Category: Precision Oncology

Emerging Biomarker Insights in Esophageal Squamous Cell Carcinoma: NOTCH1 Mutations as a Predictor of Anti–PD-1 Benefit

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SUMMARY: The American Cancer Society estimates that in 2025, about 22,070 new cases of esophageal cancer will be diagnosed in the US and about 16,250 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma (SCC) accounts for approximately 85% of cases. Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse, and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

Recent advancements in the treatment of advanced or metastatic Esophageal Squamous Cell Carcinoma (ESCC) have firmly positioned Immune Checkpoint Inhibitors (ICIs) as a cornerstone of second-line therapy. Numerous agents targeting PD-1 have demonstrated superior clinical outcomes compared to chemotherapy.

Tislelizumab (TEVIMBRA®)  is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid immune cells of the body to detect and fight tumors, while minimizing off-target effects. The FDA in 2024 approved Tislelizumab in combination with platinum-containing chemotherapy for the first-line treatment of adults with unresectable or metastatic ESCC whose tumors express PD-L1 (≥1) and also as a single agent in adults with unresectable or metastatic ESCC after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor.

RATIONALE-302 is a randomized, open-label, multicenter, Phase 3 study in which 512 patients with advanced or metastatic ESCC whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive Tislelizumab 200 mg IV every 3 weeks or chemotherapy (investigators choice of Paclitaxel, Docetaxel, or Irinotecan). The trial met its Primary endpoint, demonstrating a significant improvement in Overall Survival (OS) with Tislelizumab over chemotherapy.

A comprehensive biomarker analysis stemming from the pivotal RATIONALE-302 trial has shed light on a promising genomic signal that could shape future treatment pathways. Researchers conducted extensive tumor profiling using PD-L1 ImmunoHistoChemistry (N=359), Gene Expression Profiling (N=346), and Mutation analysis (N=209) on tumor samples from patients enrolled in the RATIONALE-302 trial. The aim of this study was to uncover molecular determinants of response to Tislelizumab.

Clinical Findings: NOTCH1 as a Predictive Biomarker
Among the 209 patients with available mutation data, 22% harbored NOTCH1 mutations. This subgroup demonstrated a markedly improved Overall Survival (OS) with Tislelizumab, compared to chemotherapy:

  • Median OS with tislelizumab: 18.4 months
  • Median OS with chemotherapy: 5.3 months
  • Hazard Ratio: 0.35 (95% CI, 0.17–0.71)

In contrast, patients with wild-type NOTCH1 derived minimal OS benefit from tislelizumab (6.0 vs 6.9 months; HR 0.81), underscoring the potential of NOTCH1 status to guide therapeutic decisions.

Mechanistic Insights: An Immunologically Favorable TME
Transcriptomic data linked NOTCH1 mutations to increased expression of Type I interferon (IFN-I) and Toll-Like Receptor (TLR) signatures—hallmarks of an activated Tumor MicroEnvironment (TME). Concurrently, these tumors exhibited reduced infiltration by B cells and neutrophils, which have been associated with resistance to immunotherapy.

Further validation using murine models showed that NOTCH1 deficiency promotes a TME, more permissive to anti–PD-1 activity, supporting a biological rationale for these clinical findings.

Independent of PD-L1 and TMB
Importantly, the survival benefit associated with NOTCH1 mutations was independent of PD-L1 expression levels and Tumor Mutational Burden (TMB). Even among patients with low PD-L1 tumor positivity (<10%), those with NOTCH1 mutations showed a trend toward improved OS with Tislelizumab over chemotherapy.

Broader Genomic Context
In addition to NOTCH1, alterations in genes such as KMT2D also correlated with improved response to Tislelizumab compared to investigator chosen chemotherapy, while EGFR alterations were associated with diminished benefit. The frequently mutated genes in the RATIONALE-302 cohort – TP53, CCND1, FGF3/4/19, CDKN2A, PIK3CA, KMT2D, NFE2L2, and TP63- fall into functional categories including cell cycle regulation, differentiation, PI3K signaling, and chromatin remodeling consistent with previous reports.

Clinical Implications
These findings strongly suggest that NOTCH1 mutation status should be evaluated in patients with advanced ESCC being considered for anti–PD-1 therapy. Routine integration of Next-Generation Sequencing (NGS) may enhance treatment personalization by identifying patients most likely to derive significant benefit from immunotherapy, beyond the current reliance on PD-L1 ImmunoHistoChemistry or TMB alone.

Next Steps
While these results are promising, prospective validation is needed. A clinical trial is currently being planned to assess whether patients with NOTCH1-mutated ESCC may be optimally treated with ICI monotherapy. Additional translational studies are underway to further clarify resistance mechanisms and inform future biomarker-driven strategies.

NOTCH1 Mutation and Survival Analysis of Tislelizumab in Advanced or Metastatic Esophageal Squamous Cell Carcinoma: A Biomarker Analysis From the Randomized, Phase III, RATIONALE-302 Trial. Lu Z, Du W, Jiao X, et al. J Clin Oncol. Published online April 3, 2025. https://doi.org/10.1200/JCO-24-01818

 

Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.

The five year survival among patients first diagnosed with metastatic prostate cancer is approximately 30%. Early detection and treatment may improve outcomes. Risk factors for prostate cancer include age, ethnicity, and family history of prostate cancer. In individuals with a family history of prostate cancer in one or more first-degree relatives, the Relative Risk of prostate cancer increases approximately 2-3 fold, and the risk increases with an increasing number of affected relatives, and is inversely related to the age at time of diagnosis among those relatives.

It is estimated that approximately 40% of all diagnosed prostate cancers are inherited and prostate cancer risk also has been implicated in other familial cancer syndromes such as Hereditary Breast and Ovarian Cancer (HBOC) syndrome and Lynch Syndrome (LS). HBOC syndrome typically is found in families with early onset cancer and multiple cancer diagnoses such as, breast, ovarian and pancreatic cancer. Tumor suppressor DNA repair genes BRCA1 and BRCA2, has been implicated in prostate cancer, particularly in HBOC families. Patients with a BRCA1 mutation have a nearly 2-fold Relative Risk of prostate cancer among men less than 65 years, whereas those with BRCA2 mutations have a more than 7 fold Relative Risk. Further, patients with BRCA2 mutations are also associated with clinically aggressive disease, progression, and higher rates of cancer-specific mortality. It is estimated that the frequency of BRCA2 mutations ranges from 1-3%.

