Caroline Seymour

Akeega delayed progression and symptoms in patients with HRR-positive castration-sensitive prostate cancer.

A 37% reduction in the risk of radiographic progression or death was observed with Akeega (niraparib plus abiraterone acetate [Zytiga]) plus prednisone compared with Zytiga, prednisone, and placebo (AAP), in patients with metastatic castration-sensitive prostate cancer (mCSPC) who had homologous recombination repair (HRR) gene alterations and had previously received androgen deprivation therapy (ADT), according to results from the phase 3 AMPLITUDE trial presented at the 

After a median follow-up of 30.8 months, the median radiographic progression-free survival (rPFS) was not estimable in the Akeega group compared with 29.5 months in the placebo arm. Furthermore, Akeega significantly reduced the risk symptomatic progression by 50% compared with AAP and placebo. Overall survival (OS) was not statically significant at the analysis, with trends beginning to emerge showing improvement with Akeega.

“Improvements in rPFS are supported by a statistically significant benefit in time to symptomatic progression and a trend toward improved OS,” lead investigator Dr. Gerhardt Attard, Cancer Institute, University College London, said during a presentation of the findings. “In my opinion, AMPLITUDE supports [Akeega] as a treatment option for patients in this poor prognostic disease group.”

HRR gene alterations: changes in genes like BRCA1 or BRCA2 that affect the cell’s ability to repair DNA damage.

Radiographic progression-free survival (rPFS): time during and after treatment that a patient lives without cancer getting worse on scans.

Overall survival (OS): time from start of treatment until death from any cause.

PARP inhibitor: a type of drug that blocks a protein cancer cells use to repair DNA damage, making them more likely to die.

Androgen deprivation therapy (ADT): treatment that lowers testosterone to slow prostate cancer growth.

De novo M1: metastatic cancer present when the disease is first diagnosed.

High-volume metastatic disease: cancer that has spread widely, often to multiple bones or organs.

Patient Demographics and Additional Findings From AMPLITUDE

In the study, 696 patients were evenly randomized to receive Akeega (348 patients) or placebo plus AAP (348 patients). The median age of enrolled patients was 68 years. Overall, 78% of patients had high-volume metastatic disease (M1), of which 87% were de novo M1. All patients had received ADT for six months or less and 16% of patients had received prior docetaxel. All patients in the study had an alteration in genes associated with HRR, which included BRCA1/2 alterations for 55.6% of patients. Remaining alterations could have been in BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B or RAD54L.

For patients specifically with BRCA mutations, the improvements in rPFS were more pronounced. In this group, there was a 48% reduction in the risk of radiographic progression or death with the addition of the PARP inhibitor. The median for the Akeega arm was not estimable compared with 26 months with AAP.

“This was a really exciting result,” said Attard. “This is the first study to show efficacy for PARP inhibition and androgen receptor inhibition in CSPC, the benefit [of which] might be greatest in patients with BRCA mutations.”

Those with BRCA1/2 mutations also had a significant reduction in the risk of symptomatic progression. In this subgroup, there was a 56% reduction in the risk of symptom progression with the PARP inhibitor compared with the androgen synthesis inhibitor and placebo.

“This is a patient-centric end point, measuring the time to worsening of symptoms, which includes needing radiation or a procedure or intervention or further cancer treatment,” said Attard. “Very convincingly we show a clear benefit with [Akeega].”

OS was still immature across the study. At the analysis, the BRCA1/2 subgroup showed similar trends as in the full population of those with HRR gene alterations. In this group, there was an early 25% reduction in the risk of death observed with Akeega.

“Half the number of patients have died from the target number we would require for the final analysis, but in my view, there’s a clear trend for favoring survival in the patients randomized to [Akeega],” said Attard.

Diving Into the Safety and Possible Implications

Grade 3 (severe) or 4 (life-threatening) adverse effects (AEs; side effects) were observed in 75.2% of those receiving Akeega compared with 58.9% of those in the control arm. The most common AEs were anemia (29.1% with Akeega versus 4.6% with placebo) and hypertension (26.5% versus 18.4%). Of those with anemia, the majority required a transfusion.

