Category: Hem/Onc Updates

FDA Approves Pirtobrutinib in Relapsed/Refractory CLL/SLL

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SUMMARY: The FDA on December 3, 2025 granted traditional approval to Pirtobrutinib (JAYPIRCA®) for adults with relapsed or refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor. In 2023, FDA granted accelerated approval to Pirtobrutinib for adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

The American Cancer Society estimates that for 2025, about 23,690 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4460 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM).

The 3 covalent BTK inhibitors (cBTKi) presently approved by the FDA for CLL/SLL include Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®), and Zanubrutinib (BRUKINSA®). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

Pirtobrutinib (JAYPIRCA®) is a next-generation, highly selective, reversible, non-covalent BTK inhibitor (BTKi), developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib is well tolerated and demonstrated encouraging efficacy and safety in early-phase studies, leading to FDA accelerated approval in December 2023 for patients with CLL/SLL who have received ≥2 prior lines of therapy, including both a BTKi and a BCL-2 inhibitor.

Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) in the post–covalent Bruton Tyrosine Kinase Inhibitor (cBTKi) setting remains a major therapeutic challenge. No prospective, randomized trials have previously evaluated treatment options in this population, and real-world data suggest poor outcomes, particularly after sequential covalent BTKi and BCL-2 inhibitor exposure. The present FDA approval was based on the BRUIN CLL-321 study.

Study Design
BRUIN CLL-321 is the first global, randomized, multicenter, Phase III trial conducted exclusively in patients with R/R CLL/SLL previously treated with a cBTKi.

  • Design: Open-label, 1:1 randomization to Pirtobrutinib 200 mg PO daily (N=119) vs. investigator’s choice (IC) of Idelalisib plus Rituximab (IdelaR-N=82) or Bendamustine plus Rituximab (BR-N=37).
  • Population: 238 patients; median 3 prior therapies; 50% had prior Venetoclax; high prevalence of high-risk genomic features (del[17p]/TP53 mutation ~54%, complex karyotype up to 72%).
  • Endpoints: Primary endpoint was Independent Review Committee (IRC)–assessed Progression-Free Survival (PFS). Secondary endpoints included Time to Next Treatment or death (TTNT), Overall Survival (OS), Overall Response Rate (ORR), and Safety.

Patients could cross over from IC to Pirtobrutinib upon confirmed progression, and treatment beyond IRC-defined progression was permitted if clinical benefit was maintained.

Efficacy Outcomes

  • PFS: Median 14.0 months with Pirtobrutinib vs. 8.7 months with IdelaR/BR (HR = 0.54; P =0.0002), representing a 46% reduction in the risk of progression or death.
  • TTNT: Median 24.0 months with Pirtobrutinib vs. 10.9 months with IC (HR = 0.37), reflecting sustained clinical benefit beyond protocol-defined progression in many patients.
  • OS: No statistically significant difference at final analysis (HR = 1.09), likely influenced by crossover (75.8% of eligible IC patients switched to Pirtobrutinib).
  • Subgroup Benefit: PFS improvement was consistent across key high-risk subgroups, including those with del(17p)/TP53 mutation, complex karyotype, and unmutated IGHV.

Safety Profile
Pirtobrutinib was generally well tolerated:

  • Grade ≥3 adverse events (AEs): 57.7% with Pirtobrutinib vs. 73.4% with IC.
  • Discontinuations due to AEs: 17.2% vs. 34.9%, respectively.
  • Class-related BTKi toxicities (atrial fibrillation, hypertension, major bleeding) were infrequent, with rates comparable to or lower than background incidence in CLL populations.
  • No cases of Richter transformation were reported in the Pirtobrutinib arm, versus three in the IC group.

Clinical Implications
The BRUIN CLL-321 trial establishes Pirtobrutinib as a new standard of care option for patients with CLL/SLL previously treated with cBTKi, offering:

  • Significant PFS improvement in a population with historically poor prognosis.
  • Prolonged TTNT, which may be more reflective of real-world benefit than PFS alone.
  • Favorable safety profile supporting long-term tolerability.

