Category: Precision Oncology

Late Breaking Abstract – 2026 ASCO GI Symposium: Redefining First-Line Therapy in HER2-Positive Gastroesophageal Adenocarcinoma with Zanidatamab-Based Combinations

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Persistent Unmet Need in HER2-Positive Disease

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 20% of patients with GastroEsophageal Adenocarcinoma (GEA), encompassing gastric, gastroesophageal junction, and esophageal adenocarcinomas, harbor HER2-positive tumors. Despite the incorporation of HER2-directed therapy into first-line management more than a decade ago, long-term outcomes remain suboptimal. With Trastuzumab (HERCEPTIN®) plus chemotherapy, median Progression-Free Survival (PFS) has historically hovered around 10 months, and median Overall Survival (OS) around 20 months.

More recently, the addition of immune checkpoint inhibition has modestly improved outcomes in selected patients. Based on KEYNOTE-811, Pembrolizumab (KEYTRUDA®) plus Trastuzumab and chemotherapy is now standard for PD-L1–positive tumors. However, early relapse, often within the first year, remains common, underscoring the need for more effective HER2-targeted strategies.

Zanidatamab: A Next-Generation HER2-Targeted Approach

Preclinical and clinical data suggest greater antibody saturation on HER2-expressing tumor cells than with Trastuzumab or Pertuzumab (PERJETA®).

Zanidatamab (ZIIHERA®) is a novel, humanized IgG1 bispecific monoclonal antibody designed to bind two non-overlapping extracellular domains of HER2 (ECD2 and ECD4). This biparatopic binding leads to enhanced HER2 receptor clustering, internalization, and downregulation, resulting in more complete inhibition of HER2 signaling compared with single-epitope antibodies. Beyond direct signal blockade, Zanidatamab’s unique binding geometry promotes robust immune-mediated antitumor activity, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP).

Zanidatamab’s clinical momentum was reinforced by its FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, highlighting the platform’s broader relevance across HER2-driven gastrointestinal malignancies.

Rationale for Combining HER2 Blockade and Immunotherapy

The HERIZON-GEA-01 trial also explored synergy between dual HER2 targeting and immune checkpoint inhibition. Tislelizumab (TEVIMBRA®), a humanized IgG4 anti-PD-1 monoclonal antibody, is engineered to minimize Fc-gamma receptor binding on macrophages, potentially reducing antibody-dependent clearance of activated T cells. Tislelizumab received FDA approval in March 2024 for previously treated metastatic esophageal Squamous Cell Carcinoma, supporting its activity in upper gastrointestinal cancers.

HERIZON-GEA-01: Trial Design and Patient Population

HERIZON-GEA-01 (NCT05152147) is a global, open-label, Phase III study evaluating Zanidatamab-based regimens versus standard Trastuzumab plus chemotherapy in the first-line setting for HER2-positive metastatic GEA (GastroEsophageal Adenocarcinoma).

A total of 914 patients with unresectable, locally advanced, recurrent, or metastatic disease were enrolled between December 2021 and February 2025. More than two-thirds had gastric primaries. Patients had received no prior systemic therapy, HER2-targeted therapy, or immunotherapy in this setting.

Participants were randomized 1:1:1 to:

  • Arm A: Trastuzumab plus chemotherapy
  • Arm B: Zanidatamab plus chemotherapy
  • Arm C: Zanidatamab plus Tislelizumab plus chemotherapy

CAPOX was the chemotherapy backbone in approximately 90% of patients. Zanidatamab-based regimens in Arm B and Arm C were compared with standard Trastuzumab plus chemotherapy in Arm A. The dual Primary endpoints were PFS by Blinded Independent Review and OS.

Efficacy Results: Clinically Meaningful and Practice-Changing

At the interim analysis (data cutoff October 2025; median follow-up 26 months), there was a clear and consistent improvement in Progression-Free Survival with Zanidatamab-based therapy compared with Trastuzumab plus chemotherapy. Median PFS reached 12.4 months with Zanidatamab plus chemotherapy and 12.4 months with Zanidatamab plus Tislelizumab and chemotherapy, compared with 8.1–8.2 months in the Trastuzumab control arm. These gains translated into a 35–37% reduction in the risk of disease progression or death, with Hazard Ratios of 0.65 for Zanidatamab plus chemotherapy and 0.63 for the triplet regimen (both P <0.0001). Importantly, the separation of the PFS curves was maintained over time, highlighting the durability of benefit. The 1-year PFS was 38.0% with Zanidatamab plus chemotherapy and 43.9% with the triplet, versus 20.9% and 38.2% respectively with Trastuzumab-based therapy. The 2-year PFS was 31.5% and 20.9%, respectively, compared with 15.6% in the Trastuzumab group. These findings mark the first time a majority of patients receiving first-line HER2-targeted therapy remain progression-free at one year, a notable advance in a disease historically characterized by early relapse.

Median OS improved from 19.2 months with Trastuzumab plus chemotherapy to 24.4 months with Zanidatamab plus chemotherapy and 26.4 months with Zanidatamab plus Tislelizumab and chemotherapy. The addition of Tislelizumab yielded a statistically significant 28% reduction in the risk of death (HR 0.72; P =0.0043). While OS data for Zanidatamab plus chemotherapy alone were not yet statistically significant at this interim analysis (HR 0.80; P =0.0564), the observed survival extension of more than five months suggests meaningful clinical activity, with further analyses planned as follow-up matures. The 2-year OS was 50.3% with Zanidatamab plus chemotherapy and 54.3% with the triplet, versus 42.2% and 43.8% respectively with Trastuzumab-based therapy. The 30-month OS was 38.8% and 43.8%, respectively, compared with 30.0% in the Trastuzumab group.

Notably, the triplet regimen is the first HER2-directed first-line strategy to achieve median Overall Survival exceeding two years in a randomized phase III trial. Further, the benefits in both PFS and OS were consistent across key subgroups, including geographic region and PD-L1 status, an especially notable finding given that checkpoint inhibitor benefit has traditionally been restricted to PD-L1–positive tumors.

Depth and Durability of Response

Zanidatamab-based regimens also produced deeper and more durable responses. Confirmed Objective Response Rates approached 70% in both Zanidatamab arms, with Complete Response rates nearing 20% when Tislelizumab was added. Median duration of response was particularly striking, exceeding 20 months with the triplet regimen and substantially longer than the 8-month duration observed with Trastuzumab plus chemotherapy.

Safety and Tolerability

The safety profiles of Zanidatamab and Tislelizumab were consistent with their known toxicities. Grade ≥3 treatment-related adverse events occurred in approximately 59% of patients receiving Zanidatamab plus chemotherapy and 72% with the addition of Tislelizumab, compared with 60% in the Trastuzumab arm.

Diarrhea was the most common toxicity across all arms, typically occurring early and resolving within several weeks. Rates of HER2-targeted therapy discontinuation due to adverse events were higher with Zanidatamab-based regimens but remained manageable, with no new safety signals identified.

Clinical Implications and Future Directions

HERIZON-GEA-01 represents a landmark study in HER2-positive gastroesophageal adenocarcinoma. It is the first phase III trial to demonstrate superiority of a novel HER2-targeted agent over Trastuzumab in the first-line metastatic setting, and the first to achieve median PFS beyond one year and median OS beyond two years in this population.

While cross-trial comparisons should be interpreted cautiously, outcomes with Zanidatamab plus Tislelizumab and chemotherapy compare favorably with historical results from KEYNOTE-811. The observation of benefit irrespective of PD-L1 status further broadens the potential impact of this strategy.

As longer follow-up matures and guideline bodies evaluate these data, Zanidatamab, particularly in combination with immunotherapy appears poised to redefine the standard of care for HER2-positive metastatic gastroesophageal adenocarcinoma, offering patients a meaningful extension of disease control and survival.

Zanidatamab + chemotherapy ± tislelizumab for first-line HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma: Primary analysis from HERIZON-GEA-01. Elimova E, Rha SY, Shitara K, et al. 2026 ASCO Gastrointestinal Cancers Symposium. Abstract LBA285. Presented January 8, 2026.

Reconsidering Menopausal Hormone Therapy in BRCA1/2 Carriers: Emerging Evidence Challenges Longstanding Concerns

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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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

The tumor suppressor genes such as BRCA1 and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when a second copy of the gene in an individual is normal. Women with germline BRCA1 or BRCA2 mutations face markedly elevated lifetime risks of breast cancer, estimated at up to 70%. More than half of these cancers occur before the age of 50, underscoring the importance of informed counseling regarding risk-modifying exposures. 