Somatic genomic testing in metastatic prostate cancer can offer insights into both prognosis and potential treatment responses, helping guide clinical decisions. Germline genetic testing can also yield similar insights, with the added benefit of revealing inherited cancer risks that may be relevant to patients relatives, including risks for cancers such as breast, pancreatic, colon, and endometrial. As a result, research has focused on determining which germline and somatic genetic tests deliver the most valuable information for individual patient cases.

The present ASCO guideline was developed by a multidisciplinary Expert Panel, following review of evidence on germline and somatic genomic testing for patients with metastatic prostate cancer. A total of 1,713 papers were identified in the literature search, and the recommendations are based on evidence from eight systematic reviews and six trials. This guideline is applicable to a patient who has a life expectancy of more than 6 months, is a candidate for systemic treatment, and for whom appropriate germline and somatic testing, including expertise in interpretation, is readily available.

This guideline addresses the following questions:
1) Why germline and somatic genomic testing should be offered?
2) The criteria for which patients should be offered testing?
3) Which test(s) to use?
4) When in the disease course testing should be considered?
5) Which biospecimens should be used for testing?

RECOMMENDATIONS

Clinical Question: Who should receive germline testing with NGS technologies?

Recommendation: All patients with metastatic prostate cancer should undergo germline genetic testing with next-generation sequencing technologies.

Clinical Question: Who should receive somatic testing with NGS technologies?

Recommendation: Those patients with metastatic prostate cancer (both Castrate Sensitive and Castrate Resistant Prostate Cancer) who are being considered for biomarker-directed systemic treatment should undergo somatic testing with next-generation sequencing technologies. While there are no current FDA-approved biomarker-directed treatments following somatic testing for metastatic Castrate Sensitive Prostate Cancer, somatic testing may be warranted in the presence of high-volume disease, or where there is a high likelihood the patient’s disease will progress to Castrate Resistant Prostate Cancer, where the patient is a candidate for future treatment with a biomarker-directed therapy (PARP inhibitor or checkpoint inhibitor).

Clinical Question: Who should receive sequential somatic testing with NGS technologies?

Recommendation: The panel recommends that sequential somatic testing may be offered when there has been a meaningful change in the patient’s status or treatment plan, especially in cases where prior tests were negative or uninformative (eg, insufficient or low tumor content).

Clinical Question: What are the strengths and weaknesses of primary tumor archival tissue versus fresh metastatic biopsy tissue versus ctDNA testing for somatic testing?

Recommendation: Archival tissue samples are preferred in initial testing. ctDNA is preferred when there is no accessible metastatic site to biopsy or for sequential testing. In the setting of minimal disease burden associated with low ctDNA fraction, metastatic biopsy is preferred.

Clinical Question: What are the key therapeutic impacts of germline or somatic testing for single-gene genetic variants (eg, BRCA1, BRCA2)?

Recommendation: Patients with pathogenic germline variants or somatic alterations in BRCA1 and BRCA2 demonstrate poorer outcomes, but are candidates for treatment with PARP inhibitor monotherapy, PARP inhibitor with Androgen Receptor Pathway Inhibitor combination therapy, and platinum-based agents.

Clinical Question: What are the key prognostic impacts of germline or somatic testing?

Recommendation: Treatment recommendations should not be made based on prognostic only biomarkers. However, they may be considered for directing patients to clinical trials. Germline information may still be important for patient counseling, informing hereditary risk for patients and families.

Pre-Test Genetic Counseling for Germline Testing

Before conducting germline testing, clinicians should ensure patients understand the following essential aspects:

  • Purpose of Testing: Explain the goals and implications of germline genetic testing.
  • Hereditary Nature: Emphasize that the results can reveal inherited cancer risks.
  • Family Impact: Discuss how findings might indicate elevated cancer risks for relatives.
  • Testing Options: Inform patients about the availability of gene panel testing.
  • Possible Outcomes:
    • Pathogenic/Likely Pathogenic Variants (P/LPVs)
    • Variants of Uncertain Significance (VUS)
    • Negative or Inconclusive Results
  • Legal Protections: Outline patient protections under the Genetic Information Nondiscrimination Act (GINA).
  • Cascade Testing: Stress the importance of testing family members when a P/LPV is found.

Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline. Yu EY, Rumble RB, Agarwal N, et al. J Clin Oncol. 2025;43:748-758. DOI:10.1200/JCO-24-02608.

FDA Approves Radioligand Therapy with PLUVICTO® Before Chemotherapy in Castrate Resistant Prostate Cancer

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SUMMARY: The FDA on March 28, 2025, expanded the indication for Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO&reg;) to include adults with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC) who have been treated with Androgen Receptor Pathway Inhibitor (ARPI) therapy and are considered appropriate to delay taxane-based chemotherapy. Patients with previously treated mCRPC should be selected for PLUVICTO&reg; using LOCAMETZ&reg; (active ingredient Gallium Ga 68 gozetotide) or another approved PSMA Positron Emission Tomography (PET) product based on PSMA expression in tumors.

Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies. Patients who progress on Androgen Deprivation Therapy are often switched to second line hormonal treatments that block testosterone with a different mechanism of action, and upon further progression, offered taxane based chemotherapy.

Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer.

Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO®) is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, a cytotoxic radionuclide, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with PLUVICTO® targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell.

The FDA in March 2022, approved PLUVICTO® for the treatment of adult patients with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC), who had been treated with Androgen-Receptor Pathway Inhibitors (ARPI) such as Enzalutamide or Abiraterone acetate and 1 or 2 taxane based chemotherapy regimens. This approval was based on the VISION Phase III study.

