Genomic determinants of response and resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer are not well characterized. We analyzed serial circulating tumor DNA from the PACE trial in which patients who progressed on ET and CDK4/6i were randomized to fulvestrant, fulvestrant plus palbociclib, or fulvestrant, palbociclib, and avelumab.

In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.6 months. Overall, 148 patients were randomized to receive ivosidenib-azacitidine (n = 73) or placebo-azacitidine (n = 75). Median OS was significantly longer with ivosidenib (29.3 months; 95% confidence interval [CI], 13.2 to not reached) than with placebo (7.9 months; 95% CI, 4.1-11.3; hazard ratio, 0.42 [95% CI, 0.27-0.65]; P < .0001). Hematologic recovery was faster, more durable, and conversion to transfusion independence (53.8% vs 17.1%; P = .0004) was more common with ivosidenib than with placebo. Of 33 ivosidenib-treated patients evaluable for molecular measurable residual disease (MRD), 10 converted to MRD negativity. Although OS did not differ significantly between MRD-negative and MRD-positive responders at the 0.1% variant allele frequency (VAF) threshold, MRD-negative patients had numerically longer survival. MRD status appeared more predictive of long-term OS when an exploratory 1% VAF threshold was applied. MRD response was not associated with IDH1 variant, VAF, inferred clonality, or number of baseline comutations. The previously reported safety profile was maintained. These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy-ineligible patients with IDH1-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03173248.

BACKGROUNDEndocrine therapy (ET) with tamoxifen (TAM) or aromatase inhibitors (AI) is highly effective against hormone receptor-positive (HR-positive) early breast cancer (BC), but resistance remains a major challenge. The primary objectives of our study were to understand the underlying mechanisms of primary resistance and to identify potential biomarkers.METHODSWe selected more than 800 patients in 3 subcohorts (Discovery, n = 364, matched pairs; Validation 1, n = 270, Validation 2, n = 176) of the West German Study Group (WSG) ADAPT trial who underwent short-term preoperative TAM or AI treatment. Treatment response was assessed by immunohistochemical labeling of proliferating cells with Ki67 before and after ET. We performed comprehensive molecular profiling, including targeted next-generation sequencing (NGS) and DNA methylation analysis using EPIC arrays, on posttreatment tumor samples.RESULTSTP53 mutations were strongly associated with primary resistance to both TAM and AI. We identified distinct DNA methylation patterns in resistant tumors, suggesting alterations in key signaling pathways and tumor microenvironment composition. Based on these findings and patient age, we developed the Predictive Endocrine ResistanCe Index (PERCI). PERCI accurately stratified responders and nonresponders in both treatment groups in all 3 subcohorts and predicted progression-free survival in an external validation cohort and in the combined subcohorts.CONCLUSIONOur results highlight the potential of PERCI to guide personalized endocrine therapy and improve patient outcomes.TRIAL REGISTRATIONWSG-ADAPT, ClinicalTrials.gov NCT01779206, retrospectively registered 01-25-2013.FUNDINGGerman Cancer Aid (Grant Number 70112954), German Federal Ministry of Education and Research (Grant Number 01ZZ1804C, DIFUTURE).

Invasive lobular carcinoma (ILC) has lower response rates to neoadjuvant chemotherapy (NAC) than invasive ductal carcinoma. While ILC often has low-risk biology, there is a high-risk subset within this heterogeneous tumor type. We compared surgical treatment and response rates by histology in I-SPY2, a multicenter NAC trial.

Rucaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor with proven efficacy in multiple tumor types. The efficacy of PARP inhibition in endometrial cancer remains unclear.

Patients with platinum-resistant/platinum-refractory high-grade serous ovarian cancer (HGSOC) without a BRCA mutation have poor prognosis and limited treatment options. We report efficacy and biomarker data from EPIK-O, which investigated alpelisib + olaparib versus single-agent chemotherapy in these patients.