For much of the latter half of the 20th century, Hormone Replacement Therapy (HRT) was widely prescribed to alleviate menopausal symptoms and protect against long-term complications such as osteoporosis. This practice shifted dramatically in 2002, when the Women’s Health Initiative reported increased risks of cardiovascular events and breast cancer associated with hormone therapy in older, postmenopausal women. In the aftermath, both patients and clinicians largely retreated from Menopausal Hormone Therapy (MHT), and its use declined sharply.

While those findings reshaped care in the general population, their applicability to women with hereditary cancer predisposition, particularly carriers of pathogenic BRCA1 or BRCA2 variants, has remained uncertain. These women face markedly elevated risks of ovarian and fallopian tube cancers and are therefore advised to undergo risk-reducing bilateral salpingo-oophorectomy at relatively young ages. The procedure is effective for cancer prevention but induces abrupt surgical menopause, often decades earlier than natural menopause, with well-documented short- and long-term consequences including vasomotor symptoms, sexual dysfunction, bone loss, and adverse cardiovascular and cognitive effects.

Menopausal Hormone Therapy (MHT) is the most effective intervention for mitigating these outcomes of early menopause. However, concerns that hormone exposure could further increase breast cancer risk in BRCA carriers have led to substantial hesitation, misinformation, and, in many cases, prolonged untreated symptoms. Researchers have emphasized, recommending premenopausal oophorectomy without offering a safe strategy to manage its consequences creates an untenable clinical dilemma.

Study Design: Emulating a Trial in a High-Risk Population

To address this evidence gap, investigators conducted the largest prospective matched analysis to date examining MHT use and breast cancer risk in BRCA1 and BRCA2 carriers. Using data from a longitudinal cohort, the study sought to emulate a randomized clinical trial by carefully matching women who initiated MHT after menopause, predominantly surgical menopause, to those who did not.

Eligible participants had no prior cancer history, no bilateral mastectomy, and had entered menopause. A total of 676 matched pairs were created, matched one-to-one by gene mutation (BRCA1 or BRCA2), year of birth, and age at menopause. Participants ranged in age from 22 to 76 years, with a mean age of 43.8 years. MHT formulations initiated after menopause included estrogen-only therapy, combined estrogen–progestogen therapy, progestogen alone, tibolone, and conjugated equine estrogen plus bazedoxifene. Cox proportional hazards models were used to estimate breast cancer risk.

Results: No Signal of Increased Breast Cancer Risk

After a mean follow-up of 5.6 years from the date of first MHT use, breast cancer incidence was significantly lower among women who used MHT compared with their matched, unexposed counterparts. Incident breast cancer occurred in 12.9% of MHT users versus 18.9% of non-users (P = 0.002).

Notably, estrogen-only therapy was associated with a substantial reduction in breast cancer risk, corresponding to a 63% relative decrease compared with non-users. In contrast, no increased or decreased risk was observed with combined estrogen–progestogen therapy, progestogen monotherapy, or tibolone. Among the 43 women who received conjugated equine estrogen plus bazedoxifene, no breast cancer diagnoses were reported during follow-up, an exploratory finding that warrants further investigation. Importantly, risk estimates were consistent across BRCA1 and BRCA2 carriers, underscoring the relevance of these findings across mutation subtypes.

Clinical Implications

These data provide critical reassurance for clinicians managing young women with hereditary breast and ovarian cancer syndromes. In contrast to earlier studies conducted in the general population, MHT use in BRCA1/2 carriers was not associated with an increased risk of breast cancer, regardless of formulation. Estrogen-only regimens, in particular, appeared protective, although causality cannot be inferred.

While limitations include a relatively modest follow-up duration and small numbers in certain subgroups, this prospective analysis offers the strongest evidence to date supporting the safety of MHT in this high-risk population. The findings reinforce the need for individualized, evidence-based counseling that balances cancer risk reduction with quality-of-life preservation.

Moving Forward

As MHT formulations continue to evolve, ongoing research will be essential to refine risk stratification and optimize menopause management strategies in BRCA mutation carriers. For now, these results support a personalized approach to MHT use in women experiencing surgical or natural menopause after risk-reducing oophorectomy, provided there are no contraindications. For many patients, informed use of MHT may offer not only symptom relief, but also a path toward improved long-term health and wellbeing without compromising breast cancer risk.

GS3-01. Menopausal Hormone Therapy and the Risk of Breast Cancer in Women with a Pathogenic Variant in BRCA1 or BRCA2. Kotsopoulos J, Seca M, Jacek G, et al. Presented at the 2025 San Antonio Breast Cancer Symposium (SABCS; Abstract GS3-01). 

FDA Approves First Line ENHERTU® plus PERJETA® for HER2-Positive Metastatic Breast Cancer

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SUMMARY: The FDA on December 15, 2025, approved ENHERTU® in combination with Pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer as determined by an FDA-approved test.

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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 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. Trastuzumab (HERCEPTIN®) is a humanized monoclonal antibody targeting HER2. Trastuzumab binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). Pertuzumab (PERJETA®) is a recombinant humanized monoclonal antibody that binds to the HER2 at a different epitope of the HER2 extracellular domain (subdomain II) compared to Trastuzumab, and prevents the dimerization of HER2 with HER3 receptor. Pertuzumab stimulates ADCC similar to Trastuzumab. By combining Trastuzumab and Pertuzumab, a more comprehensive blockade of HER2 signaling can be accomplished, as these two agents bind to different HER2 epitopes and may complement each other and improve efficacy.

Trastuzumab deruxtecan (T-DXd) (ENHERTU®) is a next-generation Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike  ado-Trastuzumab emtansine, another ADC targeting HER2, T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

Background and Clinical Rationale
Trastuzumab deruxtecan (T-DXd) has demonstrated potent antitumor activity in HER2-positive breast cancer across multiple treatment lines. However, prior to the DESTINY-Breast09 study, all approved indications for T-DXd required patients to have received prior systemic therapy in either the metastatic or adjuvant setting. With the longstanding CLEOPATRA regimen, Docetaxel, Trastuzumab, and Pertuzumab (THP) established over a decade ago as the first-line standard of care, the oncology community has been eager to evaluate whether T-DXd could improve frontline outcomes.

Study Design and Patient Population
DESTINY-Breast09 (NCT04784715) is a randomized, global Phase 3 study designed to evaluate the efficacy and safety of first-line T-DXd with or without Pertuzumab, versus Taxane plusTrastuzumab plus Pertuzumab (THP), in patients with HER2-positive advanced/metastatic breast cancer. A total of 1,157 patients were enrolled across 283 sites worldwide. Eligible patients had centrally confirmed HER2-positive disease (IHC 3+ or ISH+), no prior chemotherapy or HER2-targeted therapy in the metastatic setting, and ≤1 prior line of endocrine therapy. Patients were stratified by Hormone Receptor (HR) status, PIK3CA mutation status, and de novo vs recurrent disease, and randomized 1:1:1 to:

  • T-DXd + placebo – N=387
  • T-DXd + Pertuzumab (T-DXd + P) – N=383
  • THP (control arm) – N=387

The interim analysis presented at ASCO 2025 focused on the comparison between T-DXd + P and THP. The T-DXd monotherapy arm remains blinded until the final PFS analysis.

The Primary endpoint was Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) in the intent-to-treat population. Secondary endpoints included Overall Survival (OS), PFS by investigator (INV), Objective Response Rate (ORR), Duration of Response (DOR), and Safety.

Efficacy Outcomes: Progression-Free Survival and Response
At a median follow-up of 29 months, T-DXd + P demonstrated a statistically significant and clinically meaningful improvement in PFS compared to THP:

  • Median PFS by BICR:
    • T-DXd + P: 40.7 months
    • THP: 26.9 months
    • HR: 0.56; P <0.00001
  • PFS by Investigator Assessment:
    • Median: 40.7 months vs 20.7 months
    • HR: 0.49 (95% CI: 0.39–0.61)
  • Overall Response Rate (ORR):
    • T-DXd + P: 85.1%
    • THP: 78.6%
  • Complete Response Rate:
    • T-DXd + P: 15.1%
    • THP: 8.5%
  • Median Duration of Response:
    • T-DXd + P: 39.2 months
    • THP: 26.4 months

The PFS benefit was consistent across all patient subgroups, including HR status and PIK3CA mutation.