PSMAfore is a Phase III trial conducted to assess the benefit of PLUVICTO® in patients with metastatic Castration-Resistant Prostate Cancer who had progressed on ARPIs, but had NOT received taxane based chemotherapy, with the hope of making this promising therapy available to more patients earlier in the course of their treatment journey. This study enrolled 468 patients (N=468) with taxane-naive metastatic CRPC who had PSMA-positive disease on gallium-68–PSMA-11 PET/CT, and were candidates for an ARPI change after one progression on prior ARPI. Patients were randomized (1:1) to receive PLUVICTO® 7.4 GBq (200 mCi) IV every 6 weeks for 6 doses, or a change in ARPI (Abiraterone or Enzalutamide). The Primary endpoint was radiographic Progression Free Survival (rPFS). Secondary endpoints included Overall Survival (OS), Prostate-Specific Antigen (PSA) declines of 50% or more from baseline – known as a PSA50 response, Quality of Life measures, and Safety profiles.

At the Primary analysis conducted at 7.3 months, patients treated with PLUVICTO® demonstrated a median rPFS of 9.3 months compared to 5.6 months in the ARPI change group, showing a statistically significant and clinically meaningful benefit (HR=0.41; P<0.0001).

In the updated exploratory analysis, performed with a median follow-up of 24 months, PLUVICTO® more than doubled median rPFS versus ARPI change group (11.6 months versus 5.6 months, HR=0.49), with a 51% reduction in the risk of radiographic progression or death with PLUVICTO® versus a change in ARPI. At the preplanned final analysis, Overall Survival (OS) numerically favored PLUVICTO® but was not statistically significant. The median OS was 24.5 months with PLUVICTO® and 23.1 months with a change in ARPI (HR=0.91 (95% CI, 0.72-1.14). High crossover rate may have confounded OS analysis. Approximately 60% of patients randomized to the change in ARPI group subsequently crossed over to receive PLUVICTO® following confirmed radiographic progression. The Objective Response Rate (ORR) in the PLUVICTO® group was 49% versus 14% in the change in ARPI group, with Complete Response Rates of 21% versus 2.8%, respectively. PSA50 response was 51% with PLUVICTO® and 17% with change in ARPI.

The most frequently reported all-grade adverse events for PLUVICTO® included dry mouth, fatigue, nausea, and constipation, and were primarily Grade 1-2. Further, PLUVICTO® did not impair the ability of patients to be treated with subsequent chemotherapy.

It was concluded that in the updated analysis of the PSMAfore trial, PLUVICTO® more than doubled median rPFS versus a change in ARPI, with favorable safety profile and proven tolerability. The findings from the PSMAfore study suggest that PLUVICTO® could provide a viable therapeutic option earlier in the disease course, potentially delaying or obviating the need for more toxic chemotherapy regimens.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication

KADCYLA® Improves Overall Survival in Residual HER2-Positive Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive early stage, as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival (OS), when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.

It is well established that patients with HER2-positive early breast cancer, following HERCEPTIN® based neoadjuvant therapies, have a pathological Complete Response rate of 40-60%. Those without a pathological Complete Response tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy.

KATHERINE trial was conducted to evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy along with either single or dual HER2 targeted therapy, in patients with residual invasive cancer at surgery. This study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy.

The KATHERINE trial is an open-label, Phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Patients also received standard-of-care radiation and endocrine therapy as per institutional guidelines. Both treatment groups were well balanced and Hormone Receptor positive disease was present in 72% of the patients. The majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® (dual HER2 blockade) had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival-iDFS (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). The Primary analysis showed that 3-year invasive DFS was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (88.3% vs. 77.0%; HR=0.50; P<0.001), suggesting that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%.

The researchers in this publication reported the prespecified final analysis of invasive DFS, and the second interim analysis of Overall Survival. With a median follow-up of 8.4 years, KADCYLA® sustained its superiority over HERCEPTIN® in improving invasive DFS and OS. The 7-year invasive DFS rate was 80.8% with KADCYLA® vs. 67.1% with HERCEPTIN® (unstratified HR=0.54, confirming a 46% reduction in risk. The 7-year OS was 89.1% with KADCYLA® vs. 84.4% with HERCEPTIN® (unstratified HR=0.66; P=0.003), demonstrating a 34% reduction in mortality risk.

Further analyses revealed consistent benefits across key subgroups which included patients with low tumor burden minimal residual disease (1 cm or less, node-negative), HER2-negative residual disease on retesting, both ER-positive and ER-negative patients, as well as HER2 expression level, with patients with IHC 3+ HER2 expression experiencing the most significant benefit (HR=0.47), whereas those with IHC 2+ ISH-amplified tumors had a smaller, though still positive, effect (HR=0.84).

The incidence of adverse events of Grade 3 or higher was noted in 26.1% of patients receiving KADCYLA® compared to 15.7% in the HERCEPTIN® group. The frequency of CNS metastases was comparable between the two cohorts, suggesting that while KADCYLA® enhances control of extracranial disease, it does not necessarily reduce CNS metastases.

In conclusion, the KATHERINE trial has established KADCYLA® as the new standard of care for patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant therapy. Long-term follow-up confirms sustained benefits in invasive DFS and OS, with an acceptable safety profile. While KADCYLA® significantly reduces recurrence and improves survival, certain high-risk subgroups may require additional therapeutic strategies, prompting the need for ongoing research. Future advancements in HER2-targeted therapies, including Tyrosine Kinase Inhibitors, Antibody Drug Conjugates, and immunotherapy combinations, will further refine treatment strategies and improve outcomes for this high-risk patient population.

Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. Geyer CE, Untch M, Huang C-S, et al. for the KATHERINE Study Group. N Engl J Med 2025;392:249-257

BIZENGRI® for Non Small Cell Lung Cancer and Pancreatic Adenocarcinoma

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SUMMARY: The FDA granted accelerated approval to Zenocutuzumab-zbco (BIZENGRI®) for adults with advanced, unresectable, or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy, or advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy. This represents the first FDA approval of a systemic therapy for patients with NSCLC or pancreatic adenocarcinoma harboring an NRG1 gene fusion.