Dose interruptions were required for 66.9% of patients in the Akeega arm compared with 42.4% for the control arm. Dose reductions were needed to address AEs for 21.9% of those in the Akeega arm compared with 6.9% of those in the placebo group. Treatment was discontinued for 14.7% of those in the Akeega arm compared with 10.3% of those in the placebo group. Treatment-emergent AEs led to death for 14 patients in the investigational arm compared with seven in the control group.

“We’re used to the side effect profile with these drugs, and we aren’t seeing any new side effects but clearly those randomized to [Akeega] have more AEs than those randomized to placebo,” said Attard. “But critically, I think, the proportion of patients who [were] required to discontinue treatment was fewer than 5% for those on [Akeega] versus placebo.”

In 2023, Akeega was approved by the FDA in combination with AAP for patients with deleterious or suspected deleterious BRCA-mutated castration-resistant prostate cancer, based on findings from the phase 3 MAGNITUDE study. Results from the AMPLITUDE study could expand this approval to those with castration-sensitive disease.

“This is really exciting news for our patients,” ASCO expert commentator Dr. Bradley McGregor, from Dana-Farber Cancer Institute, said of the results. “PARP inhibitors have been a mainstay in the treatment of metastatic castrate-resistant prostate cancer for those patients with HRR alterations, and this is the first time we’ve seen data for these in the hormone-sensitive setting. As you heard this is a very poor prognostic group, so I think this is incredibly exciting.”

“Phase 3 AMPLITUDE trial: Akeega for metastatic castration-sensitive prostate cancer with homologous recombination repair gene alterations” by Dr. Gerhardt Attard, et al., 

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Articles

The addition of the PARP inhibitor Zejula to Zytiga and prednisone significantly reduced the risk of radiographic progression or death by 37% in patients with metastatic castration-sensitive prostate cancer (mCSPC) with HRR gene alterations, as shown in the phase 3 AMPLITUDE trial. The trial demonstrated a 50% reduction in symptomatic progression risk and a trend towards improved overall survival. However, Zejula was associated with higher rates of severe adverse effects, including anemia and hypertension, necessitating dose adjustments and treatment discontinuations in some cases.

Akeega delayed cancer growth and symptoms in patients with castration-sensitive prostate cancer and HRR gene mutations.

Akeega Combo Delays Progression in HRR+ Castration-Sensitive Prostate Cancer

Camizestrant and continued therapy with CDK4/6 inhibition benefits patients who present with ESR1-mutated, ER+, HER2– advanced breast cancer: © stock.adobe.com.

Among patients with patients with ESR1-mutated, estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, camizestrant plus continued therapy with CDK4/6 inhibition significantly improved progression-free survival outcomes compared with continued therapy with an aromatase inhibitor (AI) and CDK4/6 inhibitor when given prior to disease progression on frontline therapy.

These findings were derived from the phase 3 SERENA-6 trial, data from which was shared in a press briefing at the 

The median investigator-assessed progression-free survival was 16.0 months with camizestrant plus CDK4/6 inhibition (157 patients treated) versus 9.2 months with continued AI/CDK4/6 inhibition (158 patients treated). The 12- and 24-month progression-free survival rates in the camizestrant arm were 60.7% and 29.7%, respectively, versus 33.4% and 5.4% in the continued AI/CDK4/6 inhibition arm.

“SERENA-6 is the first global registrational phase 3 study to demonstrate the clinical utility of circulating tumor DNA [ctDNA] monitoring to detect and treat emerging resistance ahead of disease progression,” Dr. Nicholas C. Turner, lead study author and director of The Royal Marsden and Institute of Cancer and National Institute for Health and Care Research Biomedical Research Centre in London, United Kingdom, said in the press briefing.

Echoing the significance of these findings, Dr. Eleonora Teplinsky,, stated, “When patients progress on scans, we’re already behind. We’re switching therapy, and we’ve already lost control [of the disease]. What this study does is [adopt] an early switch approach before we see disease progression on imaging, allowing us to stay ahead of the curve.” Teplinsky is head of Breast and Gynecologic Medical Oncology at Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, and a clinical assistant professor of medicine at The Icahn School of Medicine at Mount Sinai in New York, New York.