These findings also raise important considerations for sequencing strategies, including potential use of Pirtobrutinib prior to Venetoclax in certain patients, pending further prospective data (e.g., BRUIN-322 trial).

Takeaway for Practice:
For CLL/SLL patients progressing after cBTKi therapy, Pirtobrutinib offers a meaningful advancement, providing durable disease control with a manageable toxicity profile. BRUIN CLL-321 delivers the first randomized evidence supporting treatment in this setting, addressing a long-standing gap in the therapeutic landscape.

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). Sharman JP, Munir T, Grosicki S, et al. J Clin Oncol. 2025;43:2538-2549

 

 

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®) 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

Late Breaking Abstract – ESMO 2025: Early Radioligand Intensification in mHSPC: Key Findings from the Phase III PSMAddition Trial

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

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) remains a challenging disease state, even with modern intensification strategies. Androgen-Deprivation Therapy (ADT) combined with an Androgen Receptor Pathway Inhibitor (ARPI) is a widely adopted standard of care. Yet many patients continue to progress and long-term disease control remains elusive.

Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer. The emergence of PSMA-targeted radioligand therapy validated in metastatic Castration-Resistant Prostate Cancer (mCRPC) through the VISION and PSMAfore studies, has prompted investigation of earlier integration.

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

The Phase III PSMAddition trial represents the first randomized effort to evaluate a targeted radionuclide therapy in the hormone-sensitive setting.

Study Design and Patient Population

PSMAddition enrolled 1,144 men with treatment-naïve or minimally treated (≤45 days of hormonal therapy) mHSPC. All patients had PSMA-positive metastatic disease confirmed by 68Ga-PSMA-11 PET/CT, defined as at least one lesion with uptake exceeding liver activity. Participants were randomized 1:1 to:

  • Experimental arm: 177Lu-PSMA-617 (7.4 GBq every 6 weeks for up to six cycles) + ADT + an ARPI of physician’s choice
  • Control arm: ADT + ARPI alone, with crossover to 177Lu-PSMA-617 permitted upon centrally confirmed radiographic progression

Baseline characteristics were well balanced. Half had de novo metastatic disease and more than two-thirds had high-volume disease by conventional imaging criteria. Abiraterone was the most commonly selected ARPI, followed by Apalutamide and Enzalutamide. In the experimental arm, treatment adherence was high, with 86% completing all six cycles.

This report reflects the second interim analysis for radiographic Progression-Free Survival (rPFS; data maturity 74%) and the first interim analysis for Overall Survival (OS; data maturity 47%) after a median follow-up of 23.6 months.

Efficacy Outcomes

Radiographic Progression-Free Survival: Primary Endpoint Achieved

The addition of 177Lu-PSMA-617 significantly prolonged rPFS compared with ADT + ARPI alone (HR 0.72; P=0.002). Median rPFS has not been reached in either arm. Importantly, benefit was observed across all predefined subgroups, including high- vs low-volume disease, de novo vs recurrent mHSPC, as well as varying ARPI backbones. These findings confirmed that PSMA-targeted radioligand therapy can improve disease control even in the presence of potent systemic hormonal intensification.

Early Overall Survival Trends

Although OS data are immature, there is a favorable trend for early 177Lu-PSMA-617 (HR 0.84). As nearly 60% of progressing control-arm patients crossed over to 177Lu-PSMA-617, subsequent analyses may be confounded, potentially attenuating the ability to detect an OS difference with further follow-up.

Secondary Efficacy Measures

Across all Secondary endpoints, outcomes favored the 177Lu-PSMA-617 arm:

  • ORR: 85% vs 81%
    • Complete responses: 57% vs 42%
  • PSA endpoints:
    • PSA <0.2 ng/mL rates at multiple prespecified time points were higher in the experimental arm
    • PSA progression significantly delayed (HR 0.42)
  • Time to mCRPC: HR 0.70
  • Investigator-assessed PFS: HR 0.64
  • Time to symptomatic skeletal events: Comparable between arms, but favored 177Lu-PSMA-617 numerically

Collectively, these findings indicate deeper and more durable disease responses with early radioligand therapy.