Safety Profile and Adverse Events
The safety profile of T-DXd + P in the frontline setting was consistent with known toxicities of T-DXd, with no new safety signals. Adjudicated drug-related Interstitial Lung Disease/pneumonitis occurred in 12.1% of patients receiving T-DXd + P (mostly grade 1 and 2) in contrast to only 1.0% among patients receiving THP. Other treatment-related toxicities such as nausea, vomiting, and constipation were more common with T-DXd + P, possibly due to longer median treatment exposure (~3.5 years).

Clinical Implications and Emerging Questions
The marked 13.8-month PFS improvement positions T-DXd + P as a strong candidate to replace THP as the first-line standard for HER2-positive advanced metastatic breast cancer. These results mirror the transformative impact of T-DXd seen in the second-line DESTINY-Breast03 trial comparing T-DXd with ado-Trastuzumab emtansine, where it yielded a median PFS of 28.8 months.

However, while efficacy is unquestionable, questions remain around treatment sequencing, duration, and long-term quality of life:

  • Could T-DXd be reserved for second-line therapy in select patients with less aggressive disease?
  • Might a strategy of T-DXd + P induction followed by de-escalation to maintenance Trastuzumab/Pertuzumab reduce toxicity?
  • Can biomarker-driven personalization, refine who should receive first-line T-DXd?

The researchers of this study emphasized that these results represent a paradigm shift in first-line treatment of advanced HER2-positive breast cancer.

Conclusion
DESTINY-Breast09 demonstrates that T-DXd + Pertuzumab significantly improves PFS compared to THP, with durable responses and manageable toxicity. The findings suggest a potential new first-line standard for HER2-positive metastatic breast cancer. While overall survival and long-term safety data are still maturing, the study sets a new benchmark in the frontline treatment landscape and invites critical dialogue on optimizing sequencing, duration, and patient-centered outcomes.

Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer. Tolaney SM, Jiang Z, Zhang Q, et al. for the DESTINY-Breast09 Trial Investigators. N Engl J Med. DOI: 10.1056/NEJMoa2508668

Neoadjuvant Niraparib Plus Dostarlimab in BRCA or PALB2-Mutated Triple Negative Breast Cancer: Phase II TBCRC 056 Results

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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 were diagnosed in 2025, and about 42,170 women died of the disease, largely due to metastatic recurrence.

Rationale for a Chemotherapy-Free Neoadjuvant Strategy

Patients with germline BRCA1/2 or PALB2–mutated breast cancer represent a biologically distinct population with heightened sensitivity to PARP inhibition. Beyond synthetic lethality, accumulating preclinical evidence suggests that PARP inhibitors activate the cGAS/STING pathway, increasing intratumoral inflammation, recruiting CD8+ T cells, and potentially priming tumors for immune checkpoint blockade.

While prior studies have not demonstrated a clear benefit for combining PARP inhibitors with immunotherapy in the advanced TNBC (Triple-Negative Breast Cancer) setting, investigators hypothesized that the early-stage, neoadjuvant context, characterized by less immune exhaustion and lower tumor burden, might offer a more permissive environment for synergy.

Study Design and Patient Population

TBCRC 056 is a randomized, Phase II study evaluating the PARP inhibitor Niraparib (ZEJULA&reg;) in combination with the anti–PD-1 antibody Dostarlimab (JEMPERLI&reg;) as neoadjuvant therapy for patients with HER2-negative breast cancer harboring germline BRCA1/2 or PALB2 mutations. The trial includes cohorts for both triple-negative and Estrogen Receptor (ER) positive disease. The current analysis focuses on TNBC cohorts (Arms A and B). Participants with ER positive breast cancer will be placed directly into Arm C. There is no randomization for these participants.

Eligible patients were ≥18 years old with Stage I–III TNBC, primary tumors ≥1.0 cm, HER2-negative disease, and confirmed germline BRCA1/2 or PALB2 mutations. Patients were randomized to:

  • Arm A: Niraparib 200 mg orally once daily plus Dostarlimab 500 mg IV every 3 weeks for 18 weeks
  • Arm B: Niraparib monotherapy for 3 weeks followed by Niraparib plus Dostarlimab for 15 weeks

Tumor biopsies were obtained at baseline and week 3 to assess immune modulation. Surgery followed 18 weeks of therapy, with optional additional neoadjuvant treatment at investigator discretion if residual disease was detected.

RCB (Residual Cancer Burden in the breast tissue and axillary lymph nodes) Categories:

  • RCB 0:No invasive cancer cells found (pCR).
  • RCB I (Minimal):Very small amount of residual disease.
  • RCB II (Moderate):Moderate amount of residual disease.
  • RCB III (Extensive):Significant amount of residual disease.

Endpoints and Statistical Considerations

The Primary endpoints were:

  • Pathologic Complete Response (pCR; RCB-0) rate in Arms A and B combined
  • Change in stromal Tumor-Infiltrating Lymphocytes (sTILs) from baseline to week 3

The study was powered to detect a pCR rate of ≥50%, allowing rejection of a null hypothesis pCR rate <30%.

Baseline Characteristics

A total of 46 patients with TNBC were enrolled across Arms A and B. The median age was 39.3 years, reflecting the young demographic typical of germline BRCA-associated disease. Most patients were White (84.8%), with representation from Black, Asian, and Hispanic populations. Clinically, 37.0% had Stage I disease, 45.7% Stage II, and 17.4% Stage III. The majority had node-negative and high-grade (grade 3) tumors. BRCA1 mutations predominated (82.6%), with the remainder harboring BRCA2 mutations. No PALB2-mutated TNBC patients were enrolled in this cohort.

Efficacy Outcomes: pCR and Residual Disease

Neoadjuvant Niraparib plus Dostarlimab achieved a pCR rate of 50.0% (90% CI, 37.1%–62.9%) among evaluable patients, meeting and exceeding the study’s predefined efficacy threshold.

Notably:

  • pCR rates were identical in both treatment strategies, at 50% in Arm A (concurrent therapy) and Arm B (niraparib lead-in)
  • The combined RCB-0/I rate was 60.0%, suggesting meaningful tumor eradication or minimal residual disease in a majority of patients
  • Approximately 24% of patients crossed over to additional preoperative therapy, reflecting real-world decision-making when residual disease is identified

These findings support the robustness of the regimen regardless of initial PARP inhibitor lead-in.

Immune Modulation and Biomarker Insights

A key translational objective of TBCRC 056 was to characterize early immune changes within the tumor microenvironment.

Both treatment arms demonstrated statistically significant increases in sTILs from baseline to week 3:

  • Arm A: Mean sTILs increased from 16% to 27.4%
  • Arm B: Mean sTILs increased from 19.5% to 42.1%, suggesting a pronounced immune activation following PARP inhibitor exposure

Importantly, patients who achieved pCR had higher baseline sTIL levels than those who did not, underscoring the prognostic relevance of preexisting immune infiltration. Baseline sTILs were also associated with achieving RCB-0/I.

In contrast, baseline PD-L1 expression, estrogen receptor status (ER-0 vs ER-low), and short-term changes in sTILs were not independently associated with pCR, highlighting the complexity of immune–genomic interactions in BRCA-driven TNBC.

Safety and Tolerability

The safety profile of Niraparib plus Dostarlimab was consistent with known toxicities of PARP inhibition and immune checkpoint blockade.

  • Grade ≥2 treatment-related adverse events occurred in 82.6% of patients
  • Grade 3 events were reported in 26.1%, and grade 4 events were rare (2.2%)
  • The most common higher-grade toxicities included anemia, fatigue, hypertension, hypothyroidism, and neutropenia

Treatment discontinuation occurred in 13% of patients, with discontinuations split between Niraparib and Dostarlimab, suggesting manageable but clinically relevant toxicity in a neoadjuvant setting.

Key Takeaways for Oncology Practice

  • TBCRC 056 demonstrates that a chemotherapy-free neoadjuvant therapy with Niraparib combined with Dostarlimab achieved a 50% pathologic Complete Response (pCR) rate in patients with germline BRCA-mutated early-stage TNBC, exceeding the study’s predefined efficacy threshold.
  • pCR rates were identical whether Dostarlimab was administered concurrently with Niraparib or following a short PARP inhibitor lead-in, suggesting flexibility in treatment sequencing.
  • Treatment was associated with a significant increase in stromal Tumor-Infiltrating Lymphocytes (sTILs) within 3 weeks, supporting biologic synergy between PARP inhibition and PD-1 blockade in early-stage disease.
  • Higher baseline sTIL levels were associated with both pCR and minimal residual disease (RCB-0/I), whereas baseline PD-L1 expression and ER-low status were not predictive.
  • These findings support further investigation of biomarker-driven, non-chemotherapy neoadjuvant strategies in genetically defined TNBC populations.

