-govitecan in metastatic triple-negative breast cancer: a multicenter effectiveness and safety study.

Aim: Sacituzumab-govitecan (Sgov) is a new antibody-drug conjugate recently approved for metastatic triple negative breast cancer (mTNBC), so there are still few data published in the real-world setting.Materials & methods: This study was to analyze the effectiveness and safety of Sgov in mTNBC of patients from the three main hospitals of a city and to compare with the pivotal ASCENT-trial. A total of 46 patients were included, all women diagnosed with mTNBC, with a median age of 52 years and Eastern Cooperative Oncology Group performance status 0-1 71.8% of patients.Results: Sgov effectiveness data seem to be slightly inferior than expected. Furthermore, it is observed that patients with an Eastern Cooperative Oncology Group of two or higher benefit significantly less from treatment with the drug. Safety profile of Sgov is acceptable.

What is this article about? Sacituzumab-govitecan (Sgov) is a new drug recently approved for metastatic triple negative breast cancer, so there is still little data on patients receiving treatment outside of a clinical trial.What were the results? At the cut-off date, 33 patients (71.7%) had withdrawn from treatment with Sgov, and 21 patients (45.7%) had died. Disease remained stable or shrank in 23.9% of patients (n = 11). Median time to disease progression was 4.1 months (IC 95%: 2.6­5.6) and median overall survival 11.0 months (95% CI: 6.1­15.9), with a median duration of follow-up of 6.6 months (interquartile range: 2.1­10.5). Patients with ECOG 0­1 (better performance status) show a higher overall survival than patients with higher ECOG (Not reached [95% CI: NR-NR] vs 3.8 [95% CI: 2.7­4.9]; p = 0.009). No patients stopped treatment due to side effects and almost two thirds of patients did not have to have their dose reduced or delayed due to adverse events (AE). Asthenia (71.7%) and anemia (60.9%) were the most frequent AE. No patient characteristics were identified that predicted less or worse toxicity.What do the results of the study mean? This suggests that sacituzumab-govitecan effectiveness data seem to be slightly worse than expected, even more when performance status before starting Sgov is poor (ECOG 2). AE profile of Sgov is acceptable.

Preliminary results from ASCENT-J02: a phase 1/2 study of sacituzumab govitecan in Japanese patients with advanced solid tumors.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate approved outside Japan for second-line and later metastatic triple-negative breast cancer (mTNBC), based on the ASCENT study (NCT02574455). We report SG safety and efficacy in an open-label, phase 1/2 bridging study in Japanese patients with advanced solid tumors (ASCENT-J02; NCT05101096; jRCT2031210346). METHODS: Phase 1 was a standard 3 + 3 design. Patients received intravenous SG 6 mg/kg, escalating to 10 mg/kg, on Days 1 and 8 per 21-day cycle; primary endpoints were safety, incidence of dose-limiting toxicity/toxicities (DLTs), and determination of the recommended phase 2 dose (RP2D). In the multicohort phase 2 study, patients in the mTNBC cohort with previously treated disease received SG at the RP2D; primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; RECIST v1.1). Safety was a secondary endpoint. RESULTS: In phase 1 (N = 15), one DLT (grade 3 elevated transaminases) occurred with SG 10 mg/kg; RP2D was SG 10 mg/kg regardless of UGT1A1 status. In phase 2, 36 patients with mTNBC received SG 10 mg/kg. At median follow-up of 6.1 months, IRC-assessed ORR was 25.0% (95% CI 12.1-42.2; P = 0.0077). Median progression-free survival was 5.6 months (95% CI 3.9-not reached [NR]); median overall survival was NR. No treatment-emergent adverse events led to discontinuation or death. CONCLUSIONS: SG RP2D was established as 10 mg/kg in Japanese patients. SG showed efficacy in Japanese patients with previously treated mTNBC, a manageable safety profile, and no new safety signals, consistent with the previous ASCENT study.

Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer.