Safety and Tolerability

Overall toxicity was higher with the addition of 177Lu-PSMA-617 but consistent with the known safety profile of radioligand therapy. Common all-grade adverse events (experimental arm) included dry mouth (46%), fatigue (35%), nausea (34%), Hot flashes (29%) and anemia (27%). Grade ≥3 cytopenias occurred more often with 177Lu-PSMA-617 (14% vs 5%), though most were low grade and manageable. Importantly, no treatment-related deaths were reported. Despite higher toxicity rates, Quality-of-Life measures including FACT-P and EQ-5D were not adversely impacted, and time to worsening pain was similar between arms.

Clinical Implications

PSMAddition provides the first Phase III evidence supporting integration of PSMA-targeted radioligand therapy into initial systemic treatment for PSMA-positive mHSPC. While rPFS and multiple disease-control endpoints clearly favor the triplet approach, questions remain regarding long-term survival benefit, patient selection, and optimal treatment duration. Additional biomarker-driven analyses and longer follow-up will be critical in defining how broadly early LuPSMA-617 should be adopted in routine practice.

Phase 3 trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Tagawa ST, Sartor O, Piulats JM, et al. Presented at: European Society for Medical Oncology (ESMO) Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA6

Chronic Hepatitis C as a Modifiable Risk Factor for Pancreatic Cancer: Insights from a National VA Cohort

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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. Detecting cancer at early stages can significantly increase survival rates and outcomes.

A large population–based cohort study from the US Veterans Health Administration (VA) provides compelling new evidence that chronic hepatitis C virus (HCV) infection independently increases PDAC risk, strengthening the rationale for broad HCV screening and antiviral treatment initiatives.

Study Design

This retrospective cohort study evaluated 6.3 million veterans with documented HCV testing between 2001 and 2020, leveraging two decades of integrated VA electronic health records and linked Medicare data. Veterans were classified into three groups:

  • Chronic HCV infection (confirmed via viral load, genotype, or treatment history)
  • HCV exposure only (positive antibody or diagnostic code without RNA confirmation)
  • No HCV infection

More than 5.6 million individuals comprised the final analytic cohort. Individuals were followed for a median 5.1 years, with adjustment for key PDAC risk factors such as smoking, alcohol use, pancreatitis, diabetes, liver disease, and demographic variables.

Key Findings

  1. HCV infection significantly increases PDAC risk.
    Compared with veterans without HCV, the risk of PDAC was higher among those with:
  • Chronic HCV Infection: adjusted HR=1.76 (95% CI, 1.67–1.86)
  • HCV exposure: adjusted HR=1.18 (95% CI, 1.11–1.25)

Veterans with chronic HCV infection developed PDAC at markedly younger ages (median 65 years vs 72 years in non-HCV patients), suggesting accelerated carcinogenesis.

  1. PDAC incidence rates were substantially higher with chronic HCV.
  • 107.7 per 100,000 person-years (chronic HCV infection)
  • 68.0 per 100,000 person-years (HCV exposure)
  • 51.9 per 100,000 person-years (non-HCV)
  1. HCV genotype influences PDAC risk.
    Among individuals with chronic HCV infection, risk varied significantly compared with no HCV infection:
  • Genotype 3: adjusted HR=2.02
  • Genotype 1: adjusted HR=1.75
  • Genotype 2: adjusted HR=1.35

Higher-risk genotypes (1 and 3) parallel patterns previously observed in HCV-associated hepatocellular carcinoma.