TBCRC-056: A phase II study of neoadjuvant niraparib with dostarlimab for patients with BRCA- or PALB2-mutated breast cancer: results from the TNBC cohorts. Mayer EL, Graham N, Leon-Ferre RA, et al. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF5-02.

 

 

 

 

Reassessing First-Line Chemotherapy Selection in Metastatic PDAC: Insights from the PASS-01 Trial

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SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Pancreatic Ductal AdenoCarcinoma (PDAC) remains one of the most lethal malignancies, with most cases diagnosed at advanced stages and few modifiable risk factors identified to date.

Pancreatic ductal adenocarcinoma is characterized by marked biological heterogeneity and limited therapeutic durability. While combination chemotherapy regimens have modestly extended survival in the metastatic setting, outcomes remain poor for the majority of patients, underscoring the urgent need for better treatment selection strategies. Molecular stratification has emerged as a promising approach in PDAC, supported by well-established predictive biomarkers such as germline BRCA2 and PALB2 alterations, which identify a subset of patients more likely to benefit from platinum-based chemotherapy and PARP inhibition. Beyond DNA damage repair defects, transcriptomic profiling has further refined the molecular landscape of PDAC, consistently identifying two dominant expression subtypes-Classical and Basal-like, with important prognostic and potentially predictive implications.

The Classical subtype is generally associated with a more differentiated epithelial phenotype and improved survival, whereas Basal-like tumors exhibit stem-like features, relative chemoresistance, and inferior outcomes. Prior nonrandomized and prospective studies have suggested differential chemotherapy sensitivity between these subtypes, raising the question of whether transcriptional classification could inform first-line regimen selection. The Pancreatic Adenocarcinoma Signature Stratification for Treatment-01 (PASS-01) trial was designed to address this gap by prospectively comparing two commonly used first-line chemotherapy regimens, modified FOLFIRINOX (mFOLFIRINOX) and Gemcitabine plus nab-Paclitaxel (GnP), while embedding comprehensive molecular and translational analyses.

PASS-01 Trial Design and Study Objectives

PASS-01 was a randomized, open-label, multinational Phase II study conducted across centers in Canada and the United States. The trial enrolled patients with de novo metastatic PDAC who were chemotherapy-naïve between October 2020 and January 2024, and excluded individuals harboring germline pathogenic variants in BRCA1, BRCA2, or PALB2, thereby removing a population with known platinum sensitivity. Patients were randomized 1:1 to receive either mFOLFIRINOX (N=80) or GnP (N=80. The Primary endpoint was Progression-Free Survival (PFS) in the intention-to-treat population, using a relaxed significance threshold appropriate for a signal-seeking Phase II design. Key Secondary objectives included Overall Survival (OS), Safety, Objective Response Rates (ORR), and exploratory analyses evaluating outcomes according to RNA expression subtype, GATA6 expression, Patient-Derived Organoid (PDO) data, and other molecular correlatives.

Importantly, PASS-01 incorporated mandatory pretreatment tumor biopsies whenever feasible. These samples underwent whole-genome and transcriptome sequencing, RNA-based subtype classification, and PDO generation, with results reviewed in a molecular tumor board to inform later-line treatment decisions. This design allowed for a real-world assessment of the feasibility and clinical relevance of upfront molecular profiling in metastatic PDAC.

First-Line Efficacy Outcomes in the Overall Study Population

With a median follow-up of 8.3 months, PFS was numerically longer with GnP compared with mFOLFIRINOX, although the difference did not reach conventional statistical significance. Median PFS in the intention-to-treat population was 5.3 months with GnP versus 4.0 months with mFOLFIRINOX. Similar trends were observed in the per-protocol analysis.

Overall Survival outcomes favored GnP more clearly. Median OS approached 10 months with GnP and was under 9 months with mFOLFIRINOX, translating into a statistically significant hazard ratio favoring the Gemcitabine-based regimen. Notably, these differences persisted after adjustment for key clinical covariates, including performance status, liver metastases, and KRAS mutation status. While absolute survival gains were modest, these findings are clinically relevant given the lack of head-to-head randomized data comparing these regimens in Western populations. Objective Response Rates were comparable between treatment arms. However, Disease Control Rate and Durability of Response favored GnP. Patients treated with GnP experienced a higher Disease Control Rate and a longer Duration of Response, suggesting more sustained benefit in a subset of patients.

Safety Profile and Treatment Tolerability

Treatment-related toxicity differed meaningfully between regimens. Hospitalizations due to adverse events were more frequent in the mFOLFIRINOX arm, driven primarily by gastrointestinal complications, febrile neutropenia, and serious infections. In contrast, severe toxicities with GnP were less common and more limited in scope. These safety differences are particularly relevant in a population with aggressive disease biology and limited physiologic reserve, where treatment tolerability may influence both quality of life and the ability to receive subsequent therapy.

Impact of Transcriptional Subtypes on Clinical Outcomes

One of the most informative aspects of PASS-01 was its prospective evaluation of RNA expression subtypes. Among patients with adequate tissue for analysis, approximately 75% were classified as Classical and 25% as Basal-like, consistent with prior reports. Across the entire cohort, Basal-like tumors were associated with numerically shorter PFS and OS compared with Classical tumors, reinforcing their adverse prognostic significance.

When outcomes were examined by treatment arm within each subtype, important patterns emerged. In patients with Classical PDAC, PFS was similar between regimens, but OS was notably longer with GnP compared with mFOLFIRINOX. Conversely, in Basal-like disease, outcomes were uniformly poor regardless of regimen, though trends consistently favored GnP across PFS, Response Rate, and Duration of Response. These findings suggest that Basal-like tumors may derive limited benefit from intensified multi-agent chemotherapy and may be particularly resistant to Fluorouracil and Irinotecan-based approaches.

GATA6 Expression as a Pragmatic Surrogate Biomarker

Given prior evidence linking GATA6 expression with the Classical subtype, PASS-01 also evaluated GATA6 RNA in situ hybridization as a pragmatic surrogate biomarker. High GATA6 expression correlated strongly with Classical transcriptional identity. While patients with high GATA6 expression demonstrated a trend toward longer PFS, GATA6 status alone did not reliably predict differential benefit from mFOLFIRINOX versus GnP. These findings suggest that while GATA6 may serve as a useful prognostic marker, its role as a standalone predictive tool for chemotherapy selection remains limited and may require integration into broader multiplex or composite biomarker platforms.

Early CA 19-9 Dynamics as a Biomarker of Treatment Response

PASS-01 also provided important insights into the utility of early CA 19-9 changes as a biomarker of treatment response. Among patients with evaluable markers, a decline in CA 19-9 within four weeks of therapy initiation was associated with significantly prolonged PFS, whereas early increases were linked to inferior outcomes. However, a subset of patients with early CA 19-9 rises subsequently achieved radiographic disease control, underscoring that CA 19-9 kinetics should not be used in isolation to prompt premature treatment discontinuation. These findings support the potential role of early biomarker dynamics, particularly when combined with emerging tools such as circulating tumor DNA, in adaptive treatment strategies.

Translational Findings and the Challenge of Second-Line Therapy

Despite the extensive molecular profiling and use of correlate-guided recommendations, outcomes in the second-line setting were uniformly poor. Only about half of patients were able to receive subsequent therapy, and survival following progression was measured in months. Correlate-guided treatment selection did not meaningfully improve outcomes compared with standard approaches, highlighting the clinical reality that opportunities for precision intervention in PDAC are often lost once patients progress beyond first-line therapy.

Clinical Implications for First-Line Treatment Selection

PASS-01 confirms that outcomes with standard first-line combination chemotherapy for metastatic PDAC remain disappointing, even in carefully selected clinical trial populations. Within this context, the modest but consistent efficacy and safety advantages observed with GnP over mFOLFIRINOX are practice-informing, particularly for patients without known DNA repair defects. More importantly, the trial reinforces the prognostic importance of transcriptional subtypes and supports the concept that molecular features should be assessed early, when they are most likely to influence meaningful treatment decisions.

