Category: Meeting Updates

Late Breaking Abstract – ASCO 2025: A New Era for High-Risk Resected Head and Neck Cancer: Nivolumab Adds Disease-Free Survival Benefit in NIVOPOSTOP Trial

RR

SUMMARY: The American Cancer Society estimates that 59,660 new cases of cancer involving the oral cavity and pharynx will be diagnosed in the US in 2025 and 12,770 will die of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma (SCC) of the Head and Neck accounts for about 3-5% of all cancers in the United States. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Even though tobacco has long been associated with head and neck cancer development, cannabis has similar carcinogens.

The Standard of Care for patients with Stage III–IVA Head and Neck Squamous Cell Carcinoma (HNSCC) has remained largely static for nearly 2 decades: surgery followed by risk-adapted adjuvant radiotherapy, with or without concurrent Cisplatin based chemotherapy. Despite refinements in technique and supportive care, relapse rates remain high, particularly among patients with adverse pathological features such as extranodal extension and positive margins.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Phase 3 NIVOPOSTOP trial (GORTEC 2018-01) provides compelling evidence that integrating immunotherapy into the adjuvant setting may finally shift this long-standing treatment landscape. Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.

Study Design and Patient Population
NIVOPOSTOP (NCT03576417) was an international, randomized, open-label Phase 3 study that enrolled 680 patients with completely resected LA-SCCHN (Locally Advanced Squamous Cell Carcinoma of the Head and Neck), which included the oral cavity, oropharynx, hypopharynx, and larynx. Eligible patients were less than 75 years old, with ECOG performance status 0-1, and exhibited high-risk features for recurrence, including extracapsular nodal extension, positive surgical margins, involvement of 4 or more lymph nodes, or extensive perineural invasion. PD-L1 expression was not required for study eligibility. Majority of patients had disease of the oral cavity (58%), about 50% were current smokers, most patients had Stage IVA or IVB disease (83%), and slightly more than one-half of patients (56%) had a PD-L1 Combined Positive Score less than 20. Patients were first stratified by HPV status and enrolling center before being randomly assigned to receive standard CRT or standard CRT plus nivolumab.

Patients were randomized 1:1 to receive:

  • Control Arm (SOC CRT): 66 Gy radiotherapy with three cycles of Cisplatin 100 mg/m² Q3W (N=334).
  • Experimental Arm (NIVO + CRT): One lead-in dose of Nivolumab 240 mg, followed by CRT plus Nivolumab 360 mg Q3W for three cycles, followed by six cycles of Nivolumab 480 mg Q4W for maintenance (N=332).

Both treatment groups were well balanced. The Primary endpoint was Disease Free Survival (DFS). Key Secondary endpoints include Overall Survival (OS) and Safety.

Primary Endpoint Met: Significant Improvement in Disease-Free Survival
At a median follow-up of 30.3 months, the trial met its Primary endpoint. Among the 666 patients included in the Disease-Free Survival (DFS) analysis (ITT population), the addition of adjuvant Nivolumab significantly reduced the risk of disease recurrence or death compared with CRT alone (HR 0.76; 95% CI, 0.60–0.98; P = 0.034).

Three-year DFS rates were 63.1% with NIVO + CRT (95% CI, 57.0–68.7) and 52.5% with CRT alone (95% CI, 46.2–58.4). This represents a 24% relative reduction in recurrence risk with Nivolumab. Importantly, this benefit was observed across all PD-L1 expression levels, supporting the use of this strategy in an unselected population.

Safety Profile: Manageable Toxicity with Increased Grade 3–4 Events
While the addition of Nivolumab was associated with an increase in grade 3-4 adverse events, particularly within the first 100 days post-CRT (13.1% vs. 5.6%), no increase in treatment-related mortality was seen (0.6% vs. 0.7%). Late grade ≥3 toxicities occurring beyond 9 months were rare in both groups and did not exceed grade 3. The overall safety profile was considered acceptable and consistent with known immune-related toxicities.

Locoregional Control Improved with Nivolumab
One of the most noteworthy findings was a significant reduction in locoregional recurrences. At 3 years, locoregional failure occurred in 13% of patients in the NIVO + CRT arm versus 20% in the CRT-only arm (HR 0.63; 95% CI, 0.42–0.94). Interestingly, unlike perioperative immunotherapy regimens such as KEYNOTE-689 that predominantly reduced distant failures, NIVOPOSTOP’s benefit was concentrated in locoregional disease control, suggesting a synergistic effect between radiotherapy and immune checkpoint inhibition.