Biological Context

The study supports earlier observations linking HCV to pancreatic injury and inflammation. Proposed mechanisms include:

  • Chronic inflammation induced by persistent viral infection may create a tumor-promoting microenvironment similar to that seen in HCV-associated hepatocellular carcinoma.
  • Viral antigens identified in pancreatic acinar cells suggest the possibility of direct infection, with potential for genomic injury and local inflammation.
  • Activation of pancreatic stellate cells, analogous to hepatic stellate cell activation in liver fibrosis and cirrhosis, may facilitate desmoplasia and tumor progression

These pathways align with known inflammatory drivers of PDAC, including tobacco use, alcohol-associated disease, and metabolic dysfunction.

Clinical and Public Health Implications

This analysis, the largest of its kind, suggests that chronic untreated HCV is a modifiable PDAC risk factor, independent of other established contributors. With direct-acting antiviral (DAA) therapies achieving >95% cure rates, improving HCV screening and treatment uptake may hold downstream benefits for PDAC prevention.

Key implications include:

  • Risk stratification: Incorporating HCV status into PDAC prediction models may enhance early detection strategies.
  • Genotype-specific counseling: Patients with genotype 1 or 3 may represent a higher-risk subgroup requiring closer surveillance.
  • Therapeutic impact: Future research is needed to clarify whether DAA-mediated HCV eradication attenuates long-term PDAC risk.

Conclusion

In a nationwide cohort of more than 6 million veterans, chronic HCV infection was associated with a 1.8-fold increase in PDAC risk, with particularly elevated risk among those with HCV genotypes 1 and 3. These findings underscore the importance of early HCV identification and treatment, not only to prevent liver disease, but potentially to reduce the burden of pancreatic cancer.

Pancreatic Ductal Adenocarcinoma After Hepatitis C Infection. Levinson RN, Bushman R, Tate JP, et al. JAMA Netw Open. Published online:November 14, 2025;8;(11):e2543701. doi:10.1001/jamanetworkopen.2025.43701.

First Line Sacituzumab Govitecan in Advanced Triple-Negative 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.

Clinical Context

TNBC accounts for roughly 10–15% of breast cancers and is characterized by its aggressive biology and lack of targetable receptors. Survival prospects in the metastatic setting are particularly poor and fewer than 20% of patients are alive at 5 years. Treatment options remain limited for patients with newly diagnosed, locally advanced unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 blockade, as approximately 60% of metastatic TNBCs are PD-L1–negative (CPS <10), excluding them from approved chemo-immunotherapy regimens. Aside from PARP inhibitors, which apply only to a minority with germline BRCA1/2 mutations, cytotoxic chemotherapy has remained the default first-line therapy despite short survival and limited durability. Compounding this unmet need, real-world data show that nearly half of patients never receive second-line therapy due to rapid progression or early mortality. Thus, optimizing first-line outcomes is essential, particularly for patients not eligible for immunotherapy.

TRODELVY® (Sacituzumab govitecan) is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38. The Phase 3 ASCENT-03 trial provides important new evidence supporting Sacituzumab govitecan as a frontline therapeutic foundation for this high-risk group.

ASCENT-03 Trial Overview

ASCENT-03 was an International, open-label, randomized Phase 3 trial evaluating Sacituzumab govitecan versus investigator’s choice of chemotherapy (Paclitaxel, nab-Paclitaxel, or Gemcitabine/Carboplatin) in patients with untreated advanced or metastatic TNBC who were not candidates for PD-1/PD-L1 inhibitors. Most participants (about 99% in each arm) had PD-L1–negative disease. Eligibility also included PD-L1–positive patients previously treated with checkpoint inhibitors or those with comorbidities precluding immunotherapy. A total of 558 patients were enrolled globally and randomized 1:1 to receive Sacituzumab govitecan (279 patients) or chemotherapy (279 patients – 56% were selected to receive a taxane and 44% to receive Gemcitabine plus Carboplatin). Treatment continued until disease progression, or unacceptable toxicity. Crossover to Sacituzumab govitecan was permitted for patients in the chemotherapy arm after progression. The Primary endpoint was Progression-Free Survival (PFS) assessed by Blinded Independent Central Review. Key Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), and Safety.