As novel therapeutic strategies, including KRAS-targeted agents and rational combination approaches, move into earlier lines of therapy, transcriptional subtype may prove critical in guiding regimen selection and trial design. PASS-01 demonstrates that comprehensive upfront molecular profiling is feasible in multicenter settings and provides a framework for future biomarker-driven trials aimed at improving first-line outcomes in this highly lethal disease.

Key Takeaways and Conclusions

In the Phase II PASS-01 trial, Progression-Free Survival was similar between mFOLFIRINOX and Gemcitabine plus nab-Paclitaxel. However, Overall Survival, treatment durability, and safety trends favored the Gemcitabine-based regimen. Molecular analyses confirmed the adverse prognosis associated with Basal-like PDAC and suggested limited benefit from intensified chemotherapy in this subgroup. Collectively, these findings emphasize the critical importance of optimizing first-line treatment strategies and integrating molecular stratification early in the disease course, as opportunities for effective intervention rapidly diminish after progression.

PASS-01: Randomized Phase II Trial of Modified FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel and Molecular Correlatives for Previously Untreated Metastatic Pancreatic Cancer. Knox JJ, O’Kane G, King D, et al. J Clin Oncol. 2025;43:3355-3368.

Therapeutic Prowess and Potential of Multifunctional Therapeutics: A Review of Bispecific Antibodies

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Written by: Jaffer A. Ajani, MD, FASCO
This educational opportunity is sponsored by: Jazz Pharmaceuticals

Concept and Technology

Bispecific antibodies (BsAbs) transcend conventional limitations of therapeutic protein engineering by simultaneously engaging two distinct biological targets. Rooted in molecular cooperation, BsAbs combine two functional antigen-binding fragments (often Fab arms) into a single molecule.1 A considerable novelty over traditional monoclonal antibodies (mAbs), which target a single epitope, BsAbs lead to forced cellular proximity or receptor clustering.1–3  Technological challenges of manufacturing BsAbs for optimal pharmacokinetics (PK), stability, and purity remain. Yet, their dual-targeting allows BsAbs to mediate synergistic effects and intervene in complex, multi-factorial disease pathways—for example, in oncology, where we find multiple redundant receptors, ligands, and evasion mechanisms.1 The following review will review BsAb structures, mechanisms of action, safety profiles, and future directions.

Structural Variants

  1. Non-IgG-like (Fc-Silent) variants are characterized by a lack of the Fragment crystallizable (Fc) domain, resulting in small molecules that are rapidly cleared by the kidneys, necessitating frequent dosing. Their advantage is high potency and efficient tissue penetration.4 These include:
    • Bispecific T-Cell Engagers (BiTEs): Typically constructed as tandem single-chain variable fragments (scFv) that link a tumor-associated antigen (TAA) binder and a CD3 binder via a peptide linker.4 Blinatumomab is a well-known example that achieves potent cellular redirection.
    • Dual Affinity Re-targeting Molecules (DARTs): Similar to BiTEs, DARTs incorporate an additional disulfide bridge to improve structural stability.
    • Killer Cell Engagers (BiKEs/TriKEs): These target the innate immune system by engaging CD16 on NK cells. Trispecific Killer Engagers (TriKEs) feature a third component, such as an IL-15 crosslinker, to sustain NK cell proliferation and cytotoxicity.4
  2. IgG-like (Fc-Containing) formats retain the Y-shaped IgG structure, including the Fc domain, conferring prolonged serum half-life via FcRn recycling.4 However, assembling two different heavy chains and two different light chains into a functional heterodimer without forming undesirable mispaired byproducts demands intensive engineering—e.g., CrossMab and/or Knobs-into-Holes (KiH) technologies.4–6

Mechanisms of Action (MOA)

The therapeutic power of BsAbs lies in their ability to execute mechanisms categorized as acting in-trans or in-cis, based on their molecular or cellular target configuration.

  1. In-Trans Mechanisms: The core in-trans function is creating a physical linkage between two distinct molecular or cellular entities. These include:
    • Cellular Bridging (T-Cell Engagers; TCEs): This is the hallmark of oncology BsAbs. By simultaneously binding a TAA and CD3 on T cells, the BsAb forces a physical link, forming a cytolytic synapse.6 This mechanism bypasses the need for natural T-cell receptor (TCR) clustering and Major Histocompatibility Complex (MHC) presentation, allowing the T cell to attack regardless of the tumor’s MHC status.4,6
    • Co-factor Mimicry: Outside of cytotoxicity, BsAbs can direct components to form a functional complex. Emicizumab, approved for Hemophilia A, is an example.2–6
  2. In-Cis Mechanisms: Involve targeting components that reside on the same cell or act within the same signaling pathway. These include:
    • Dual Signaling Inhibition (Dual Blockade): Simultaneously blocks two different receptors or ligands to suppress synergistic pathways crucial for disease progression.
      • Examples: Targeting HER2/HER3 (Zenocutuzumab) or EGFR/MET (Amivantamab) to halt parallel proliferation cascades in cancer.1–6
    • Biparatopic Engagement: By binding two distinct, non-overlapping epitopes on the same antigen4,5, biparatopics intensify control over one oncogenic “addiction” pathway via geometry-driven clustering, internalization, and boosted Fc effector functions. Biparatopics enhance binding avidity and promote superior functional modulation of the target, such as forced receptor clustering and internalization, the latter being highly beneficial for Antibody-Drug Conjugates (ADCs). Biparatopic binding drives dense clustering of the same receptor, leading to “caps” on the cell surface, resulting in potent receptor internalization and degradation. This yields deeper and more durable signal blockade than a single monoclonal antibody or cocktail.7 The high local receptor and antibody density also enables multimodal effector functions, and helps overcome resistance within a single pathway by engaging distinct functional domains to block both ligand-dependent and ligand-independent signaling and interfere with heterodimerization (e.g., HER2/HER3). They also retain efficacy when tumors escape mono-epitope antibodies through epitope masking or mutation.
      • Example: Zanidatamab, which targets two distinct HER2 epitopes, and is unique in its ability to induce receptor clustering and “capping.”8-9

Clinical Landscape

The BsAb landscape has rapidly expanded since the first approval of Blinatumomab in 2014, reflecting a growing therapeutic impact across multiple disease areas. As of late 2025, fifteen bispecific molecules have secured FDA approval, spanning both oncology and non-oncology indications. This surge underscores the versatility of BsAbs and their ability to address complex biological pathways through innovative mechanisms of action.

Approved-Bispecific-Antibodies

Limitations, Safety, and Risk Mitigation

  1. Manufacturing Challenges: The inherent complexity of BsAbs introduces challenges related to stability, manufacturability, and impurity control.1 The fusion of exogenous antigen-binding domains can decrease biophysical stability, and the complex assembly process frequently results in the formation of product-related impurities and mispaired species, which are difficult to remove during purification. These factors are not merely manufacturing hurdles; they directly influence the biological activity and, critically, the immunogenic potential of the final drug product.
  2. MOA-Specific Toxicity: The safety profile of BsAbs is highly dependent on their MOA
    • T-Cell Engager Toxicity: The highly potent, acute T-cell activation triggered by TCEs results in two major, distinct safety concerns. The first is Cytokine Release Syndrome (CRS), a serious acute toxicity caused by the mass release of systemic cytokines. CRS has been reported in up to 70% of patients receiving BsAbs, often necessitating hospitalization and precise management protocols. Severe cases (Grade ≥ 3) occur in 5–10% of patients.6 The second concern is Neurotoxicity (ICANS), which, while less frequent than CRS, affects 10–15% of patients and can range from mild confusion to cerebral edema.6 In addition, there is an Immune Regulation Paradox. Paradoxically, T-BsAb therapy can trigger the expansion and activation of inhibitory Regulatory T (Treg) cells in the tumor microenvironment, leading to the production of anti-inflammatory cytokines like IL-10. This critically inhibits the desired effector T-cell response, suggesting that combination strategies—such as transient Treg ablation—may be necessary to maximize efficacy.6
    • Pathway Blocker and Biparatopic Toxicity: These agents generally do not induce acute, systemic cytokine surges. Instead, their adverse event profiles reflect the targeted receptors. For example, the dual signaling blocker Amivantamab (targets EGFR/MET) exhibits EGFR-inhibition-related dermatologic toxicities, like paronychia, skin fissures, and pruritus, as well as infusion reactions. Dual checkpoint inhibitors can have classic IO toxicities. Biparatopic antibodies, like Zanidatamab, demonstrate a manageable profile but frequently cause gastrointestinal toxicities (such as diarrhea and nausea/vomiting) and infusion-related reactions (IRRs).9 Importantly, clinical data for Zanidatamab confirmed no reports of CRS.9
  3. Mitigating Immunogenicity Risk: The complex structures, engineered sequences, and immunostimulatory MOAs of oncology BsAbs contribute to an increased risk of immunogenicity compared to mAbs. Mitigation must begin at the engineering stage, utilizing in silico prediction and in vitro assays to guide the selection of low-risk antibody constructs through deimmunization and tolerization methods.