Survival Data Pending but Trending Favorably
Although Overall Survival (OS) data remain immature, early trends favor the Nivolumab arm. At the time of reporting, 74% of patients receiving NIVO + CRT remained alive at 3 years, compared to 68% in the CRT-alone group. The final OS analysis is planned upon reaching 283 events (currently at 158).

Clinical Context and Expert Perspectives
The NIVOPOSTOP findings stand in sharp contrast to prior trials like KEYNOTE-412 and JAVELIN Head and Neck 100, which failed to show benefit from concurrent immune checkpoint inhibitor with CRT in unselected populations. Notably, the timing and sequencing of immunotherapy in NIVOPOSTOP, administered in the postoperative setting and continued as maintenance may have circumvented the immunosuppressive milieu of CRT and allowed more robust immune priming. The researchers emphasized the clinical need among the ~40–45% of LA-SCCHN patients who relapse after surgery and CRT.

Conclusion
NIVOPOSTOP represents the first successful Phase 3 trial to demonstrate a Disease-Free Survival advantage with the addition of immunotherapy to adjuvant CRT in high-risk, resected LA-SCCHN. With a favorable balance of efficacy and manageable toxicity, this regimen is poised to reshape clinical practice, marking a long-overdue advancement in the postoperative management of head and neck cancer.

NIVOPOSTOP (GORTEC 2018-01): A phase III randomized trial of adjuvant nivolumab added to radio-chemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse. Bourhis J, Auperin A, Borel C, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA2).

Pregnancy-Specific Glycoproteins Linked to Poorer Prognosis in Female Lung Adenocarcinoma Patients

RR

SUMMARY: Pregnancy-Specific Glycoproteins (PSGs), traditionally known for their role in fetal development and maternal immune tolerance, are emerging as unexpected contributors to oncologic processes. These placental proteins, members of the CarcinoEmbryonic Antigen Cell Adhesion Molecule (CEACAM) family and the broader immunoglobulin superfamily, are produced by trophoblasts and secreted into maternal circulation during pregnancy in high concentrations and act as immunomodulators, facilitating maternal-fetal tolerance and vascular remodeling. However, recent evidence suggests that these proteins may be aberrantly expressed in several malignancies, including lung cancer, with potentially detrimental effects, particularly among female patients.

Background and Rationale
While PSGs are primarily restricted to the placenta under normal physiological conditions, prior research has revealed their ectopic expression in various cancers such as breast, ovarian, uterine, and colon tumors. Their expression in these settings has been correlated with poorer overall survival. Yet the mechanisms and potential sex-specific effects remained unclear. Recognizing the immunological parallels between pregnancy and tumor immune evasion, researchers hypothesized that PSGs might confer a selective disadvantage in cancers by modulating the tumor microenvironment in a sex-dependent manner.

Study Design and Methodology
To explore this hypothesis, investigators conducted a sex-stratified analysis of PSG expression and survival outcomes using two independent transcriptomic datasets: The Cancer Genome Atlas (TCGA), encompassing 235 male and 271 female Lung Adenocarcinoma patients, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), including 70 male and 36 female patients. PSG mRNA expression profiles were integrated into machine learning models to assess their prognostic value. Key PSG family members, PSG3, PSG7, and PSG8 were specifically examined for their association with survival outcomes.

Key Findings
This analysis revealed a striking sex-specific prognostic disparity in Lung Adenocarcinoma. Female patients with elevated PSG expression exhibited significantly worse Overall Survival compared to their PSG-negative counterparts, a trend not observed in male patients. Notably, a combined expression signature of PSG3, PSG7, and PSG8 identified a high-risk subgroup encompassing approximately 30% of female patients. This signature was significantly associated with poor prognosis.

Pathway enrichment analysis further uncovered that PSG-expressing female Lung Adenocarcinoma tumors showed upregulation of the “KRAS Signaling Down” pathway, suggesting a potential mechanistic link. Incorporating KRAS pathway activity into the predictive model improved its prognostic performance in female patients, reinforcing the notion that PSGs may interface with oncogenic KRAS signaling in a sex-dependent fashion.