Background: Treatment of recurrent platinum-resistant high grade serous ovarian cancer (HGSOC) remains a challenge. Novel treatment options for recurrent disease are an unmet need. Case: A 69-year-old with recurrent, metastatic, platinum-resistant HGSOC overexpressing TROP2 experienced a significant response to the antibody-drug conjugate (ADC) sacituzumab govitecan after multiple failed lines of chemotherapy and targeted treatment. Following sacituzumab govitecan treatment she experienced a confirmed partial response as well as a return of CA-125 to baseline. Having now completed 8 cycles (ie, over 6 months of treatment), her disease continues to demonstrate a response to sacituzumab govitecan treatment. The ADC has been well tolerated at a dose of 10 mg/kg with no dose-limiting toxicity or need for dose reductions. Conclusion: Sacituzumab govitecan may represent a treatment option for platinum-resistant/recurrent HGSOC that have previously failed prior lines of chemotherapy. Clinical trials with sacituzumab govitecan in platinum-resistant ovarian cancer patients are currently ongoing (https://classic.clinicaltrials.gov/ct2/show/NCT06028932).

Sacituzumab govitecan for hormone receptor-positive HER2-negative advanced breast cancer.

INTRODUCTION: Initial treatment for hormone-receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) typically involves endocrine therapy (ET) combined with different targeted agents. When hormonal therapies fail, until recently, the only option available was chemotherapy (ChT), presenting a significant therapeutic challenge. However, the recent introduction of antibody-drug conjugates (ADCs) has provided new treatment alternatives in this context. Sacituzumab govitecan (SG), a novel trophoblast cell-surface antigen 2 (Trop-2)-targeting ADC, has been evaluated following disease progression to ET and ChT in HR+/HER2- ABC. AREAS COVERED: This review examines the latest clinical trials, including phase I/II and III studies and evaluates the impact of SG on HR+/HER2- ABC. The literature search focused on clinical outcomes, particularly regarding efficacy and safety, comparing them with traditional ChT. EXPERT OPINION: SG has demonstrated to be an effective treatment for patients with HR+/HER2- ABC after progression to ET and cyclin-dependent kinase 4/6 inhibitors (CDKi) in any setting, and at least two ChT-containing regimens in the advanced setting. With a manageable toxicity profile, SG represents a significant advancement in the treatment landscape for this patient population. However, further research is essential to optimize its application and establish long-term benefits.

Sacituzumab govitecan response in extensive leptomeningeal carcinomatosis from triple-negative breast cancer: a case report.

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate (ADC), was the first ADC approved for patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior lines of therapy for advanced disease. Although SG has shown promising clinical activity in treating brain metastases in both ASCENT randomized trials and real-world analysis, its utility in leptomeningeal carcinomatosis (LC) remains underexplored. We report the diagnostic and therapeutic process of a patient who develops extensive LC from TNBC treated with SG. She presented a clinical response after the first cycle of SG with a PFS of 6 months. This case report highlights the need for further inquiry into the use of SG in LC.

Sacituzumab govitecan in triple-negative breast cancer: from bench to bedside, and back.

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.

UGT1A1*28 polymorphism and the risk of toxicity and disease progression in patients with breast cancer receiving sacituzumab govitecan.

BACKGROUND: Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2-negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. METHODS: In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). RESULTS: We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple-negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. CONCLUSION: This retrospective, real-world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes.

Efficacy of Antibody Drug Conjugates Alone and in Combination with other Agents in Metastatic Urothelial Carcinoma: A Scoping Review.