Future Directions

The BsAb pipeline remains robust, reflecting a continuous drive toward addressing current clinical limitations and expanding into novel biological territories. The future of BsAbs is characterized by a strategic shift toward overcoming the immunosuppressive tumor microenvironment (TME). Emerging candidates are now focused on targets that modulate the innate immune system and TME suppression, such as LILRB1/2 bispecific IgG1 antibodies for advanced solid tumors.10-11 Furthermore, BsAbs are expanding beyond simple blockade, with molecules like SAR446422 (CD28xOX40 bispecific) in trial for inflammatory indications, demonstrating the potential for BsAbs to achieve synergistic co-stimulatory agonism.10-11 The continuous innovation in structural design, focused now on minimizing impurity-driven immunogenicity and maximizing the therapeutic window, ensures that BsAbs are poised to become the standard for highly tailored, multifunctional therapeutic intervention across diverse and complex diseases. The future of BsAbs is very promising.10-11

References:

  1. Shan KS, Musleh Ud Din S, Dalal S, Gonzalez T, Dalal M, Ferraro P, Hussein A, Vulfovich M. Bispecific Antibodies in Solid Tumors: Advances and Challenges. International Journal of Molecular Sciences. 2025; 26(12):5838. https://doi.org/10.3390/ijms26125838.
  2. The Bispecific 2024 Landscape Review. Beacon Intelligence. 2024. https://beacon-intelligence.com/landscape-reviews/bispecific/. Accessed November 23, 2025.
  3. Ai Z, Wang B, Song Y, Cheng P, Liu X, Sun P. Prodrug-based bispecific antibodies for cancer therapy: advances and future directions. Front Immunol. 2025;16:1523693. Published 2025 Jan 22. doi:10.3389/fimmu.2025.1523693.
  4. Amash A, Volkers G, Farber P, et al. Developability considerations for bispecific and multispecific antibodies. MAbs. 2024;16(1):2394229. doi:10.1080/19420862.2024.2394229.
  5. Shui L, Wu D, Yang K, Sun C, Li Q, Yin R. Bispecific antibodies: unleashing a new era in oncology treatment. Mol Cancer. 2025;24(1):212. Published 2025 Aug 4. doi:10.1186/s12943-025-02390-y.
  6. Dewaele L, Fernandes RA. Bispecific T-cell engagers for the recruitment of T cells in solid tumors: a literature review. Immunother Adv. 2025;5(1):ltae005. Published 2025 Jan 27. doi:10.1093/immadv/ltae005.
  7. Kast F, Schwill M, Stüber JC, et al. Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action. Nat Commun. 2021;12(1):3790. Published 2021 Jun 18. doi:10.1038/s41467-021-23948-6.
  8. Elimova E, Ajani J, Burris H, et al. Zanidatamab plus chemotherapy as first-line treatment for patients with HER2-positive advanced gastro-oesophageal adenocarcinoma: primary results of a multicentre, single-arm, phase 2 study. Lancet Oncol. 2025;26(7):847-859. doi:10.1016/S1470-2045(25)00287-6.
  9. Ziihera Safety Information. Ziihera HCP (Jazz Pharmaceuticals). https://www.ziiherahcp.com/safety. Accessed November 23, 2025.
  10. Wen J, Cui W, Yin X, et al. Application and future prospects of bispecific antibodies in the treatment of non-small cell lung cancer. Cancer Biol Med. 2025;22(4):348-375. doi:10.20892/j.issn.2095-3941.2024.0470.
  11. Engineering the Next Generation of Bispecific Antibodies. PEGS Europe 2024 Archive. https://www.pegsummiteurope.com/24/engineering-bispecifics. Accessed November 23, 2025

FDA Approves Niraparib with Abiraterone Acetate plus Prednisone for BRCA2-Mutated mCSPC

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SUMMARY: The FDA on December 12, 2025, approved Niraparib and Abiraterone acetate (AKEEGA&reg;) with prednisone for adults with deleterious or suspected deleterious BRCA2-mutated (BRCA2m) metastatic Castration-Sensitive Prostate Cancer (mCSPC), as determined by an FDA-approved test.

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.

Metastatic Castration-Sensitive Prostate Cancer (mCSPC) is a heterogeneous disease. Despite therapeutic advances, outcomes vary significantly based on underlying tumor biology. Approximately 25% of patients with mCSPC harbor Homologous Recombination Repair (HRR) gene mutations, including BRCA1, BRCA2, CHEK2, CDK12, PALB2, and others. Among these, BRCA1/2 mutations account for nearly half of HRR alterations and are particularly associated with aggressive disease biology, resistance to Androgen Receptor Pathway Inhibitors (ARPIs), and shortened Progression-Free and Overall Survival. The integration of AR-pathway inhibitors such as Abiraterone Acetate plus Prednisone into first-line treatment has meaningfully improved outcomes in the general mCSPC population. However, patients with HRR mutations, especially those with BRCA1/2, derive significantly less benefit from these agents alone, highlighting a substantial unmet clinical need.

Rationale for PARP Inhibition in HRR-Altered Prostate Cancer
Cancer cells with HRR deficiencies are vulnerable to PARP (Poly ADP-Ribose Polymerase) inhibition, which blocks DNA repair pathways and induces synthetic lethality. Prior landmark trials, MAGNITUDE (Niraparib with Abiraterone Acetate plus Prednisone) and TALAPRO-2 (Talazoparib  plus Enzalutamide), demonstrated the value of combining PARP inhibitors with ARPIs in Castration-Resistant Prostate Cancer (mCRPC) with HRR mutations. However, whether such a combination could offer meaningful benefit earlier in the disease course, in the castration-sensitive setting, remained unknown, until now.

AMPLITUDE Trial Design and Methods

Study Overview
The AMPLITUDE trial (NCT04497844) is a global, Phase 3, randomized, double-blind, placebo-controlled trial designed to evaluate whether combining the PARP inhibitor Niraparib with Abiraterone Acetate plus Prednisone improves clinical outcomes in patients with mCSPC (metastatic Castration-Sensitive Prostate Cancer) and HRR gene alterations.

Patient Population

  • Total enrolled: 696 men with mCSPC and at least one HRR gene mutation (germline or somatic)
  • Mutation profile: BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, RAD54L
  • BRCA1/2 prevalence: 55.6% of enrolled patients
  • Metastatic disease burden: 78% were high-volume M1disease, 87% had de novo M1disease and 16% had prior therapy with Docetaxel.
  • Prior therapies allowed:
    • 6 months or less of Androgen Deprivation Therapy (ADT)
    • 6 cycles or less of Docetaxel
    • 45 days or less of prior Abiraterone and Prednisone

Randomization and Treatment Arms

Patients were randomized 1:1 to:

  • Experimental arm: Niraparib 200 mg once daily plus Abiraterone acetate 1000 mg daily and Prednisone 5 mg daily (N=348)
  • Control arm: Placebo plus Abiraterone acetate 1000 mg along with Prednisone 5 mg daily (N=348)
    All patients continued on ADT.

Endpoints

  • Primary: Radiographic Progression-Free Survival (rPFS), assessed by investigator
  • Secondary: Time to Symptomatic Progression (TSP), Overall Survival (OS), Safety/tolerability

Key Results and Interpretation

Efficacy Outcomes

Radiographic Progression-Free Survival (Primary Endpoint)

  • Median rPFS:
    • Niraparib plus Abiraterone and Prednisone: Not reached
    • Abiraterone and Prednisone alone: 5 months (95% CI, 25.8–NR)
  • Hazard ratio: 0.63 (P=0.0001)
  • BRCA1/2 subgroup: HR =0.52 (P<0.0001)

This translates into a 37% relative risk reduction in progression or death in the overall population, and a 48% reduction in the BRCA1/2 subgroup, indicating a clear therapeutic effect in genetically defined populations.

Time to Symptomatic Progression

  • HR (overall): 0.50 (P<0.0001)
  • BRCA1/2 subgroup: HR 0.44 (P=0.0001)

This is clinically meaningful, and delaying symptom onset can preserve quality of life and extend time before additional therapies are needed.