Clinical Implications
These findings underscore a previously unrecognized, sex-specific role for PSGs in modulating lung cancer outcomes. The ectopic expression of PSGs appears to mimic their immune-regulatory function during pregnancy, potentially allowing tumors to evade immune surveillance, particularly in female patients. As a result, PSG expression may serve as a prognostic biomarker and a novel therapeutic target in Lung Adenocarcinoma.

The research team is now investigating the development of antibody-based therapeutics aimed at inhibiting PSG expression, with the goal of improving outcomes in this vulnerable subgroup of female Lung Adenocarcinoma patients. Given that PSGs are typically silenced outside of pregnancy, targeting them may provide a tumor-specific strategy with minimal off-target effects.

Future Directions
Further investigations are planned to delineate the interplay between PSG expression, pregnancy history, and hormone-related gene activity. Such studies could elucidate whether reproductive history or endocrine factors influence the reactivation of PSG genes in female tumors, potentially refining risk stratification and therapeutic approaches.

Conclusion
This research highlights the adaptive reuse of fetal tolerance mechanisms by tumors and reveals PSGs as key contributors to sex-specific disparities in Lung Adenocarcinoma prognosis. By integrating transcriptomic profiling with clinical outcomes and pathway analysis, this study provides a compelling rationale for the clinical development of PSG-targeted therapies in female Lung Adenocarcinoma.

Pregnancy-specific glycoproteins in tumors are strong predictors of outcome in female lung adenocarcinoma patients. Oh JH, Rizzuto G, Elkin R, et al. Presented on April 28, 2025: AACR Annual Meeting 2025.

Zongertinib Shows Promising Efficacy and Safety in HER2-Mutant NSCLC: Insights from the Beamion LUNG-1 Trial

RR

SUMMARY: The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein, and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers and are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases.

The FDA in 2022 granted accelerated approval to ENHERTU® (Trastuzumab deruxtecan), for adult patients with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) mutations. This is the first drug approved for HER2-mutant NSCLC. Trastuzumab deruxtecan however can be associated with toxicities including Interstitial Lung Disease (ILD). Similarly, pan-HER TKIs such as Poziotinib and Pyrotinib have shown limited efficacy and are frequently associated with EGFR-related adverse events, underscoring the urgent need for more targeted, better-tolerated therapies.

Zongertinib is a novel, oral, irreversible Tyrosine Kinase Inhibitor designed to selectively target HER2 while sparing EGFR, thus minimizing common toxicities such as rash and diarrhea.

Beamion LUNG-1 is an ongoing Phase 1a/1b trial evaluating Zongertinib in previously treated patients with HER2-altered advanced or metastatic solid tumors (Phase 1a) and those with HER2-mutant advanced or metastatic NSCLC across multiple clinically relevant patient cohorts (Phase 1b). In the Phase 1a dose-escalation trial, Zongertinib showed encouraging preliminary activity at the recommended expansion doses of 120 mg and 240 mg once daily, with a low incidence of Grade 3 or higher adverse events.

The Phase 1b portion of the study evaluated Zongertinib in three key populations:

  • Cohort 1: Patients with tumors harboring HER2 mutations in the TKD (Tyrosine Kinase Domain), the most common category of HER2 mutations encountered in the clinic.
  • Cohort 5: Patients whose tumors had HER2 mutations within the TKD and had previously received HER2-directed ADCs, including Trastuzumab deruxtecan.
  • Cohort 3: Patients whose tumor had HER2 mutations outside the TKD.

Patients were initially treated at 120 mg or 240 mg daily and following interim analysis, 120 mg was selected as the optimal dose based on a favorable efficacy and safety balance. The median age in Cohort 1 was 62 yrs. The Primary end point was an Objective Response Rate (ORR) assessed by Blinded Independent Central Review (Cohorts 1 and 5) or by Investigator Review (Cohort 3). Secondary end points included the Duration of Response and Progression-Free Survival (PFS).

Efficacy Outcomes
The median follow-up was 11.3 months at the data-cutoff date. Zongertinib demonstrated robust and durable activity, particularly in Cohort 1:

  • Cohort 1 (N=75 at 120 mg daily dose):
    • Objective response rate (ORR): 71% (P<0.001)
    • Median Duration of Response (DoR): 14.1 months
    • Median progression-free survival (PFS): 12.4 months

Importantly, responses were consistent across subgroups, including patients with brain metastases (ORR: 64%) and common TKD insertion subtypes such as A775_G776insYVMA (ORR: 81%).