Genomic rearrangements involving the neuregulin 1 (NRG1) gene have been implicated in a variety of solid tumors, including lung, breast, pancreas, ovarian, and prostate cancers. NRG1 fusions are rare oncogenic drivers occurring in less than 1% of solid tumors, highly enriched in KRAS-wild-type pancreatic adenocarcinoma and invasive mucinous adenocarcinoma of the lung. NRG1 fusions produce chimeric ligands that activate the ERBB Receptor Tyrosine Kinase (RTK) family, a group of proteins frequently exploited by cancer cells to promote tumor growth. In lung cancer, NRG1 fusions are associated with poor prognosis in patients with lung cancer, with low Response Rates to standard chemotherapy and immunotherapy, and a short Overall Survival.

The ERBB RTK family includes EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These proteins mediate crucial cell signaling pathways that regulate growth and survival. They can be oncogenically activated by ligand stimulation such as NRG1 fusion proteins binding to HER3 or HER4, mutations and translocations that may confer constitutive enzymatic activity, such as EGFR kinase domain mutations, the EGFRvIII variant (where the extracellular region of EGFR is deleted), EGFR fusions or gene amplification, or protein overexpression resulting in increasing receptor abundance on cell surfaces to amplify signaling.

NRG1 preferentially binds to HER3 and HER4, promoting their heterodimerization with other ERBB family members like HER2 and EGFR. This interaction is critical because HER3, a pseudokinase, lacks intrinsic enzymatic activity and depends on phosphorylation by its heterodimer partners. The activated HER3 forms docking sites for SH2-domain proteins, triggering multiple downstream signal transduction pathways like the PI3K pathway, which drive proliferation and survival.

Zenocutuzumab is a bispecific humanized immunoglobulin G1 (IgG1) containing two different Fab arms targeting the extracellular domains of HER2 and HER3. The HER2-targeting arm binds HER2, concentrating the antibody locally and positioning it (Dock) to block NRG1 binding to HER3 (Dock-and-block mechanism). The HER3-targeting arm prevents HER3 from undergoing the conformational changes necessary for heterodimerization with HER2 and EGFR. This dual targeting halts HER3 phosphorylation, disrupting downstream oncogenic signaling. Moreover, the glycoengineered IgG1 backbone of Zenocutuzumab enhances its affinity for Fc receptors, boosting Antibody-Dependent Cellular Cytotoxicity (ADCC)-a mechanism by which immune cells destroy antibody-coated tumor cells.

eNRGy is a Phase 2 part of an open-label, multicenter, multicohort, registrational, Phase 1–2 clinical study of Zenocutuzumab, in patients with solid tumors with a NRG1 fusion. A total of 204 patients (N=204) with 12 tumor types were enrolled and patients had a median of one prior line of therapy, including platinum chemotherapy (72%) and Afatinib (11%). The median patient age was 62 years and most were female (60%), and 35% were Asian. The most common NRG1 fusion partners were CD74 (35%), SLC3A2 (14%), ATP1B1 (11%), SDC4/7 (7%), and CDH1/2 (3%). The most common fusion partners among patients with NSCLC were CD74 (in 56%) and SLC3A2 (in 23%), and the most common fusion partner among those with pancreatic cancer was ATP1B1 (in 44%). Most NRG1 fusions were identified by RNA sequencing (81%), followed by DNA sequencing (14%). Patients received Zenocutuzumab 750 mg IV every 2 weeks until disease progression. The Primary efficacy outcome measure was confirmed Overall Response Rate (ORR) and Secondary end points included Duration of Response (DOR), Progression Free Survival (PFS) and Safety. 

Among 158 patients who had measurable disease, the ORR among patients with NSCLC was 29% and median DOR was 12.7 months. The ORR among pancreatic adenocarcinoma patients was 42% and the DOR was 7.4 months. Responses were noted across multiple NRG1 fusion partners. In the pooled safety population, the most common adverse reactions were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common Grade 3 or 4 laboratory abnormalities were increased gamma-glutamyl transferase, anemia, thrombocytopenia and hyponatremia.

It was concluded from this analysis that Zenocutuzumab provided robust and durable efficacy in advanced NRG1 positive NSCLC and pancreatic adenocarcinoma, with a well-tolerated safety profile, and represents a potential first and best-in-class therapy for patients with NRG1 fusion solid tumors.

Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer. Schram AM, Goto K,  Kim D-W, et al. for the eNRGy Investigators. N Engl J Med 2025;392:566-576

Late Breaking Abstract – 2025 ASCO GI Symposium: Circulating Tumor DNA (ctDNA) as a Predictive Biomarker for Celecoxib Benefit in Stage III Colon Cancer: Insights from CALGB/SWOG 80702

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

It is estimated that approximately 30% of patients with Stage II or III CRC and 60-70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation.

More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of Cyclooxygenase 2 (COX-2). Aspirin and COX-2 inhibitors such as Celecoxib have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies.

The CALGB/SWOG 80702 is a randomized Phase III trial conducted to determine if the addition of Celecoxib to adjuvant chemotherapy with Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) improves Disease-Free Survival (DFS) in patients with Stage III colon cancer. Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 versus 6 months with or without 3 years of Celecoxib (400 mg orally daily; N=1263) versus placebo; N=1261). In this study, the addition of Celecoxib for 3 years to standard adjuvant chemotherapy did not significantly improve Disease-Free Survival (DFS).

The present analysis evaluated the prognostic and predictive value of circulating tumor DNA (ctDNA) in identifying a subpopulation of patients in the above study, who may potentially benefit from Celecoxib therapy. A subset of 1,011 patients from the CALGB/SWOG 80702 trial with adequate biospecimen availability was included in this analysis. ctDNA status was assessed using a tumor-informed, clinically validated 16-plex multiplex Polymerase Chain Reaction Next-Generation Sequencing (mPCR-NGS) assay (Signatera(TM), Natera, Inc.). Plasma samples were collected post-surgery and before the initiation of adjuvant chemotherapy. Survival outcomes, including DFS and Overall Survival (OS), were analyzed using Kaplan-Meier estimates and Cox proportional hazards models.