INTRODUCTION: Antibody drug conjugates represent a promising class of antineoplastic agents comprised of a monoclonal antibody linked to a potent cytotoxic payload for targeted delivery of chemotherapy to tumors. Various antibody drug conjugates have demonstrated impressive efficacy in patients with metastatic urothelial carcinoma in clinical trials, leading to two FDA approved therapies and several other agents and combinations in clinical development. MATERIALS AND METHODS: A comprehensive systematic review was undertaken utilizing the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Queried databases included Ovid MEDLINE, Ovid Embase, Web of Science Core Collection and Cochrane CENTRAL Trials. The search sought to identify prospective therapeutic clinical trials in humans with metastatic urothelial carcinoma with a single-arm or randomized controlled trial design investigating antibody drug conjugate-containing regimens. RESULTS: The literature search yielded 4,929 non-duplicated articles, of which 30 manuscripts and conference abstracts were included, which derived from 15 clinical trials including 19 separate cohorts with efficacy outcome results. Eleven trials investigated ADC monotherapy, while two investigated combination regimens, and the remaining two studies were mixed. Five unique ADC targets were represented including Nectin-4, Trop-2, HER2, Tissue Factor, and SLITRK6. Twelve clinical trial cohorts required prior treatment (63%). Objective response rate was reported for all studies and ranged from 27-52% for ADC monotherapies and 34-75% for ADC plus anti-PD-1 agents. Time to event outcome reporting was highly variable. CONCLUSION: In addition to enfortumab vedotin and sacituzumab govitecan, various HER2-targeted antibody drug conjugates and ADC-anti-PD-1 combination regimens have demonstrated efficacy in clinical trials and are poised for clinical advancement.

Sacituzumab govitecan vs. chemotherapy for metastatic breast cancer: a meta-analysis on safety outcomes.

Aim: There is limited data available regarding the comparison of Sacituzumab govitecan (SG) vs. chemotherapy in metastatic breast cancer patients.Materials & methods: We performed a systematic review and meta-analysis aimed to assess the safety profile of SG vs. chemotherapy for metastatic breast cancer (mBC) clinical trials.Results: The pooled odds ratio for outcomes such as grade 3-4 and all grade neutropenia, leukopenia, anemia and other non-hematological adverse events showed a higher risk for patients receiving SG. No statistically significant differences were reported in terms of grade 3-4 fatigue, all grade nausea, febrile neutropenia and treatment discontinuation due to adverse events.Conclusion: Our data, coupled with a statistically and clinically meaningful survival benefit, support the use of SG for mBC.

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Real-world use patterns, effectiveness, and tolerability of sacituzumab govitecan for second-line and later-line treatment of metastatic triple-negative breast cancer in the United States.

PURPOSE: Patients with metastatic triple-negative breast cancer (mTNBC) have poor prognosis and limited treatment options. Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with mTNBC who have received ≥ 2 systemic therapies (≥ 1 in the metastatic setting) based on the ASCENT study (NCT02574455). The current study describes real-world SG use and outcomes in patients with mTNBC in the United States. METHODS: This retrospective, observational study included adult patients with mTNBC from the ConcertAI Patient360™ database who received SG in the second line (2L) and later from April 2020 to May 2022. SG use patterns, effectiveness, and tolerability are described. RESULTS: This analysis included 230 patients (median age 60 years, 26% Black, 17% with ECOG performance status ≥ 2, 66% in community settings; median of 2 prior lines of treatment in the metastatic setting); median follow-up was 7.2 months. Median (95% CI) real-world overall survival was 10.0 (8.3-11.1) months for all patients and 13.9 (9.8-not estimable) months in the 2L subgroup (n = 77). Granulocyte-colony stimulating factor (G-CSF) was administered concomitantly with SG in 134 (58%) patients; 35 (15%) received G-CSF for the first time. Median (IQR) time from SG start to G-CSF use was 8.5 (8.0-29.0) days. Seventeen (7%) patients discontinued SG due to toxicity. CONCLUSIONS: Using a real-world, ethnically diverse population of patients with mTNBC presenting with poor prognosis, these data reinforced the findings from ASCENT. In routine clinical practice, SG is an effective treatment in the 2L setting, consistent with treatment guidelines.

OptimICE-RD: sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer.

Patients with early-stage triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence even with neoadjuvant and adjuvant treatment with pembrolizumab. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload, improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with pre-treated metastatic TNBC. Moreover, preclinical data suggest that topoisomerase I inhibitors may enhance the effects of immune checkpoint inhibitors through activation of the cGAS-STING pathway. Here we describe the international randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial, which evaluates the efficacy and safety of sacituzumab govitecan plus pembrolizumab versus treatment of physician's choice (pembrolizumab ± capecitabine) among patients with early-stage TNBC with residual invasive disease after neoadjuvant therapy.Clinical Trial Registration: NCT05633654 (ClinicalTrials.gov)Other Study ID Number(s): Gilead Study ID: GS-US-595-6184Registration date: 1 December 2022Study start date: 12 December 2022Recruitment status: Recruiting.