About 15-20% of breast cancers (BC) overexpress Human Epidermal Growth Factor Receptor 2 (HER2+), and 50% of them are also oestrogen receptor positive (ER+). Patients with ER+/HER2+ BC with a limited response to systemic therapies are at an increased risk of relapse, thus understanding the mechanisms of resistance is crucial. This study investigates the changes in gene signature expression (ΔGSE) within ER+/HER2+ tumours and their intrinsic subtype (IS) in response to peri-operative aromatase inhibitors (POAI).

Metastatic castration-resistant prostate cancer remains incurable and is particularly aggressive in patients with alterations in DNA damage repair genes involved directly or indirectly in homologous recombination repair (HRR). In the primary analysis of TALAPRO-2, talazoparib plus enzalutamide significantly improved radiographic progression-free survival (rPFS) versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer harbouring HRR gene alterations. At primary analysis, overall survival was immature. Here we report final prespecified overall survival analysis, updated rPFS, safety, and patient-reported outcomes in the HRR-deficient cohort of TALAPRO-2.

NRG/RTOG 0521 randomized men with high-risk localized prostate cancer (PC) to androgen suppression (AS) and definitive radiotherapy (RT) ± docetaxel-based chemotherapy (CT). The overall survival (OS) benefit with CT initially reported was lost on longer follow-up. The Decipher genomic classifier (GC) measures multiple transcripts relevant to docetaxel action. Basal/luminal differentiation portends differential response to AS and CT for high-risk localized and metastatic hormone-sensitive PC. We validated the Decipher GC in pretreatment biopsy samples for risk stratification and examined basal-luminal subtyping to predict docetaxel response.

Ibrutinib (I) and ibrutinib plus rituximab (I+R) are highly efficacious in treating Waldenström macroglobulinemia (WM). However, the benefit of adding rituximab remains unclear, and a prospective trial to compare these two regimens has not been undertaken. Therefore, we performed a pooled analysis of prospective studies to compare their effectiveness. Patient-level demographic, response, and survival data were pooled from three prospective studies (ClinicalTrials.gov identifiers: NCT01614821, NCT02604511, NCT02165397). We included patients treated with I+R or I, excluding those without MYD88 mutations. Among 174 patients (58 I+R, 116 I), very good partial response (VGPR) rates were comparable across treatment groups (38% I+R vs 28% I; P = .21). The 48-month progression-free survival (PFS) rate was 74% with I+R vs 61% with I (P = .22). The 48-month overall survival rate was 94% vs 89% (P = .45). In patients with CXCR4 mutations, I+R trended toward higher VGPR (27% vs 11%; P = .10), and had a superior 48-month PFS rate (72% vs 43%; P = .03). CXCR4 mutations were associated with inferior VGPR (42% vs 17%; P = .001) and 48-month PFS in the I arm (43% vs 72%; P = .002). In the I+R arm, CXCR4 mutations were associated with numerically inferior VGPR (47% vs 27%; P = .12), but the 48-month PFS rate was not impacted (74% vs 72%; P = .96). I+R significantly improved PFS over I in patients with CXCR4-mutated WM, along with a nonsignificant increase in VGPR in this subgroup. These results support routine CXCR4 testing in patients with WM, and clinical trials of rituximab with covalent or noncovalent Bruton tyrosine kinase inhibitors.