Results:

  • Of the 1,011 patients with ctDNA data, 189 (18.7%) tested ctDNA-positive.
  • ctDNA positivity correlated with male sex, advanced T stage, and N2 nodal disease.
  • Patients with detectable ctDNA had significantly worse outcomes:
    • DFS: Hazard Ratio (HR)=6.52; P<0.0001
    • OS: HR=6.28; P<0.0001
  • Three-year DFS rates were:
    • 6% in ctDNA-negative patients
    • 8% in ctDNA-positive patients
  • Celecoxib did not significantly impact DFS in ctDNA-negative patients (HR=0.75; P=0.095, 3-year DFS: 87.7% vs. 85.5%).
  • However, in ctDNA-positive patients, Celecoxib was associated with a notable improvement in DFS (HR=0.59; P=0.004, 3-year DFS: 44.1% vs. 26.6%).
  • OS trends mirrored those observed for DFS:
    • ctDNA-negative group: HR=0.86 (P=0.49) with Celecoxib versus placebo.
    • ctDNA-positive group: HR=0.63 (P=0.028) with Celecoxib versus placebo.
  • Multivariate analysis confirmed a statistically significant benefit of Celecoxib in ctDNA-positive patients.

Conclusion: ctDNA serves as a strong prognostic biomarker for both DFS and OS in Stage III colon cancer. Furthermore, ctDNA positivity appears to predict a significant therapeutic benefit from adjuvant Celecoxib, suggesting its potential role in stratifying patients for COX-2 inhibitor therapy. These findings highlight the utility of ctDNA assessment in guiding adjuvant treatment decisions and optimizing personalized therapeutic strategies in colon cancer.

Clinical Implications:

  • Post-surgical ctDNA testing can help identify patients at elevated risk of recurrence.
  • Celecoxib may offer a survival advantage for ctDNA-positive patients when used alongside standard FOLFOX chemotherapy.
  • Further research is warranted to elucidate the role of ctDNA-guided treatment in personalizing colon cancer therapy.

Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: Findings from CALGB (Alliance)/SWOG 80702. Nowak JA, Shi Q, Twombly T, et al. J Clin Oncol. 2025;43(4):LBA14.

Breakthroughs in Targeted Therapy for Low-Grade Serous Ovarian Carcinoma

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Written by: Dr. Charles K Anderson, MD
Sponsored by Verastem

Low-grade serous ovarian carcinoma (LGSOC) is a rare and molecularly distinct ovarian cancer accounting for <10% of new epithelial ovarian cancers.1,2 Recently, significant progress has been made with new therapy options currently in the developmental phase. LGSOC commonly presents at advanced stages, with over 70% of patients experiencing relapse.3  There is an indication of slower tumor progression, leading to an extended overall survival (OS) of around 97 months, in contrast to the 72 months typically seen in high-grade serous ovarian carcinoma (HGSOC) cases.4 LGSOC patients tend to have a longer median progression-free survival (PFS) of 97 months, whereas HGSOC patients usually experience 35 months before progression.4 While LGSOC tends to progress slowly, the relatively young age of patients at diagnosis and their resistance to traditional cytotoxic therapy indicate that the majority will ultimately succumb to the disease.3,5,6 

Primary treatment for newly diagnosed patients typically involves primary debulking surgery (PDS) if feasible. The historical standard-of-care (SOC) treatment options include cytotoxic platinum and taxane based regiments often combined with bevacizumab or primary endocrine targeted therapy (ET) with aromatase inhibitors, selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs). In a study of 58 patients with recurrent LGSOC who were treated with a total of 108 cytotoxic regimens, a response rate of only 3.7% was observed with other combined data showing a response rate of 0-13%.3,5,6,7

Promising advancements in targeted therapies such as MEK inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with concurrent endocrine therapy, have exhibited potential in treating LGSOC with improved response rates. LGSOC tumors frequently exhibit activating mutations in the mitogen-activated protein kinase (MAPK) pathway and lack TP53 mutations.8 Given that over 60% of LGSOC tumors carry RAS/RAF mutations, multiple phase 2/3 trials have explored the clinical effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitors in patients with recurrent or persistent LGSOC. Response rates of 26% and 16% were observed with trametinib and binimetinib, respectively, but with discontinuation rates of 36% and 31% due to toxicity.2,7

It has been realized that focal adhesion kinase (FAK) activation in the development of resistance to MEK inhibitors, the phase II trial RAMP201 assessed the effectiveness of avutometinib, a dual RAF/MEK inhibitor, administered alone and in combination with defactinib, a FAK inhibitor, for the treatment of recurrent LGSOC. This trial also included stratification by KRAS mutation status.3 In May of 2023, at the American Society of Clinical Oncology, the findings from the RAMP201 trial were unveiled, indicating an objective response rate (ORR) of 45% and tumor shrinkage in 86% of assessable patients who received the combination therapy of avutometinib and defactinib. The phase 3 confirmatory trial, RAMP 301, will evaluate the effectiveness of avutometinib and defactinib compared to SOC chemotherapy or hormone therapy options. These trials indicate that MAPK pathway inhibitors hold promise in offering clinical advantages to individuals with LGSOC.