  • Cohort 5 (N=31):
    • ORR: 48%, including patients previously treated with Trastuzumab deruxtecan (ORR: 42%)
  • Cohort 3 (N=20):
    • ORR: 30%
    • Activity observed across several non-TKD mutations (e.g., S310X, V659E)

These findings suggest that Zongertinib may offer a viable treatment option even in patients who have progressed on ADCs or harbor atypical HER2 alterations.

Safety and Tolerability
Zongertinib was well tolerated across all cohorts:

  • Grade ≥3 drug-related adverse events occurred in:
    • 17% of patients in Cohort 1
    • 3% in Cohort 5
    • 25% in Cohort 3
  • No cases of drug-related interstitial lung disease were observed
  • Most common adverse event was diarrhea (any grade: 56%; grade ≥3: 1%), followed by rash (all grade ≤2)

The safety profile compares favorably with existing HER2-targeted agents, including Trastuzumab deruxtecan, which has reported interstitial lung disease rates of up to 26% in earlier trials.

Clinical Context and Future Directions
Compared with other HER2-targeted agents including Trastuzumab deruxtecan and investigational pan-HER TKIs, Zongertinib stands out for its high response rates, durability, and manageable toxicity. While cross-study comparisons have inherent limitations, these results support Zongertinib as a promising, HER2-selective oral agent for patients with HER2-mutant NSCLC. The ongoing Phase 3 Beamion LUNG-2 trial (NCT06151574) will further assess Zongertinib in the first-line setting, providing critical data on its role relative to current standard-of-care therapies.

Conclusion
Zongertinib has emerged as a strong candidate in the evolving landscape of HER2-mutant NSCLC. With high response rates, durable outcomes, and a favorable safety profile, it may soon offer oncologists a powerful new tool for treating this difficult-to-manage patient population.

Zongertinib in Previously Treated HER2-Mutant Non–Small-Cell Lung Cancer. Heymach JV, Ruiter G, Ahn M-J, et al. for the Beamion LUNG-1 Investigators. Published April 28, 2025. DOI: 10.1056/NEJMoa2503704

Perioperative KEYTRUDA® Reshapes the Treatment Landscape for Resectable Locally Advanced HNSCC

RR

SUMMARY: The American Cancer Society estimates that 59,660 new cases of cancer involving the oral cavity and pharynx will be diagnosed in the US in 2025 and 12,770 will die of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma (SCC) of the Head and Neck accounts for about 3-5% of all cancers in the United States. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Even though tobacco has long been associated with head and neck cancer development, cannabis has similar carcinogens.

The Standard of Care for patients with Stage III–IVA Head and Neck Squamous Cell Carcinoma (HNSCC) has remained largely static for nearly 2 decades: surgery followed by risk-adapted adjuvant radiotherapy, with or without concurrent chemotherapy. Despite refinements in technique and supportive care, relapse rates remain high, particularly among patients with adverse pathological features such as extranodal extension and positive margins.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Pembrolizumab (KEYTRUDA&reg;) is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. Pembrolizumab has been shown to improve Overall Survival in patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

KEYNOTE-689, a landmark Phase 3 trial, has provided the most compelling evidence to date that perioperative immunotherapy, specifically Pembrolizumab, can significantly improve clinical outcomes for patients with resectable, locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC). This international, randomized, placebo-controlled study enrolled 714 patients (N=714) with newly diagnosed, resectable, Stage III–IVA HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx.

Patients were randomized 1:1 to receive:

  • Investigational arm (N=356):
    • 2 cycles of neoadjuvant Pembrolizumab (200 mg IV Q3W) starting about 3 weeks before surgery.
    • Standard-of-care surgery.
    • Up to 3 doses of Pembrolizumab administered concurrently with adjuvant chemoradiotherapy (depending on pathologic risk).
    • 12 additional adjuvant doses of Pembrolizumab Q3W (total treatment duration: about 1 year).
  • Control arm (N=358):
    • Identical treatment structure, substituting placebo for Pembrolizumab.