Turner started the presentation by acknowledging the present unmet need for patients with ESR1-mutant, advanced hormone receptor–positive breast cancer. Although rare at diagnosis, comprising less than 5% of advanced cases, ESR1 mutations will develop in approximately 40% of cases, resulting in disease progression on frontline therapy with an AI and CDK4/6 inhibitor.

However, ESR1 mutations can be isolated in ctDNA approximately 6 months before progression. 

Camizestrant is a next-generation oral selective ER degrader and complete ER antagonist that’s designed to inhibit and degrade the mutant and wild-type forms of the ER. Previously, the FDA granted fast track designation to the agent for the population enrolled in SERENA-6. By coupling the use of ctDNA with early integration of camizestrant ahead of disease progression, investigators theorized they could prolong the clinical benefit of frontline treatment.

The randomized, double-blind, placebo-controlled SERENA-6 trial enrolled female and male patients with ER-positive, HER2-negative advanced breast cancer who had received at least 6 months of an AI in combination with a CDK4/6 inhibitor as initial endocrine-based therapy for advanced disease. Patients also needed to have a detectable ESR1 mutation in their ctDNA without evidence of disease progression. 

A total of 3,325 patients who were receiving frontline therapy with an AI and CDK4/6 inhibitor for at least 6 months were screened. ESR1 mutation testing (3,256 patients total) was evaluated in ctDNA with the Guardant360 CDx assay every 2 to 3 months at the time of routine staging scans. A total of 548 patients had detectable ESR1 mutations, 51% of whom were positive on the first test, 38% of whom were positive after two to five tests, and 11% of whom were positive after the fifth test. A total of 233 patients discontinued the study due to screening failure (200 patients) or consent withdrawal, lost follow-up, or other reasons (33 patients).

A total of 315 patients were randomly assigned to 75 milligrams (mg) of camizestrant daily plus continued CDK4/6 inhibition and placebo for the AI or continued AI with anastrozole or letrozole plus CDK4/6 inhibition and placebo for camizestrant. Treatment was continued until disease progression, unacceptable toxicity, and patient withdrawal or death.

The primary end point was investigator-assessed progression-free survival by RECIST 1.1 criteria. Secondary end points included time to second disease progression or death, overall survival, safety, and patient-reported outcomes.

Patients were stratified by visceral disease (yes versus no), detection of ESR1 mutation (mutation detected at first test versus a subsequent test), time from initiation of CDK4/6 inhibition plus an AI to randomization (< 18 months versus ≥ 18 months), and choice of CDK4/6 inhibitor (Ibrance [Palbociclib] versus Kisqali [ribociclib] versus Verzenio [abemaciclib]).

Secondary End Points and Trial Significance

Time to deterioration in global health status/quality of life was also presented. The median time to deterioration according to the European Organization for Research and Treatment of Cancer 30-item quality of life questionnaire was 23.0 months with camizestrant (107 patients) versus 6.4 months with continued AI/CDK4/6 inhibition (95 patients).

Turner noted that the camizestrant regimen also had a low rate of treatment discontinuations resulting from side effects.

“[These data highlight the] potential for a new treatment strategy in oncology to treat developing resistance before it causes progression,” Turner said in conclusion.

Elaborating on the novelty of the study design, Teplinsky explained, “Allowing patients to remain on first-line endocrine therapy for hormone receptor–positive, HER2-negative advanced breast cancer is critical, because we know that outcomes worsen with subsequent lines of therapy. Allowing that longer time on first-line endocrine therapy is significant, and it also improves quality of life, as we’ve seen, and that’s a huge part of living with metastatic breast cancer. [The study] uses a technology, [which] is a liquid biopsy, that doesn’t pose risks of surgical biopsies, and it’s something that can be done and is available in our clinic now. Although camizestrant is not yet FDA approved, this likely will pave the way for a new treatment strategy in first-line hormone receptor–positive, HER2-negative metastatic breast cancer in patients with ESR1 mutations.”