 Avutometinib and Defactinib Mechanism of Action

  • Avutometinib is a first-in-class oral RAF/MEK clamp that potently inhibits MEK while also blocking the compensatory reactivation of MEK by upstream RAF1,4
  • Defactinib is a selective inhibitor of FAK, a key adaptive resistance mechanism to the RAS/MAPK pathway9,10,11
  • Phase 1 FRAME study (NCT03875820) demonstrated activity of avutometinib + defactinib study -led to FDA Breakthrough Therapy Designation and rationale for the phase 2 ENGOT-ov60/GOG-3052/RAMP 201 (NCT04625270) study12,13

Summary: RAMP 201: Registration-Directed Phase 2 Trial of Avutometinib ± Defactinib in Patients with Recurrent LGSOC

  • Patient selection: Recurrent LGSOC, prior platinum chemotherapy, measurable disease (RECIST v1.1), prior MEK inhibitor allowed
  • Primary Endpoint: ORR- In KRAS mt patients and all patients (KRAS mt & wt)
  • A go forward regimen was identified with 3 sub-part study with selection phase, expansion phase, expansion combination phase
  • Eventual combination dosing chosen was: Avutometinib 3.2 mg PO BIW and Defactinib 200 mg PO BID
    • ORR: 31% overall; 44% in KRAS mt and 17% in KRAS wt
    • Median DOR: 31 months overall
    • Median PFS: 12.9 months overall; 22.0 months in KRAS mt and 12.8 months in KRAS wt
  • Safety profile: toxicity was acceptable as most adverse events were grade 1 and 2. Adverse events were managed primarily with dose interruptions and reductions with only a 10% discontinuation rate of for adverse events
  • These data support the potential for avutometinib + defactinib as a new standard of care for recurrent LGSOC, regardless of KRAS status

 In conclusion, I am impressed with the results of RAMP 201 trial showing efficacy and tolerability much higher than historical controls comparing traditional cytotoxic therapy, endocrine therapy combinations and other MEK inhibitors.  I am optimistic and excited to see the results of the ongoing RAMP 301 trial (https://clinicaltrials.gov/study/NCT06072781).

References:

  1. Lito, P., et al. (2014). Cancer Cell, 25(5), 697-710.
  2. Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A. A., O’Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., & Churchman, M. (2022). Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): An international, randomised, open-label, multicentre, phase 2/3 trial. The Lancet, 399(10324), 541–553. https://doi.org/10.1016/S0140-6736(21)02175-9Zwimpfer, T. A., Tal, O., Geissler, F., Coelho, R., Rimmer, N., Jacob, F., & Heinzelmann-Schwarz, V. (2023). Low grade serous ovarian cancer – A rare disease with increasing therapeutic options. Cancer Treatment Reviews, 112, 102497. https://doi.org/10.1016/j.ctrv.2022.102497
  3. Gonzalez-Del Pino, G. L., et al. (2021). Proceedings of the National Academy of Sciences of the United States of America, 118(36), e2107207118.
  4. Gershenson, D. M., Sun, C. C., Bodurka, D., Coleman, R. L., Lu, K. H., Sood, A. K., Deavers, M., Malpica, A. L., & Kavanagh, J. J. (2009). Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecologic Oncology, 114(1), 48–52. https://doi.org/10.1016/j.ygyno.2009.03.001
  5. Gockley, A., Melamed, A., Bregar, A. J., Clemmer, J. T., Birrer, M., Schorge, J. O., del Carmen, M. G., & Rauh-Hain, J. A. (2017). Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstetrics & Gynecology, 129(3), 439–447. https://doi.org/10.1097/AOG.0000000000001867
  6. Monk, B. J., et al. (2020). Journal of Clinical Oncology, 38(32), 3753–3762..
  7. Manning-Geist, B. L., et al. (2024). Clinical Advances in Hematology & Oncology, 22(5), 205–226.
  8. Vang, R., Shih, I. M., & Kurman, R. J. (2009). Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Advances in Anatomic Pathology, 16(5), 267-282. https://doi.org/10.1097/PAP.0b013e3181b4fffa.
  9. Dawson, J. C., et al. (2021). Nature Reviews Cancer, 21, 313–324
  10. Shinde, R., et al. (2020). Cancer Research, 80(Suppl 16), CT143.
  11. Kang, Y., et al. (2013). Journal of the National Cancer Institute, 105(19), 1485–1495
  12. Banerjee, S., et al. (2021). Annals of Oncology, 32(Suppl 5), S7.
  13. Verastem Oncology. (2021, May 24). Press release: Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. Retrieved September 28, 2023, from https://investor.verastem.com/node/12421/pdf.

 

Late Breaking Abstract – 2025 ASCO GU Cancers Symposium: Talazoparib Plus Enzalutamide Improves Overall Survival in mCRPC

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.

Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as Bicalutamide (CASODEX®), Nilutamide (NILANDRON®) and Flutamide (EULEXIN®) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPIs), which include Abiraterone (ZYTIGA®), Enzalutamide (XTANDI®), Apalutamide (ERLEADA®) and Darolutamide (NUBEQA®).

For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Pathway Inhibitors (ARPIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HRR pathway. At least 15 genes are involved in the HRR pathway including BRCA1, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 30% of patients with advanced prostate cancer, including metastatic CRPC. Patients with metastatic CRPC harboring BRCA alterations and other HRR gene alterations have poor outcomes, and earlier resistance to commonly used systemic therapies.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in HRR genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. PARP inhibitors have demonstrated significant activity in patients with prostate cancer and HRR gene alterations, with the greatest clinical benefit noted in BRCA1/2 mutation carriers.

Talazoparib (TALZENNA®) is a PARP inhibitor presently approved for HRR Gene-Mutated CRPC and for Germline BRCA- mutated advanced breast cancer.