PD-L1 expression was assessed via Combined Positive Score (CPS), and stratification included CPS ≥1 and CPS ≥10 subgroups, recognizing the prognostic and potentially predictive value of PD-L1 expression. The Primary endpoint was Event-Free Survival (EFS), defined as time from randomization to disease progression, local/regional recurrence, distant metastasis, or death from any cause. Secondary endpoints included Overall Survival (OS) and Major Pathological Response.

The trial met its Primary endpoint of EFS. At median follow-up of 38.3 months, patients in the investigational arm had significantly improved EFS compared with the Standard of Care arm (median 51.8 months vs. 30.4 months; HR=0.73; P=0.0041). Patients who received Pembrolizumab who had a CPS score ≥10 derived the greatest benefit (median 59.7 months vs. 26.9 months; HR = 0.66; P=0.002) whereas the median EFS in the CPS ≥1 subgroup was 59.7 vs. 29.6 months (HR, 0.70; P = .0014).

Major pathological response defined as 90% or more tumor regression was also notably improved. Among all patients, the major pathological response rate was 9.4% with Pembrolizumab vs. 0% with Standard of Care (P < 0.00001). In the CPS ≥10 subgroup, the major pathological response rate reached 13.7%.

While the interim analysis did not demonstrate a statistically significant OS benefit, trends were favorable, particularly in the CPS ≥10 group (HR, 0.72; P =0.02). Further OS follow-up is ongoing.

Adverse events were consistent with known profiles of checkpoint inhibitors. Grade 3 or more  Treatment-Related Adverse Events (TRAEs) occurred in 44.6% of the Pembrolizumab group and 42.9% in the Standard of Care group. Immune-mediated adverse events were observed in 43.2% of the Pembrolizumab arm, with hypothyroidism being the most common (24.7%). Mortality attributable to treatment was slightly higher with Pembrolizumab (1.1% vs. 0.3%).

The researchers concluded that perioperative Pembrolizumab is now emerging as a new standard of care in the treatment of resectable locally advanced HNSCC. The findings from this study underscore the importance of harnessing the immune system both before and after surgery. Neoadjuvant administration may prime the immune response when tumor antigen burden is highest, while adjuvant therapy may help eliminate residual microscopic disease.

Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: phase 3 KEYNOTE-689 study. Uppaluri R, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago.

 

Ongoing Benefit with Enfortumab Vedotin Plus Pembrolizumab in Metastatic Urothelial Carcinoma

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2025, about 84,870 new cases of bladder cancer will be diagnosed and approximately 17,420 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. However, approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy due to toxicities, and responses are rarely durable. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic urothelial carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is a first-in-class Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, MonoMethyl Auristatin E (MMAE), which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-302 is a landmark Phase III, global, open-label, randomized trial comparing the efficacy and safety of Enfortumab vedotin and Pembrolizumab with the efficacy and safety of platinum-based chemotherapy, in patients with previously untreated locally advanced or metastatic urothelial carcinoma. A total of 886 eligible patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of Enfortumab vedotin 1.25 mg/kg IV on days 1 and 8 and Pembrolizumab 200 mg IV on day 1 of every 3-week cycle (N=442) or chemotherapy consisting of Gemcitabine and either Cisplatin or Carboplatin (N=444), determined on the basis of eligibility to receive Cisplatin, for a maximum of 6 cycles. The maximum number of Pembrolizumab cycles allowed was 35 and there was no maximum number of cycles set for Enfortumab vedotin. The treatment groups were well balanced. The median age was 69 yrs and randomization was stratified according to eligibility to receive Cisplatin (eligible or ineligible), PD-L1 expression status (High-CPS 10 or more versus Low-CPS less than 10), and liver metastases (present or absent). The co-Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included Overall Response Rate (ORR) as assessed by BICR, Duration of Response, and Safety.

In the primary analysis of EV-302 (KEYNOTE-A39) study, the combination of Enfortumab vedotin plus Pembrolizumab group nearly doubled median PFS (12.5 months versus 6.3 months) and OS (31.5 months versus to 16.1 months), when compared to platinum-based chemotherapy, in patients with previously untreated locally advanced or metastatic urothelial carcinoma.

In this report, the researchers reported the outcomes of EV-302 study after 1 year of additional follow-up (about 2.5 years of median follow-up), and an exploratory analysis of patients with confirmed Complete Response.