On August 11, 2023, the FDA approved the fixed-dose combination of niraparib and abiraterone acetate (AA), with prednisone (AAP), for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer, as determined by an FDA-approved test. Substantial evidence of effectiveness was demonstrated by cohort 1 of MAGNITUDE (NCT03748641), a multi-cohort study. Cohort 1 was a double-blind trial that randomly assigned 423 patients with metastatic castration-resistant prostate cancer and homologous recombination repair mutations to receive niraparib 200 mg daily plus AA 1,000 mg daily and prednisone versus placebo plus AAP. The presence of BRCAm was a stratification factor. There was a statistically significant improvement in the primary endpoint of radiographic progression-free survival (rPFS) by blinded independent central review in the BRCAm subpopulation: the median rPFS was 16.6 months [95% confidence interval (CI), 13.9-not estimable] in the niraparib + AAP arm and 10.9 months (95% CI, 8.3-13.8) in the placebo + AAP arm (HR, 0.53; 95% CI, 0.36-0.79; P = 0.0014). There was also a statistically significant improvement in rPFS in the all-homologous recombination repair mutation population (intention-to-treat population); however, exploratory analyses conducted by the FDA indicated that this improvement was primarily attributed to the subgroup of patients with BRCAm, which supported limiting the indication to that population. Adding niraparib to AAP resulted in increased toxicity, including anemia requiring transfusion in 27% of patients. This article summarizes the data and the FDA's thought process supporting the traditional approval of niraparib plus AA fixed-dose combination.

CheckMate 915 (NCT03068455) compared adjuvant nivolumab monotherapy versus combination nivolumab+ipilimumab in patients with resected stage III/IV melanoma. This exploratory analysis was performed to identify biomarkers that correlate with benefit from adjuvant immunotherapy.

This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase [MEK] clamp) alone or in combination with defactinib (focal adhesion kinase inhibitor) in patients with recurrent low-grade serous ovarian cancer (LGSOC).

Osimertinib, a third-generation, central nervous system-active epidermal growth factor receptor-tyrosine kinase inhibitor, potently and selectively inhibits epidermal growth factor receptor-tyrosine kinase inhibitor sensitizing and T790M resistance mutations, with efficacy in epidermal growth factor receptor-mutated non-small cell lung cancer. In FLAURA2 (NCT04035486), first-line osimertinib plus platinum-pemetrexed chemotherapy showed significant improvement in progression-free survival over osimertinib monotherapy in patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer. A population pharmacokinetics analysis using cumulative pharmacokinetics data from 2,196 patients across six studies (AURA, AURA2, AURA3, ADAURA, FLAURA, and FLAURA2) assessed pharmacokinetics and its variability due to intrinsic and extrinsic factors. Upon a formal covariate search, none of the covariates retained in the final model had a clinically meaningful impact on the pharmacokinetics of osimertinib and its active metabolite, AZ5104. The osimertinib exposure derived from the population pharmacokinetics model was used to evaluate the relationship between osimertinib exposure and progression-free survival, as the efficacy primary end point, in the FLAURA2 combination arm. A Cox proportional hazard analysis indicated no exposure-progression-free survival relationship for osimertinib and its metabolite; the number of pemetrexed cycles was likely to be associated with progression-free survival. No exposure-safety relationship was observed between osimertinib exposure and the occurrence of adverse events, including those leading to osimertinib dose interruption/reduction/discontinuation, and other pre-determined adverse events. These results further reinforce the benefits of the FLAURA2 clinical data that establish osimertinib 80 mg once daily plus chemotherapy as a first-line treatment for patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer.