AFT-65/ASCENT-05/OptimICE-RD is an ongoing clinical trial that is testing a new treatment combination for patients with stage II or III triple-negative breast cancer (TNBC). Stage II­III means the cancer is confined to the breast and/or nearby lymph nodes and can be surgically removed. However, there remains a risk that the cancer could recur after surgery. To reduce this risk, patients with stage II­III TNBC receive anti-cancer medication before and after surgery. For some patients, receipt of anti-cancer medication before surgery produces a pathologic complete response (pCR), meaning there is no observable cancer left behind at surgery. Patients with a pCR have a lower risk of recurrence than patients with residual disease.The AFT-65/ASCENT-05/OptimICE-RD trial includes people with stage II-III TNBC who have residual cancer after completing their course of pre-surgery anti-cancer medication. All participants have any remaining cancer in their breast and/or lymph nodes removed surgically, after which they are randomly assigned to receive one of two treatments. The experimental therapy consists of pembrolizumab along with a medication called sacituzumab govitecan, which kills cancer cells directly and may strengthen the anti-cancer immune response. Pembrolizumab strengthens the anti-cancer immune response, so the hypothesis of this trial is that the two medications will be more effective together. The control therapy consists of pembrolizumab, alone or in combination with a chemotherapy medication called capecitabine, which is the current standard of care. To study the effectiveness of each treatment, the researchers are following up with all participants to learn if and when their breast cancer returns.

Use of Antibody-Drug Conjugates in the Early Setting of Breast Cancer.

Antibody-drug conjugates (ADCs) are anticancer agents with the capacity to selectively deliver their payloads to cancer cells. Antibody-drug conjugates consist of a monoclonal antibody backbone connected by a linker to cytotoxic payloads. Antibody-drug conjugate effect occurs either by directly targeting cancer cells via membrane antigen or through "bystander effect." Antibody-drug conjugates have demonstrated efficacy against various types of tumors, including breast cancer. Ado-trastuzumab emtansine is presently the only approved ADC for the treatment of breast cancer in the early setting, while several ADCs are now approved for metastatic breast cancer. Due to the transformative impact that several ADCs have reported in the setting of advanced breast cancer, researchers are now testing more of such compounds in the early setting, to portend benefits to patients through highly potent anticancer drugs. Ongoing trials hold the potential to transform treatment protocols for early breast cancer in the near future. These trials are aiming at evaluating different treatment modulation approaches, as informed by breast cancer risk of recurrence, including toward treatment de-escalation. Efforts are provided in ongoing clinical trials to identify the patients who will benefit most, to pursue paradigms of precision medicine with the novel ADCs. This review focuses on the potential role of ADCs in early breast cancer, providing an overview of the latest progress in their development and how they are implemented in ongoing clinical trials.

Preclinical evidence for the use of anti-Trop-2 antibody-drug conjugate Sacituzumab govitecan in cerebral metastasized castration-resistant prostate cancer.

PURPOSE: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC). METHODS: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro. RESULTS: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG. CONCLUSION: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.

Antibody-drug conjugates as a novel therapeutic modality to treat recurrent refractory germ cell tumors.

This review provides a rationale for using the Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) for implementing as therapy in recurrent refractory germ cell tumors similar to their position in the treatment of other types of chemoresistant solid tumors. Germ cell tumors (GCTs) originate from germ cells; they most frequently develop in ovaries or in the testes, while being the most common type of malignancy in young men. GCTs are very sensitive to cisplatin-based chemotherapy, but therapeutic resistance occurs in a considerable number of cases, which is associated with disease recurrence and poor patient prognosis. ADCs are a novel type of targeted antitumor agents that combine tumor antigen-specific monoclonal antibodies with chemically linked chemotherapeutic drugs (payload) exerting a cytotoxic effect. Several FDA-approved ADCs use as targeting moieties the antigens that are also detected in the GCTs, offering a benefit of this type of targeted therapy even for patients with relapsed/refractory testicular GCTs (rrTGCT) unresponsive to standard chemotherapy.