Efficacy: Meaningful Extension of Disease Control

Sacituzumab govitecan delivered a statistically robust and clinically meaningful improvement in PFS:

  • Median PFS:
    • 9.7 months with Sacituzumab govitecan
    • 6.9 months with chemotherapy
  • Risk reduction: 38% reduction in risk of progression or death (HR 0.62; 95% CI, 0.50–0.77; P<0.001)

Response rates were numerically similar between arms (48% vs. 46%), but Sacituzumab govitecan produced a notably longer median duration of response (12.2 vs. 7.2 months), underscoring the sustained disease control characteristic of Trop-2–targeted therapy.

Improved PFS with Sacituzumab govitecan was observed across most prespecified subgroups, including those with particularly poor prognostic indicators such as early recurrence after curative-intent therapy and the presence of liver metastases.

OS results were immature at the time of analysis and are confounded by crossover; however, the strong PFS signal aligns with survival benefits previously demonstrated in later-line settings (ASCENT) and in PD-L1–positive patients treated with Sacituzumab govitecan plus Pembrolizumab (ASCENT-04).

Safety and Tolerability

The toxicity profile of Sacituzumab govitecan was consistent with prior experience, without new safety signals. Grade ≥3 adverse events were 66% with Sacituzumab govitecan versus 62% with chemotherapy. Most common grade ≥3 events with Sacituzumab govitecan included neutropenia (43%), diarrhea (9%), leukopenia (7%). Despite comparable rates of high-grade events, Sacituzumab govitecan led to fewer dose reductions and considerably fewer discontinuations compared with chemotherapy (4% vs. 12%), suggesting improved treatment continuity. Neutropenia remains an important risk, and emerging regulatory guidance recommends considering primary G-CSF prophylaxis in patients with elevated risk for febrile neutropenia (e.g., age ≥65, prior neutropenia, poor performance status, comorbid organ dysfunction).

Positioning ASCENT-03 Within the Evolving TNBC Landscape

ASCENT-03 complements the ASCENT-04 findings, where Sacituzumab govitecan combined with Pembrolizumab demonstrated meaningful benefit in PD-L1–positive previously untreated metastatic TNBC. Together, these trials provide convergent evidence that Sacituzumab govitecan contributes substantially to disease control, regardless of PD-L1 status, and can serve as either a foundational monotherapy or as part of combination immunotherapy.

For the large subset of patients with PD-L1–negative disease, or those ineligible for checkpoint blockade, ASCENT-03 establishes Sacituzumab govitecan as a superior first-line option compared with standard chemotherapy.

Key Considerations and Limitations

  • The trial’s open-label design introduces potential bias, although PFS assessment was safeguarded by Blinded Independent Central Review.
  • Enrollment of PD-L1–positive patients and those previously treated with PD-1/PD-L1 inhibitors was limited, restricting generalizability to those subgroups.
  • Despite specific efforts to enhance racial diversity, representation of Black patients remained low, highlighting ongoing disparities in TNBC clinical trial participation.

Conclusion

Sacituzumab govitecan significantly prolonged Progression-Free Survival compared with standard chemotherapy in the first-line treatment of advanced or metastatic TNBC among patients who are not candidates for PD-1/PD-L1 inhibitors. With durable responses, a manageable safety profile, and fewer treatment discontinuations than chemotherapy, Sacituzumab govitecan offers a meaningful advance for a population in critical need of more effective therapies.

As experience accumulates from ASCENT-03, ASCENT-04, and ongoing studies in early-stage disease, Sacituzumab govitecan is poised to reshape the treatment paradigm across the TNBC continuum.

Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer. Cortés J, Punie K, Barrios C, et al. N Engl J Med 2025;393:1912-1925

ERSPC Final Analysis: Long-Term PSA Screening Reduces Prostate Cancer Deaths

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease. Prostate cancer remains one of the most pressing global cancer burdens, with mortality rates projected to double by 2040 as populations age and life expectancy increases.

PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. PSA-based screening is widely debated due to false positives, overdiagnosis, and overtreatment.

The question of how and in whom to implement early detection strategies, continues to challenge clinicians and public health systems. The European Randomized Study of Screening for Prostate Cancer (ERSPC), initiated in 1993, represents the most comprehensive effort to evaluate whether population-based Prostate-Specific Antigen (PSA) screening reduces prostate cancer mortality. Now, with more than two decades of follow-up completed for over 160,000 men, the ERSPC provides its final unified analysis, offering critical insights into both the enduring benefits and ongoing challenges of PSA-based screening.

Study Overview and Screening Approach

The ERSPC spanned eight European countries and included a predefined core cohort of men aged 55–69 years at randomization. Participants were assigned to organized repeated PSA screening or to usual care without screening invitations. Screening protocols varied modestly by country, but all centers relied on standardized PSA assays and risk-based biopsy thresholds. Most participants received screening every four years, although the interval ranged from two to seven years. The Primary outcome was prostate cancer mortality.

  • Population: 162,236 men (55–69 yrs)
    • Screening group: 72,888
    • Control group: 89,348
  • Screening Protocol: Repeated PSA, 2–8 invitations, biopsies for elevated PSA
  • Follow-Up: Median 23 years
  • Outcomes:
    • Relative reduction in prostate cancer death: 13%
    • Absolute risk reduction: 0.22%

Key Points for Clinical Practice:

Three decades after its inception, the ERSPC provides unequivocal evidence that PSA-based screening reduces prostate cancer mortality. However, it also highlights that how screening is implemented may matter, as much as whether it is implemented at all.

  • PSA-based screening reduces prostate cancer mortality by ~13% over 23 years; absolute benefit continues to rise with long-term follow-up.
  • Overdiagnosis and overtreatment remain central harms. Risk-adapted strategies (MRI, biomarkers, active surveillance) mitigate these risks.
  • Screening should ideally start at age 50 for maximal benefit and continue based on life expectancy rather than age alone.
  • Modern guidelines support selective biopsy only in patients with high-risk features and conservative management/active surveillance for low-risk disease, to optimize the harm–benefit ratio.
  • Individualized decision-making and cessation of screening is essential, particularly for older men or those with competing health risks.

Such strategies aim to preserve the mortality benefit demonstrated in ERSPC while minimizing harms associated with overdiagnosis and overtreatment.

Conclusion

The final unified analysis of the ERSPC confirms that PSA screening offers a sustained reduction in prostate cancer mortality that becomes more pronounced over long-term follow-up. While screening continues to carry risks, particularly through detection of indolent disease, its harm–benefit balance has improved with time and can be further optimized through modern, risk-adapted approaches. As prostate cancer incidence continues to rise worldwide, these data provide essential guidance for developing screening policies that maximize benefit, reduce harm, and ensure evidence-based care for patients at risk.

European Study of Prostate Cancer Screening-23-Year Follow-up. Roobol MJ, de Vos II, Månsson M, et al for the ERSPC Investigators. N Engl J Med 2025;393:1669-1680.

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.

Low Dose Aspirin Reduces Recurrence in Colorectal Cancer Patients with PI3K Pathway Alterations

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

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

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

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

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

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

Of the 626 patients (419 with colon cancer and 207 with rectal cancer) who continued participation in this trial, 157 and 156 patients in Groups A and B respectively, received Aspirin 160 mg daily for 3 years, whereas 157 and 156 patients in each respective group received placebo. The median age was 66 years, 52% of patients were female, and majority of patients were white. Fifty percent of patients with both rectal and colon cancer had received neoadjuvant therapy. The Primary end point was Time to CRC recurrence (TTR) in Group A patients. Secondary end points included Disease Free Survival (DFS) and Overall Survival (OS) in Group A, DFS and OS 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 for PI3K-Altered Localized Colorectal Cancer. Martling A, Myrberg IH, Nilbert M, et al.,  for the ALASCCA Study Group. N Engl J Med 2025;393:1051-1064.