Dr. Julie Gralow, chief medical officer and executive vice president at ASCO, added, “We are using these liquid biopsies [to detect] ctDNA. We have whole sessions at this meeting, looking at using them in colon cancer, but using them to detect emerging resistance before we see evidence of tumor progression on scans is what’s novel about this study.”

Turner N, Mayer E, Park YH, et al. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. 

. 2025;43(suppl 17):LBA4. doi:10.1200/JCO.2025.43.17_suppl.LBA4

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The SERENA-6 trial demonstrated that camizestrant combined with CDK4/6 inhibitors significantly improved progression-free survival in patients with ESR1-mutated, ER-positive, HER2-negative advanced breast cancer compared to continued AI and CDK4/6 inhibitor therapy. This study utilized ctDNA monitoring to detect resistance before disease progression, allowing for an early switch in therapy. The trial highlighted the potential of camizestrant as a new treatment strategy, emphasizing the importance of maintaining patients on first-line endocrine therapy to improve outcomes and quality of life.

Camizestrant and continued therapy with CDK4/6 inhibition benefits patients who present with ESR1-mutated, ER+, HER2– advanced breast cancer. 

Camizestrant and CDK4/6 Inhibition Benefits Outcomes in Breast Cancer Subgroups 

In ESR1-mutant, ER+, HER2– advanced breast cancer, vepdegestrant improved PFS versus Faslodex: © stock.adobe.com.

When compared with versus fulvestrant (Faslodex), vepdegestrant (ARV-471) treatment elicited a statistically significant and clinically meaningful improvement in survival without progression by blinded independent central review (BICR) in pretreated patients with ESR1-mutant estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer.

These findings were garnered from the phase 3 VERITAC-2 trial, data from which were shared at the 

Of the 136 patients in the vepdegestrant arm, and the 134 patients in the Faslodex arm, at a median follow-up of 7.4 months and 6.0 months, respectively, the median progression-free survival was 5.0 months and 2.1 months. At the time of the analysis, 58% of progression-free survival events had occurred in the vepdegestrant arm versus 71% in the Faslodex arm; treatment was ongoing in 33% and 12% of patients, respectively. The 6-month progression-free survival rates with vepdegestrant and Faslodex were 45.2% and 22.7%, respectively.

BICR-assessed progression-free survival did not show a substantial improvement with vepdegestrant versus Faslodex in the all-comer population.

“Vepdegestrant is the first PROTAC [proteolysis targeting chimera] to be evaluated in a phase 3 study,” lead study author Dr. Erika Hamilton, said in a press briefing ahead of the meeting. “These results support vepdegestrant as a potential treatment option for previously treated [patients with] ESR1-mutant ER-positive, HER2-negative advanced breast cancer.”

There is no agreed-upon standard of care for patients with ER-positive, HER2-negative advanced breast cancer following progression on frontline endocrine therapy. Faslodex is a selective estrogen receptor degrader, also known as SERDs, that is typically given in the second line even though it is associated with modest progression-free survival benefit following progression on CDK4/6 inhibition and endocrine therapy.

Since January 2023, Orserdu (elacestrant) has become an option for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. However, median progression-free survival remains limited.

Vepdegestrant is a selective, oral PROTAC ER degrader that targets the mutant and wild-type ER. In the first-in-human phase 1/2 trial, vepdegestrant was well tolerated and active, with a clinical benefit rate of 51.2% in heavily pretreated patients with ESR1-mutant ER-positive, HER2-negative advanced breast cancer who had received a median of 3 (range, 0-7) prior lines of therapy in the metastatic setting.

Overall survival (OS): the length of time from either the date of diagnosis or the start of treatment for a disease that patients diagnosed are alive.

Progression-free survival (PFS): the length of time during and after the treatment that a patient lives with the disease but it does not get worse.

Overall response rate (ORR): the proportion of patients who have a partial or complete response to therapy.

FDA granted fast track designation to vepdegestrant

 for the treatment of patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.