Overall Survival (Interim Analysis)

  • HR (overall): 0.79 (95% CI, 0.59–1.04; P=0.10)
  • BRCA1/2 subgroup: HR 0.75 (95% CI, 0.51–1.11; P=0.15)

In an exploratory analysis of 323 patients with BRCA2 mutations, the rPFS Hazard Ratio (HR) was 0.46 (95% CI: 0.32, 0.66) with median rPFS not estimable for Niraparib and Abiraterone acetate with prednisone compared with 26 months (95% CI: 18, 28) for placebo and Abiraterone acetate with prednisone.

In an exploratory analysis in 373 patients with non-BRCA2 mutations, the HR for rPFS was 0.88 (95% CI: 0.63, 1.24), indicating that the overall improvement was primarily attributed to the results seen in patients with BRCA2 mutations.

Although OS data are not yet mature, the trend suggests a potential survival benefit with longer follow-up.

Safety Profile
The safety of Niraparib plus Abiraterone and Prednisone was consistent with known profiles of both agents. Grade 3-4 AEs in the Niraparib plus Abiraterone and Prednisone was 75.2% versus 58.9% with Abiraterone and Prednisone alone, with the most common higher Grade 3-4 AEs  noted in the Niraparib plus Abiraterone and Prednisone group (Anemia: 29.1% vs 4.6% and Hypertension: 26.5% vs 18.4%). The discontinuation rates due to AEs in the Niraparib plus Abiraterone and Prednisone group was 11.0% vs 6.9% in the Abiraterone and Prednisone group. These AEs were manageable with appropriate monitoring. No new safety signals were identified.

Conclusion
The AMPLITUDE trial marks a milestone and provides robust evidence to support Niraparib plus Abiraterone and Prednisone as a new first-line option in mCSPC patients with BRCA1/2 or other HRR gene mutations. By demonstrating that Niraparib plus Abiraterone and Prednisone improves Progression-Free outcomes in HRR-altered mCSPC, especially those with BRCA mutations, it paves the way for a more personalized, biology-driven approach to therapy in this setting. Ongoing follow-up will determine whether this translates into improved survival, but the current data already support Niraparib plus Abiraterone and Prednisone as a new treatment benchmark for this high-risk subgroup.

Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. Attard G, Agarwal N, Graff J, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA5006)

 

HER2CLIMB-05: Redefining First-Line Maintenance Therapy in HER2-Positive Metastatic 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 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).

Expanding Options Beyond Standard Maintenance

Despite major advances in the management of Human Epidermal growth factor Receptor 2–positive (HER2+) metastatic breast cancer (MBC), disease progression during maintenance therapy remains a persistent challenge. The long-standing first-line (1L) standard of care, induction with Trastuzumab, Pertuzumab, and a Taxane followed by Trastuzumab plus Pertuzumab maintenance, has delivered durable benefit, yet most patients ultimately relapse within two years. This unmet need is particularly relevant in a modern population increasingly exposed to HER2-targeted therapy in the early-stage setting and enriched for de novo metastatic disease.

HER2CLIMB-05 was designed to test whether intensifying HER2 blockade during the maintenance phase, by adding the highly selective oral HER2 tyrosine kinase inhibitor (TKI) Tucatinib (TUKYSA®), could further delay disease progression while preserving tolerability and quality of life.

Study Design and Patient Population

HER2CLIMB-05 (NCT05132582) is a randomized, double-blind, placebo-controlled, International Phase 3 trial enrolling patients with centrally confirmed HER2+ unresectable locally advanced or metastatic breast cancer. Eligible patients had no evidence of disease progression following 4 to 8 cycles of standard 1L induction therapy with Trastuzumab, Pertuzumab, and a taxane, an ECOG performance status of 0 or 1, and no or asymptomatic brain metastases.

A total of 654 patients were randomized 1:1 to receive Tucatinib (300 mg PO twice daily) or placebo, in combination with Trastuzumab and Pertuzumab administered IV every 21 days. Randomization was stratified by de novo versus recurrent disease, Hormone Receptor (HR) status, and presence or history of brain metastases. Endocrine therapy was permitted for patients with HR-positive disease. The Primary endpoint was investigator-assessed Progression-Free Survival (PFS) per RECIST v1.1. Key Secondary endpoints included Overall Survival (OS), PFS by Blinded Independent Central Review (BICR), Central Nervous System (CNS) PFS, safety, and Patient-Reported Outcomes.

The enrolled population reflects current real-world patterns of HER2+ MBC. All patients were female, with a median age of 54 years. Nearly 70% presented with de novo metastatic disease, over half had HR-positive tumors, and 12.4% had a presence or history of brain metastases at baseline. Most patients had excellent performance status, with nearly two-thirds classified as ECOG 0.

Primary Endpoint Met: Significant and Clinically Meaningful PFS Improvement

At a median follow-up of approximately 23 months, HER2CLIMB-05 met its Primary endpoint. The addition of Tucatinib to Trastuzumab and Pertuzumab resulted in a statistically significant and clinically meaningful improvement in PFS compared with standard maintenance therapy alone. Median PFS was 24.9 months in the Tucatinib arm versus 16.3 months in the control arm, corresponding to a 36% reduction in the risk of disease progression or death (Hazard Ratio [HR], 0.64; P < 0.0001). Results from BICR were consistent, reinforcing the robustness of the primary analysis.

Importantly, the PFS benefit was observed across all prespecified subgroups, including patients with and without brain metastases and those with HR-positive or HR-negative disease. This consistency highlights the broad applicability of Tucatinib-based maintenance therapy in HER2+ MBC.

Early Signals in Overall Survival and CNS Outcomes

Overall Survival data remain immature, with approximately 20% of the required events observed at the time of this primary analysis. Median OS has not yet been reached in either arm, with no evidence of detriment associated with Tucatinib and a favorable trend observed.

While CNS-PFS was not reached in the overall population, patients with baseline brain metastases experienced a numerical improvement with Tucatinib, with median CNS-PFS nearly doubling compared with control (8.5 vs 4.3 months). Although preliminary, these findings align with prior HER2CLIMB data supporting Tucatinib’s activity in CNS disease.

Safety Profile: Consistent and Manageable

The safety profile of Tucatinib in combination with Trastuzumab and Pertuzumab was consistent with known toxicities of HER2-directed regimens. Diarrhea, nausea, and transaminase elevations were the most common treatment-emergent adverse events in the Tucatinib arm, the majority of which were low grade and manageable with supportive care and dose modifications.

Grade ≥3 adverse events were more frequent with Tucatinib, particularly elevated ALT and AST; however, hepatic events were generally asymptomatic, reversible, and occurred early in treatment. Discontinuation of Tucatinib due to adverse events occurred in 13.5% of patients, underscoring the importance of proactive monitoring and toxicity management in clinical practice. No new safety signals were identified.

Positioning HER2CLIMB-05 in an Evolving Treatment Landscape

HER2CLIMB-05 adds to a growing body of evidence supporting maintenance intensification strategies in HER2+ MBC. Alongside recent Phase 3 trials such as PATINA and DESTINY-Breast09, these data emphasize that meaningful improvements in disease control can be achieved beyond traditional chemotherapy-based induction regimens.

Unlike antibody–drug conjugate based approaches, Tucatinib-based maintenance offers a chemotherapy-free option that targets HER2 both extracellularly and intracellularly, with particular relevance for patients with brain metastases or those who may not be ideal candidates for prolonged cytotoxic therapy.

Clinical Implications

The HER2CLIMB-05 primary analysis demonstrates that adding Tucatinib to Trastuzumab and Pertuzumab as 1L maintenance therapy significantly prolongs PFS, extending disease control to more than two years in patients with HER2+ metastatic breast cancer. The benefit was consistent across key subgroups, including HR status and CNS involvement, and was achieved with a manageable and familiar safety profile.

As the HER2+ metastatic treatment paradigm continues to evolve, Tucatinib-based maintenance represents an important new option that may delay progression and postpone the need for subsequent cytotoxic therapy. Ongoing follow-up will clarify the impact on Overall Survival, CNS outcomes, and patient-reported Quality of Life, further informing individualized treatment decisions.