The PFS benefit with Enfortumab vedotin plus Pembrolizumab was maintained with an additional year of follow-up (12.5 versus 6.3 months; HR=0.48; P<0.00001). The OS benefit was also maintained with Enfortumab vedotin plus Pembrolizumab with a 49% reduction in the risk of death, when compared to platinum-based chemotherapy (33.8 versus 15.9 months; HR=0.51; P<0.00001). The PFS and OS benefit was observed across prespecified subgroups, including the Cisplatin-eligible and ineligible patients.

The ORR in the Enfortumab vedotin plus Pembrolizumab group was 67.5% versus 44.2% in the chemotherapy group (P<0.0.001) and the median Duration of Response was 23.3 months versus 7.0 months, respectively. A Complete Response was observed in 30.4% of patients treated with Enfortumab vedotin plus Pembrolizumab versus 14.5% among patients treated with chemotherapy. The median duration of Complete Response was not reached for Enfortumab vedotin plus Pembrolizumab and 15.2 months for chemotherapy. The probability of maintaining a Complete Response at 2 years with Enfortumab vedotin plus Pembrolizumab was 74%. For patients with a confirmed Complete Response, the 2-year PFS and OS rates were 78% and 95% in the Enfortumab vedotin plus Pembrolizumab group, respectively, versus 54% and 86% in the chemotherapy group, respectively.

It was concluded that, these data with longer follow up suggests that treatment with Enfortumab vedotin plus Pembrolizumab resulted in significantly superior outcomes, compared to chemotherapy, in patients with untreated locally advanced or metastatic urothelial carcinoma, emerging as a potential new standard of care, irrespective of Cisplatin eligibility. The results from this study mark a significant paradigm shift in the management of locally advanced or metastatic urothelial carcinoma, offering new hope for patients and clinicians alike.

EV-302: Updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). Powles T, Van Der Heijden M, Loriot Y, et al. 2025 ASCO Genitourinary Cancers Symposium. Abstract 664. Journal of Clinical Oncology. Volume 43, Number 5_suppl February 2025.

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

RR

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.

Late Breaking Abstract – 2025 ASCO GI Symposium: Personalized Neoantigen Vaccine in Metastatic Colorectal Cancer

RR

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.

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.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors.

Checkpoint inhibitors have revolutionized cancer treatment. They are however not as effective in patients with “cold tumors” (MSS), as these tumors effectively hide themselves from the immune system and do not trigger an immune response following treatment with checkpoint inhibitors.

GRANITE is a personalized neoantigen immunotherapy designed to trigger a strong T-cell immune response against a patient’s tumor. A biopsy of the tumor is performed to identify unique mutations (neoantigens) present in the tumor of patients. An AI platform, EDGE, developed and designed by Gritstone Bio is able to identify critical T-cell vaccine targets, and predict which neoantigens are most likely to be recognized by the immune system of patients. The system has an 80% accuracy rate in selecting the top 20 most immunogenic neoantigens, most likely to generate an immune response in a given patient. The selected neoantigens are incorporated into a chimpanzee adenovirus-based primer vaccine and a Self-Amplifying mRNA (SAM) booster vaccine to train the immune system that leads to an induction of both cytotoxic T-lymphocyte and memory T-cell dependent immune responses, that specifically target and destroy the patients cancer cells that express these neoantigens. This vaccine (GRANITE) is administered via intramuscular injection alongside immune checkpoint inhibitors. Thus GRANITE primes the immune system to recognize and attack these tumors. This vaccine is customized for each patient based on the unique mutations of their tumor. In essence, GRANITE helps make the “cold tumors” visible to the immune system, potentially improving patient outcomes.

GRANITE immunotherapy regimen was evaluated in combination with Nivolumab and Ipilimumab, and compared to the combination of Nivolumab and Ipilimumab alone in a Phase1/2 involving patients with advanced metastatic solid tumors. This study demonstrated robust T-cell activation against targeted neoantigens with no dose-limiting toxicities, and over 50% of patients had a reduction in their circulating tumor DNA (ctDNA) and improved Overall Survival (Palmer CD, et al. Nature 2022).