In 2023, the College of American Pathologists (CAP) supported histotype-specific scoring for HER2 testing in endometrial serous carcinoma based on enrollment criteria for trastuzumab eligibility in the NCT01367002 clinical trial. However, in 2024, the DESTINY-PanTumor02 trial showed the benefit of trastuzumab-deruxtecan in patients with HER2-IHC 2+ and 3+ tumors using CAP gastric scoring, resulting in confusion about how these criteria relate. We compare the results of these scoring schemes by interobserver agreement and correlation with HER2/Chromosome 17 dual in situ hybridization (DISH). Six observers scored 44 HER2-IHC stained p53-abnormal endometrial carcinoma specimens in tissue microarray (TMA) format by endometrial serous (NCT01367002) and gastric systems. Interobserver agreement for HER2 scores (0, 1+, 2+, and 3+) was 81.5% (kappa=0.75) for endometrial serous and 84.6% (kappa=0.79) for gastric scoring. Eight specimens showed discordant HER2 endometrial serous and gastric scores: 4 endometrial serous 1+/gastric 0 and 4 endometrial serous 2+/gastric 3+. HER2-IHC-DISH discordance occurred in 4 specimens by gastric criteria (IHC 3+/DISH negative) and 1 specimen by endometrial serous criteria (IHC 3+/DISH negative). Endometrial serous and gastric HER2-IHC scoring schemes show similar interobserver agreement. In instances of minimal, faint HER2 staining, the endometrial serous score may be 1+ when the gastric score is 0. In instances of limited, strong HER2 staining, the endometrial serous score may be 2+ when the gastric score is 3+. The endometrial serous scheme appears more concordant with DISH results than the gastric scheme, which shows non-infrequent IHC 3+ cases without HER2-DISH amplification. We emphasize recognition of HER2-IHC therapy-specific scoring in endometrial carcinomas, as these scoring systems are similar but not identical.

Few studies have compared the performance of gene-expression profiling tests (e.g. Oncotype-Dx) to clinico-pathologic risk calculators (e.g. PREDICT 2.1, INFLUENCE 2.0, and CTS5) or tools that combine both (e.g. RSClin) in patients with early breast cancer (EBC). A large trial dataset was used to evaluate the prognostic performance of different tests based on patient outcomes.

For hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC), first-line cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) is the standard of care. They are also used after progression on first-line aromatase inhibitors (AIs), but some patients may respond better to chemotherapy-based options. We examined tumor features associated with survival from GEICAM/2013-02 PEARL, a phase III trial of palbociclib + ET versus capecitabine in AI-resistant HR+/HER2- MBC.

Lazertinib is a central nervous system-penetrant, third-generation EGFR tyrosine kinase inhibitor (TKI) that was selected for combination with amivantamab due to its relatively low rates of wild-type EGFR toxicities. In the phase 3 MARIPOSA study, amivantamab plus lazertinib (amivantamab-lazertinib) significantly improved progression-free survival (PFS; p < 0.001) versus osimertinib in participants with treatment-naive EGFR-mutant advanced NSCLC. A lazertinib monotherapy arm was included to assess the contribution of components in the combination. This is the first randomized, double-blind comparison of two third-generation EGFR TKIs, lazertinib and osimertinib.

The ability of the Geneva homologous recombination deficiency (HRD) test to predict progression-free survival (PFS) in patients with high-grade ovarian cancer treated with poly (ADP-ribose) polymerase inhibitors has been demonstrated. Its performance with respect to overall survival (OS) has not been assessed yet.

Antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) are widely used for HER2-positive metastatic breast cancer, but their efficacy in the neoadjuvant setting remains under investigation. The MUKDEN 06 trial (NCT05426486), a multicentre, randomised, phase 2b study, compared ARX788 (anti-HER2 ADC) plus pyrotinib (TKI) with the standard neoadjuvant regimen of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCbHP) in female patients with early or locally advanced HER2-positive breast cancer. The primary endpoint was the pathological complete response (pCR, ypT0/is, ypN0) rate, analyzed in the intention-to-treat population. pCR was achieved in 70.6% (48/68) of patients receiving ARX788 plus pyrotinib, compared to 51.5% (35/68) in the TCbHP group, with a significant absolute difference of 19.1% (95% CI, 2.7-34.6; p = 0.023). No treatment-related deaths occurred. The most common grade 3-4 adverse events were diarrhea and hepatic dysfunction in the ARX788 plus pyrotinib group, and fatigue, nausea and anorexia in the TCbHP group. Interstitial lung disease (ILD)/pneumonitis and ocular events were observed with ARX788 plus pyrotinib, indicating a distinct safety profile. These findings offer clinical insights into the potential of dual HER2-targeted blockade with an ADC and TKI as an optional neoadjuvant strategy for patients with early or locally advanced HER2-positive breast cancer.