TALAPRO-2 trial is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study that enrolled 1,035 unique patients with mCRPC (who had not received new life-prolonging systemic treatments after documentation of mCRPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: Cohort 1 included all comers (N=805, of whom 169 had HRR mutations and 636 did not) and Cohort 2 included those with HRR gene mutations (N=399, including 169 patients from Cohort 1 and 230 enrolled in Cohort 2). A total of 805 patients in Cohort 1 were randomized in a 1:1 ratio to receive either Talazoparib 0.5 mg daily plus Enzalutamide 160 mg daily (N=402) or placebo plus Enzalutamide (N= 403). Randomization was stratified based on HRR gene alteration status and prior Abiraterone or Docetaxel (yes/no) for castration-sensitive prostate cancer. Eligible patients had asymptomatic or mildly symptomatic mCRPC, ECOG PS 1 or less, ongoing Androgen Deprivation Therapy, and no prior life-prolonging therapy for CRPC. All patients underwent tumor tissue testing before enrollment, and approximately 20% were found to have HRR alterations. Specific gene mutations, including BRCA1, BRCA2, ATM, and CDK12, were evenly distributed across treatment arms, with BRCA1 and BRCA2 alterations found in approximately 7% of patients. The Primary endpoint of the study was radiographic Progression-Free Survival (rPFS), and Overall Survival (OS) was a key Secondary endpoint. The researchers had previously reported that TALAPRO-2 trial met its Primary endpoint, showing improved radiographic PFS for Talazoparib plus Enzalutamide compared to placebo plus Enzalutamide as first line treatment in patients with mCRPC unselected for HRR gene alterations (Cohort 1). The final OS data, updated rPFS, and extended safety follow-up in Cohort 1 was reported in this publication

The final OS analysis demonstrated a statistically significant and clinically meaningful improvement in survival for patients treated with Talazoparib plus Enzalutamide compared to Enzalutamide alone. The median OS in the Talazoparib plus Enzalutamide group was 45.8 months versus 37.0 months in the placebo arm, representing a 20% reduction in the risk of death (HR=0.796; P=0.0155). Patients with HRR-deficient tumors had a greater reduction in the risk of death (38%), with a median OS improvement of 14 months (HR=0.622; P=0.0005). The median OS with Talazoparib plus Enzalutamide was 45.1 months and 31.1 months in the placebo plus Enzalutamide group. Patients without HRR mutations still benefited from an approximate 9-month OS gain.

In patients with BRCA1/2 alterations, the median OS was not reached in the Talazoparib plus Enzalutamide group versus 28.5 months in the placebo plus Enzalutamide group (HR=0.497; P =0.0017). For those with non-BRCA1/2 HRR alterations, the median OS was 42.4 versus 32.6 months (HR=0.727; P=0.0665).

The updated rPFS data continued to favor Talazoparib plus Enzalutamide. The median rPFS was 33.1 months versus 19.5 months in the placebo arm (HR=0.667; P<0.0001). In the HRR-deficient cohort, median rPFS was 30.7 months versus 12.3 months (HR=0.468; P <0 .0001).

No new safety signals emerged with extended follow-up. The most common adverse event was anemia. Grade 3-4 anemia occurred in 49% of the unselected population and 43.4% of the HRR-deficient population. Talazoparib discontinuation due to adverse events was 21.6% in the unselected population and 13.1% in the HRR-deficient cohort. Anemia-related discontinuations were 8.5% in the unselected population and 4.5% in the HRR-deficient group.

It was concluded from this study that Talazoparib plus Enzalutamide significantly improved OS and rPFS compared to Enzalutamide alone in both HRR-deficient and non-deficient populations. The findings support the broad use of this combination as a new standard of care for treatment-naïve patients with mCRPC.

Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. Agarwal N, Azad A, Carles J, et al. J Clin Oncol. 2025,43(suppl 5):LBA141. doi:10.1200/JCO.2024.42.4_suppl.LBA18.

Late Breaking Abstract – 2025 ASCO GI Symposium: Aspirin Reduces Recurrence in Colorectal Cancer Patients with PI3K Pathway Alterations

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Among patients with Stage II-III CRC, 20-40% will develop metastatic disease.

The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of CRC in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and CRC, in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.

Aspirin has been shown to lower the incidence of adenomas and CRC in high-risk patients. Additionally, observational studies suggest that treatment with Aspirin following diagnosis improves Disease-Free Survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response to Aspirin. However this has not been validated in randomized trials.

The ALASCCA trial was designed to find the impact of Aspirin, on the recurrence of CRC with PI3K pathway mutations. The ALASCCA trial is a randomized, double-blind, multicenter, placebo-controlled trial conducted across 33 hospitals in Sweden, Denmark, Finland, and Norway. Researchers screened 3,508 patients diagnosed with Stage II or III colon cancer or Stage I, II, or III rectal cancer and identified 1,103 individuals with PI3K pathway mutations. Participants were categorized into two groups:

• Group A (N=515): Patients with a PIK3CA mutation in exon 9 and/or 20.
• Group B (N=588): Patients with other PI3K mutations, including PIK3CA mutations outside exon 9/20 or mutations in PIK3R1 or PTEN genes.

Of the 626 patients (419 with colon cancer and 207 with rectal cancer) who continued participation in this trial, 157 and 156 patients in Groups A and B respectively, received Aspirin 160 mg daily for 3 years, whereas 157 and 156 patients in each respective group received placebo. The median age was 66 years, 52% of patients were female, and majority of patients were white. Fifty percent of patients with both rectal and colon cancer had received neoadjuvant therapy. The Primary end point was Time to CRC recurrence (TTR). Secondary end points included Disease Free Survival (DFS) in Group A, TTR in Group B, DFS in Group B, and Safety.

The study met its Primary end point and demonstrated that Aspirin use significantly reduced the risk of CRC recurrence. After 3 years of follow up in Group A, patients taking Aspirin had a 51% lower recurrence risk compared to the placebo group (HR=0.49; P=0.044). In Group B, patients taking Aspirin experienced a 58% reduction in recurrence risk versus the placebo group (HR=0.42; P=0.013). Overall, across all groups, Aspirin was associated with a 55% reduced risk of recurrence compared to placebo. There was no statistically significant difference in 3-year DFS rates among those who received Aspirin versus placebo in Group A (88.5% versus 81.4%, respectively; HR=0.61; P =0.091). There was however significantly improved DFS rates in Group B with Aspirin use (89.1% versus 78.7%, respectively; HR=0.51; P=0.17). Severe side effects of daily Aspirin use were rare.

The researchers concluded that this landmark study provides compelling evidence for the role of low-dose Aspirin in reducing colorectal cancer recurrence in patients with PI3K pathway mutations. By integrating precision medicine with a widely available drug, the ALASCCA trial sets the stage for a new standard in colorectal cancer management.

Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial. Martling A, Lindberg J, Myrberg IH, et al. J Clin Oncol. 2025;43(4):LBA125.