GRANITE immunotherapy regimen is now being studied as first line metastatic treatment in a randomized Phase 2 trial, among patients with Microsatellite-Stable (MSS) Colorectal cancer patients. GO-010 is an ongoing Phase 2/3, randomized, open-label, multi-center study evaluating the efficacy and safety of GRANITE immunotherapy regimen in combination with Checkpoint Inhibitors (CPIs) as an add-on to Fluoropyrimidine/Bevacizumab as maintenance treatment, following first line therapy with FOLFOX/Bevacizumab, in patients with mCRC. In this study, 104 patients were randomized in a 1:1 ratio, and 67 patients were included in this treated analysis with 39 patients assigned to the GRANITE arm and 28 patients to the control arm. (36 patients withdrew from the study primarily due to early progressive disease or withdrawal of consent, and one patient has yet to begin study treatment). The vaccine manufacturing success rate was 100%. Both treatment groups were well balanced with regards to demographics, clinical characteristics stage, sidedness and presence of liver metastases. Approximately 75% of patients had liver metastases. For the Phase 2 portion of this study, the Primary end point being assessed is molecular response defined as 30% or more decrease from baseline in ctDNA. For the Phase 3 portion of this trial, the Primary end point is Progression Free Survival (PFS). Secondary end points for both Phase 2 and 3 include Adverse Events, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DoR) and Clinical Benefit Rate.

Preliminary data from the Phase 2 portion of a Phase 2/3 study showed a positive early trend in PFS for GRANITE immunotherapy patients with a Hazard Ratio (HR) of 0.82 in all patients, HR of 0.52 in high-risk patients1 (more than 90% with liver metastases). The median PFS was 12 months with GRANITE immunotherapy versus 7 months for the control group. Long-term ctDNA responses aligned with positive PFS trend favoring GRANITE immunotherapy patients versus control patients.

In the high-risk group, between first blood draw (time of randomization) and last blood draw (most recent study visit), the ctDNA shifted from high (more than 2% VAF-Variant Allele Frequency) to low (2% or less VAF) in 56% of patients treated with GRANITE immunotherapy versus 22% of control patients. Progressive disease was observed in 44% versus 78% respectively, within this group.

In the low-risk group of patients whose ctDNA was negative after induction chemotherapy, sustained ctDNA negativity was observed in 67% of GRANITE immunotherapy recipients versus 38% in the control patients. Progressive disease was observed in 11% and 38% of these patients, respectively. GRANITE immunotherapy was well tolerated and vast majority of adverse events were Grade1/2 and no patients discontinued study treatment due to an adverse event.

In conclusion, this preliminary Phase 2 results are highly encouraging and suggested that GRANITE immunotherapy demonstrated positive early PFS and long-term ctDNA responses, compared with Fluoropyrimidine/Bevacizumab alone, in front-line metastatic MSS-Colorectal cancer, providing the rationale for a confirmatory Phase 3 trial.

A randomized phase 2 study of an individualized neoantigen-targeting immunotherapy in patients with newly diagnosed metastatic microsatellite stable colorectal cancer (MSS-CRC). Hecht JR, Spira AI, Nguyen AV, et al. J Clin Oncol 43, 2025 (suppl 4; abstr LBA13). DOI 10.1200/JCO.2025.43.4_suppl.LBA13

Survival Benefits with Perioperative IMFINZI® Combined with Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2025, about 84,870 new cases of bladder cancer will be diagnosed and approximately 17,420 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

The standard treatment for Cisplatin-eligible patients with Muscle-Invasive Bladder Cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. However, the high relapse rate and risk of death despite this treatment has prompted further research into optimizing outcomes. Perioperative immunotherapy, particularly with immune checkpoint inhibitors, has shown promise in improving these outcomes. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with Urothelial Carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.

Durvalumab (IMFINZI®) is a selective, high-affinity human IgG1 monoclonal antibody directed against PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80. A preceding single-group, Phase 2 trial indicated that perioperative Durvalumab, combined with neoadjuvant Gemcitabine plus Cisplatin chemotherapy followed by radical surgery, was both safe and effective. Building on these findings, the Phase 3 NIAGARA trial aimed to evaluate the efficacy and safety of perioperative Durvalumab combined with neoadjuvant chemotherapy (Gemcitabine plus Cisplatin), followed by radical cystectomy, compared with neoadjuvant chemotherapy alone followed by radical cystectomy, in Cisplatin-eligible MIBC patients.