Seeking confirmation of benefit in the VERITAC-2 trial, investigators enrolled patients at least 18 years of age with ER-positive, HER2-negative advanced or metastatic breast cancer that developed radiological progression during or after the last line of therapy. Prior therapy consisted of 1 line of endocrine therapy and a CDK4/6 inhibitor, and no more than 1 additional line of endocrine therapy. Patients must have been exposed to the most recent line of endocrine therapy for at least 6 months, and prior chemotherapy for advanced or metastatic disease or a selective estrogen receptor degrader like Faslodex or Orserdu was not allowed.

In total, 313 eligible patients were randomly assigned to receive 200 miligrams (mg) of oral vepdegestrant once daily or 500 mg of intramuscular Faslodex on days one and 15 of cycle one, and day one of subsequent cycles. Treatment cycles were 28 days. Patients were stratified by ESR1 status (mutated versus not) and visceral disease (yes versus no).

The primary end point was BICR-assessed progression-free survival in the ESR1-mutant and all-comer populations. Secondary end points were overall survival, clinical benefit rate and objective response rate by BICR, and side effects.

Hamilton noted that approximately 80% of patients had received 1 prior line of therapy and around 20% had received 2 prior lines of therapy in the advanced or metastatic setting.

Vepdegestrant Sails Through Secondary End Point Verification of Benefit

With respect to the secondary end points of the trial, vepdegestrant (121 patients) more than doubled the clinical benefit rate compared with Faslodex (119 patients) in the ESR1-mutant population, at 42.1% versus 20.2%, respectively. The overall response rate was 18.6% with vepdegestrant (97 patients) versus 4.0% with Faslodex. The median duration of response was not reached.

Safety was evaluated in all-treated patients who received vepdegestrant (312 patients) and Faslodex (307 patients) and was generally well tolerated.

“Vepdegestrant demonstrated a favorable safety profile, evidenced by few side effects [< 5%] leading to dose reduction or discontinuation,” Hamilton said.

Any-grade treatment-emergent side effects occurred in 87% of patients on vepdegestrant (grade 3 or higher, 23%) versus 81% of those on Faslodex (grade 3 or higher, 18%). Serious side effects occurred in 10% and 9% of patients on vepdegestrant and Faslodex, respectively. Treatment-emergent side effects leading to discontinuation and dose reduction occurred in 3% and 2% of cases, respectively, in the vepdegestrant arm. Only 1% of patients in the Faslodex arm required treatment discontinuation because of a treatment-emergent side effect. Treatment-related side effects also occurred in the vepdegestrant (any grade, 57%; grade 3 or higher, 8%) and Faslodex (any grade, 40%; grade 3 or higher, 3%) arms.

Any-grade treatment-emergent side effects that occurred in at least 10% of patients in the vepdegestrant and Faslodex arms, respectively, were fatigue (27%; 16%), alanine aminotransferase increase (14%; 10%), aspartate aminotransferase increase (14%; 10%), nausea (13%; 9%), anemia (12%; 8%), neutropenia (12%; 5%), back pain (11%; 7%), arthralgia (11%; 11%) and decreased appetite (11%; 5%).

“Overall survival analyses remain immature, and follow-up is ongoing,” Hamilton concluded.

“This is a very exciting study,” Dr. Jane L. Meisel, professor in the Departments of Hematology and Medical Oncology and Gynecology & Obstetrics, and codirector of Breast Medical Oncology at Emory University School of Medicine in Georgia, said. “This drug is something that we think is going to be a very exciting option potentially for patients with previously treated, ESR1-mutant ER-positive, HER2-negative advanced breast cancer. There are a lot of exciting things happening in this space, so seeing what the overall survival analyses show will be interesting and how this compares with some of the other things that we [have]. We all look forward to that. This is a very exciting option, and the first of its kind in terms of being a PROTAC as opposed to other mechanisms of action, so [there’s] a lot to think about, and exciting data to see.”

Hamilton E, De Laurentiis M, Jhaveri K, et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: results of the global, randomized, phase 3 VERITAC-2 study. 