HER2CLIMB-05: A Phase 3 Study of Tucatinib Versus Placebo in Combination with Trastuzumab and Pertuzumab as First-line Maintenance Therapy for HER2+ Metastatic Breast Cancer. Dieras V, Curigliano G, Martin M, et al. on behalf of the HER2CLIMB-05 investigators. J Clin Oncol. DOI: 10.1200/JCO-25-02600

PHAROS: Long-Term Efficacy and Survival Outcomes with Encorafenib Plus Binimetinib in BRAF V600E–Mutant Metastatic NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. 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.

BRAF V600E mutations occur in approximately 1% to 2% of patients with NSCLC and define a biologically distinct subset for which targeted therapy has become a cornerstone of treatment. Dual inhibition of the MAPK pathway with BRAF and MEK inhibitors is currently recommended by clinical guidelines as the preferred first-line approach for patients with BRAF V600E–mutant metastatic NSCLC (mNSCLC), with immunotherapy and chemotherapy-based regimens serving as alternative options.

The Phase II PHAROS study (NCT03915951) is an ongoing, open-label, single-arm, multicenter trial designed to evaluate the efficacy and safety of Encorafenib (BRAFTOVI®) in combination with Binimetinib (MEKTOVI®) in patients with BRAF V600E–mutant mNSCLC. Eligible patients included both treatment-naïve individuals and those with prior systemic therapy for metastatic disease. All patients received oral Encorafenib 450 mg once daily plus oral Binimetinib 45 mg twice daily, administered in continuous 28-day cycles until disease progression, unacceptable toxicity, or treatment discontinuation.

The Primary endpoint of PHAROS was Objective Response Rate (ORR) as assessed by Independent Radiology Review (IRR), with separate analyses prespecified for treatment-naïve and previously treated cohorts. Key Secondary endpoints included Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), Disease Control Rate, Safety, and Tolerability. Exploratory analyses evaluated efficacy across clinically relevant subgroups, including smoking history.

A total of 98 patients were enrolled and treated, including 59 treatment-naïve and 39 previously treated patients. At the March 14, 2025 data cutoff, a small proportion of patients in both cohorts remained on active treatment, reflecting durable disease control in a subset of patients. Median treatment duration was substantially longer in the frontline cohort compared with previously treated patients, with more than 40% of treatment-naïve patients receiving therapy for longer than two years.

PHAROS met its Primary endpoint in both cohorts.

In treatment-naïve patients, the confirmed ORR by IRR was 75%, with responses demonstrating marked durability. Median Duration of Response was 40.0 months, and median PFS reached 30.4 months. After a median follow-up of more than four years for overall survival, median OS was 47.6 months, with an estimated 4-year OS rate of 49%, underscoring the potential for prolonged survival with frontline targeted therapy.

In the previously treated cohort, Encorafenib plus Binimetinib also demonstrated clinically meaningful activity. The ORR was 49%, with a median Duration of Response of 16.7 months. Median PFS was 9.3 months, and median OS was 22.7 months after nearly four years of follow-up. The estimated 4-year OS rate in this cohort was 31%.

Post hoc subgroup analyses suggested that clinical benefit was generally consistent across baseline characteristics. Notably, both PFS and OS were numerically longer in patients without a smoking history compared with those with a history of smoking, a finding that may be related to pharmacokinetic effects on Binimetinib exposure and warrants further investigation.

The safety profile observed with extended follow-up was consistent with prior analyses and with known toxicities associated with BRAF and MEK inhibition. Most treatment-related adverse events were low grade and manageable, with gastrointestinal symptoms, fatigue, and nausea among the most frequently reported. Rates of dose modification and discontinuation were similar across treatment lines, and no new safety signals emerged with longer-term exposure.

Although cross-trial comparisons should be interpreted cautiously, the Overall Survival outcomes observed in PHAROS compare favorably with historical data for targeted therapy in this population. Given that a significant proportion of patients with metastatic NSCLC may not receive subsequent lines of therapy, these findings emphasize the importance of selecting the most effective treatment upfront.

In conclusion, updated results from the PHAROS study demonstrate durable responses and sustained long-term survival with Encorafenib plus Binimetinib in patients with BRAF V600E–mutant mNSCLC. The depth and durability of benefit, particularly in treatment-naïve patients, further support this combination as a preferred first-line targeted therapy option and reinforce its role in the evolving treatment landscape for this molecularly defined NSCLC subgroup.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer. Johnson ML, Smit EF, Felip E, et al. J Clin Oncol. 2025;43:3706-3713

Precision Medicine in Practice: Timely Use of Tumor NGS Remains Suboptimal in Common Cancers

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SUMMARY: Next-generation sequencing (NGS) has revolutionized the management of advanced cancers by enabling identification of tumor-specific genomic alterations for which targeted therapies are now available. National guidelines recommend early and routine NGS testing for patients with advanced or metastatic solid tumors to inform treatment decisions. In the United States, the five most prevalent advanced or metastatic solid tumors include advanced Non-Small Cell Lung Cancer (aNSCLC), metastatic Breast Cancer (mBC), metastatic Prostate Cancer (mPC), advanced Colorectal Cancer (aCRC), and metastatic Pancreatic Cancer (mPanC). For these malignancies, the integration of NGS has become increasingly critical in guiding targeted therapy selection and improving survival outcomes. Despite the approval of multiple targeted therapies for these malignancies, real-world utilization of NGS remains inconsistent.

In this study presented at the 2025 ASCO Annual Meeting, Chehade and colleagues,  evaluated patterns in NGS testing and its timing, relative to patient mortality.

Study Overview: This retrospective analysis leveraged the Flatiron Health EHR-derived de-identified database across 280 cancer clinics, spanning data from 2011 onward. The study included patients with a diagnosis of aNSCLC, mBC, mPC, aCRC, or mPanC, all of whom had records of NGS testing and a documented date of death. The researchers identified 86,536 patients with advanced non-small cell lung cancer, 36,000 with metastatic breast cancer, 35,702 with advanced colorectal cancer, 24,105 with metastatic prostate cancer and 14,964 with metastatic pancreatic cancer. About a third of patients from each cancer group received NGS testing (NSCLC, 36.3%; breast cancer, 32.1%; colorectal cancer, 41%; prostate cancer, 30.9%; and pancreatic cancer, 35.4%).

Patients were categorized based on the interval between receipt of NGS results and death:

  • More than 3 months before death
  • Within 3 months of death
  • After death

Key Findings Across cancer types, only 30% to 40% of patients received NGS testing. Among those who were tested and had a recorded date of death, the timing of NGS was as follows:

Timing of First NGS aNSCLC (N=19,958) mBC (N=5,689) mPC (N=3,397) aCRC (N=8,553) mPanC (N=3,957)
>3 mo before death          72.3%        81.6%        85.4%        85.0%         71.1%
Within 3 mo of death          25.6%        16.9%        13.5%        13.7%         26.5%
After death          2.1%        1.5%        1.1%        1.3%         2.4%

Notably, up to one in four patients with NSCLC or pancreatic cancer received their first NGS results within 3 months of death, a timeframe often too late for actionable therapeutic intervention.

Interpretation and Implications Despite advances in molecularly targeted therapies and growing guideline support for comprehensive genomic profiling, real-world testing patterns remain suboptimal:

  • Low uptake: Only about a third of eligible patients undergo NGS testing.
  • Late testing: A substantial proportion of tested patients receive results within 3 months of death.
  • Missed opportunities: Many patients are never tested—or are tested too late to benefit from life-extending therapies.

These findings highlight ongoing gaps in precision oncology implementation, especially in community-based settings.

Next Steps & Recommendations To improve the utility of NGS in oncology, efforts should focus on:

  • Earlier testing: At diagnosis or at first progression of advanced disease.
  • Workflow integration: Embedding NGS into routine clinical pathways.
  • Education: Raising awareness among clinicians and patients about the benefits of timely testing.
  • Health system support: Addressing barriers such as reimbursement, turnaround times, and tissue availability.

Conclusion: Real-World Data from this large retrospective analysis reveal late-stage testing and underutilization of life-prolonging genomic profiling. This study underscores an urgent need to optimize the timing and uptake of NGS testing in patients with advanced solid tumors. Earlier and broader testing is essential to ensure patients have access to the most effective, personalized treatment strategies, and to avoid the missed potential of life-extending therapies.

Utilization and timing of first tumor next-generation sequencing testing (NGS) in patients (pts) with five most common cancers in the USA. Chehade CH, Jo Y, Ozay ZI, et al. Doi: 10.1200/JCO.2025.43.16_suppl.11014. Abstract # 11014. Presented at: ASCO Annual Meeting; May 30-June 3, 2025; Chicago.