The NIAGARA trial was an open-label, randomized, multicenter, Phase 3 study, enrolling 1,063 (N=1063) Cisplatin-eligible patients with Muscle Invasive Bladder Cancer (clinical stage cT2–T4aN0/1M0). Patients were randomized in a 1:1 ratio to receive one of two treatment regimens. The experimental arm (Durvalumab group) included neoadjuvant Durvalumab 1500 mg IV alongside Gemcitabine plus Cisplatin every 3 weeks for 4 cycles, followed by radical cystectomy and adjuvant Durvalumab monotherapy 1500 mg IV every 4 weeks for up to 8 cycles (N=533). The comparison arm consisted of neoadjuvant Gemcitabine plus Cisplatin followed by radical cystectomy alone, without the addition of Durvalumab (N=530). Patients were stratified by clinical tumor stage (cT2N0 vs more than cT2N0), renal function (CrCl 60 mL/min or more vs 40 or more to less than 60 mL/min), and PD-L1 status (high vs low/negative). The dual Primary endpoints of the trial were Event-Free Survival (EFS) and pathological Complete Response (pCR), with Overall Survival (OS) as a key Secondary endpoint, as well as Metastasis Free Survival and Disease-Specific Survival. Event-Free Survival was defined as the time from randomization until progression that precluded surgery, failure to undergo surgery, recurrence after cystectomy, or death from any cause.

In the pre-planned interim analysis, the results demonstrated a significant improvement in both EFS and OS in the Durvalumab group compared to the chemotherapy-alone group. At 24 months, the estimated EFS was 67.8% in the Durvalumab group, compared to 59.8% in the comparison group (HR=0.68; P<0.001). Furthermore, the estimated OS at 24 months was 82.2% in the Durvalumab group versus 75.2% in the comparison group (HR for death=0.75; P=0.01). A pathological Complete Response (pCR) as assessed by central pathology review was noted in 37.3% of the patients in the Durvalumab group and in 27.5% of those in the comparison group. Notably, the percentage of patients who underwent radical cystectomy was similar between the two groups, with 88% in the Durvalumab group and 83% in the comparison group, indicating that the addition of Durvalumab did not reduce surgical completion rates.

An exploratory post hoc analysis of EFS and OS in patients with pCR versus those without pCR was also performed in the intent-to-treat population. The researchers herein reported additional outcomes and exploratory analysis results from NIAGARA study.

Patients in the Durvalumab group had a 33% reduction in risk of developing distant metastases or death (HR=0.67; P<0.001), and 31% reduction in risk of death from bladder cancer (HR=0.69; P=0.008) versus patients in the comparator group. More patients in the Durvalumab group achieved a pCR at the time of surgery versus the comparator (37% versus 28%) and patients who achieved a pCR had better EFS and OS, compared to those who did not. Patients in the Durvalumab group derived greater EFS and OS benefit versus the comparator group in both pCR group (EFS HR=0.58; OS HR=0.72), reducing the risk of disease progression or death by 42% and the risk of death by 28%, as well as non-pCR group (EFS HR=0.77; OS HR=0.84), reducing the risk of disease progression or death by 23% and risk of death by 16%. The most common immune-related adverse events included hypothyroidism in 10% of patients treated with Durvalumab compared to 1% in the comparator group, and hyperthyroidism in 3% versus 0.8% respectively. All immune mediated adverse events resolved in 41% of affected patients in the Durvalumab group and 44% in the comparator group.

It was concluded that the addition of perioperative Durvalumab to neoadjuvant chemotherapy significantly improved EFS and OS in both pCR and non-pCR groups, compared to chemotherapy alone, without compromising the ability to perform radical cystectomy. Further, perioperative Durvalumab combined with neoadjuvant chemotherapy reduced the risk of developing metastases and death from bladder cancer. These results are practice-changing, marking a major advancement in the treatment of MIBC. The findings support the hypothesis that perioperative immune checkpoint inhibitors, by priming the immune system before surgery and targeting residual micrometastatic disease post-surgery, improve long-term clinical outcomes. Biomarkers like circulating tumor DNA (ctDNA) could be pivotal in guiding treatment decisions, as emerging data suggests that negative ctDNA status post-neoadjuvant therapy correlates with reduced relapse risk.

Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA. Galsky M, Van Der Heijden M, Catto J, et al. J Clin Oncol 43, 2025 (suppl 5; abstr 659). DOI 10.1200/JCO.2025.43.5_suppl.659

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

RR

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

RR

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.