Anthracycline Plus Taxane Based Adjuvant Therapy for High risk Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. In the treatment of early-stage breast cancer, particularly in Hormone Receptor-positive (HR-positive) and HER2-negative cases, the standard approach to adjuvant chemotherapy has evolved, with the goal of optimizing patient outcomes while minimizing unnecessary toxicity. Historically, anthracyclines, a class of chemotherapy drugs, were combined with taxanes as part of chemotherapy regimens. However, recent studies have questioned the benefit of adding anthracyclines to treatment, for patients with HR-positive/HER2-negative breast cancer, particularly in those with lower recurrence risk. The addition of anthracyclines has not definitively demonstrated improvements in outcomes like invasive Disease-Free Survival (DFS) for patients with HR-positive/HER2-negative breast cancer who receive taxane-based chemotherapy. Anthracycline-free regimens are typically preferred for lower risk patients, as efficacy is not compromised and there is no heightened risk of long-term side effects, such as leukemia. Yet, a gap exists in the literature regarding the benefit of anthracycline therapy in patients with high-risk profiles, as identified by OncotypeDX assay.

The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy following surgery, in women with early-stage breast cancer. Oncotype Dx assay categorizes patients based on Recurrence Scores (RS) into Low risk (0-10), Intermediate risk (11-25), and High risk (26-100) helping clinicians tailor treatment decisions. Despite the widespread clinical use of OncotypeDX, the potential benefits of anthracyclines for patients with high RS scores have not been comprehensively studied.

The Anthracyclines in Early Breast Cancer (ABC) trials demonstrated that the addition of anthracyclines to a taxane-based chemotherapy regimen did not significantly improve invasive DFS for patients with HR-positive breast cancer. As a result, HR-positive/HER2-negative patients with a lower RS or smaller tumors have generally been managed with anthracycline-free regimens.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a Phase III, randomized, prospective, non-inferiority trial in which 10,273 women, 18-75 years of age, with HR-positive, HER2-negative, T1b-T2N0 early-stage axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score (RS). Women with a Low RS of 0-10 received endocrine therapy alone and those with a High RS of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy which included T-AC (Taxane usually Docetaxel along with anthracycline usually Doxorubicin plus Cyclophosphamide, or TC (Taxane plus Cyclophosphamide, but without an anthracycline). Patient with Intermediate RS of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone (N=3399) or endocrine therapy and adjuvant chemotherapy (N=3312).TAILORx study concluded that among patients with a Recurrence Score of 11-25, endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy.

A subset of 2,591 patients, who had a recurrence score between 11 and 100, formed the basis for this analysis. Among them, 437 patients received T-AC, while 2,091 received TC regimen. Outcomes were compared between patients who received T-AC and those who received TC, adjusting for key variables such as age, RS, tumor size, grade, and Estrogen/Progesterone Receptor status. Outcomes were stratified by RS > 31 and < 31.The study population had a median age of 55 years, and median follow up was 7.3 years. The Primary end point of this study was to evaluate Distant Recurrence-Free Interval (DRFI). Other outcomes included Recurrence-Free Survival (RFS) and Overall Survival (OS).

Impact of Recurrence Score
This analysis revealed that the addition of anthracyclines to chemotherapy provided distinct benefits for patients with a high RS, specifically those with an RS of 31 or higher. Among this high risk group, the 5-year Distant Recurrence-Free Interval (DRFI) was significantly improved with T-AC compared to TC (adjusted DRFI rate was 97.5% for T-AC versus 89.4% for TC (adjusted HR=0.27, P=0.01). Similarly, Distant Recurrence-Free Survival (DRFS) was 96.5% for T-AC versus 88.3% for TC (adjusted HR=0.45, P= 0.03), and Recurrence-Free Survival (RFS) was also superior with T-AC. There was a trend towards improved OS at 5 years. For patients with an RS of less than 31, no significant benefit was observed from the addition of anthracyclines. This was particularly true for patients with an RS between 26 and 30, where no clear advantage of T-AC over TC was seen. In these lower-risk patients, both the DRFI and DRFS were similar between the two regimens.
The benefit of T-AC over TC increased further for higher RS values indicating that patients with higher recurrence scores saw more significant benefits from the addition of anthracyclines (HR=0.60 for RS 40 and HR=0.45 for RS 50).

Effect of Tumor Size
The benefit of T-AC in high-risk patients was particularly pronounced in tumors larger than 2 cm. While the primary endpoint of DRFI showed improvement with T-AC when the recurrence score was higher than 31regardless of tumor size, secondary endpoints, including DRFS, were notably enhanced in patients with tumors above the 2 cm size threshold. In contrast, smaller tumors (2 cm or less) did not demonstrate a benefit from the addition of anthracyclines.

Effect in Premenopausal and Postmenopausal Patients
Both premenopausal and postmenopausal patients with high RS showed a benefit from the addition of anthracyclines to chemotherapy. The DRFI advantage was seen in both groups, with statistical significance for premenopausal patients (P=0.032) and a trend toward significance for postmenopausal patients (P=0.028).

Risk of Non-Breast Cancer Deaths
An important consideration when making treatment decisions are the potential risks associated with anthracycline use, especially long-term risks such as leukemia or other non-breast cancer deaths.

In conclusion, the TAILORx analysis suggests that for patients with early stage, HR-positive/HER2-negative breast cancer, OncotypeDX Recurrence Score appears to be a reliable predictor of which patients might benefit from anthracyclines. Patients with a high recurrence score (RS 31 or more) derived significant benefit from the addition of anthracyclines to chemotherapy, especially those with tumors larger than 2 cm. The study was a post-hoc analysis of the TAILORx trial, which was not specifically designed to evaluate the benefit of anthracyclines and must be interpreted with caution pending further validation in prospective trials.

Impact of Anthracyclines in High Genomic Risk Node-Negative HR+/HER2- Breast Cancer. Chen N, et al. Abstract GS3-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-13, 2024; San Antonio, TX. Abstract GS3-03