. 2025;43(suppl 17):LBA1000. doi:10.1200/JCO.2025.43.17_suppl.LBA1000

Schott AF, Hurvitz S, Ma C, et al. GS3-03 ARV-471, a PROTAC estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study. 

. 2023;83(suppl 5):GS3-03. doi:10.1158/1538-7445.SABCS22-GS3-03

Vepdegestrant (ARV-471) demonstrated a significant improvement in progression-free survival compared to fulvestrant (Faslodex) in patients with ESR1-mutant ER-positive, HER2-negative advanced breast cancer, as shown in the phase 3 VERITAC-2 trial. The trial revealed a median progression-free survival of 5.0 months for vepdegestrant versus 2.1 months for Faslodex. Vepdegestrant, a PROTAC ER degrader, showed a favorable safety profile and doubled the clinical benefit rate in the ESR1-mutant population. Ongoing studies aim to further evaluate overall survival and long-term benefits.

Among patients with ESR1-mutant, ER+, HER2– advanced breast cancer, vepdegestrant improved survival without progression when compared with Faslodex.

Vepdegestrant Boosts Outcomes in ESR1-Mutant ER+/HER2– Advanced Breast Cancer

Braftovi and Erbitux plus chemo improved survival without progression over standard therapy in BRAF V600E-mutant mCRC in the first-line setting: © stock.adobe.com.

Updated data from the phase 3 BREAKWATER trial showed that combining Braftovi (encorafenib) and Erbitux (cetuximab) with mFOLFOX6 chemotherapy (modified fluorouracil, leucovorin and oxaliplatin) elicited a statistically significant and clinically meaningful improvement in progression-free survival versus standard-of-care therapy in the first-line treatment for patients with metastatic colorectal cancer (mCRC) harboring BRAF V600E mutations.

Findings were presented in a press briefing ahead of the 

. Of the 236 patients treated with Braftovi plus Erbitux and mFOLFOX6, the median PFS was 12.8 at a median follow-up of 16.8 months. This number was 7.1 months at a median follow-up of 9.8 months among the 243 patients given standard-of-care treatment.

Additionally, Braftovi plus Erbitux and mFOLFOX6 generated a median overall survival of 30.3 months versus 15.1 months with standard-of-care. The estimated 12- and 24-month overall survival rates in the experimental arm were 80.1% and 52.0%, respectively. These respective rates were 66.0% and 29.0% in the standard-of-care treatment arm.

“Braftovi [in combination with] Erbitux and mFOLFOX6 — the BREAKWATER regimen — is a practice-changing, new standard-of-care for [patients] with mCRC with a 

 V600E mutation,” lead study author Elena Elez, MD, PhD, said during the press briefing.

Elez is an attending physician in the Gastrointestinal Tumors Service of the Medical Oncology Service at Vall d’Hebron University Hospital and principal investigator of the Gastrointestinal Tumor Group and Endocrine of Vall d'Hebron Instituto de Oncología in Barcelona, Spain.

the FDA granted accelerated approval to Braftovi in combination with Erbitux and mFOLFOX6

 for patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test. The regulatory decision was based on previously reported data from BREAKWATER, which showed that among the first 110 patients treated in each arm, the overall response rate was 61% for the combination versus 40% for standard-of-care. The median duration of response was 13.9 months and 11.1 months, respectively.

The open-label, multicenter study enrolled patients at least 16 years of age (or at least 18 years of age, based on the country), with mCRC who had measurable disease per RECIST 1.1 criteria and had not received prior systemic therapy in the metastatic setting. The presence of a BRAF V600E mutation was required, per local or central testing. Patients also needed to have an ECOG performance status of 0 or 1, along with adequate bone marrow, hepatic and renal function.

Combining Braftovi and Erbitux with mFOLFOX6 elicited a statistically significant and clinically meaningful improvement in progression-free survival versus standard-of-care therapy in the first-line treatment for patients with  mCRC harboring BRAF V600E mutations.

Key exclusion criteria comprised prior exposure to BRAF or EGFR inhibitors; symptomatic brain metastases; microsatellite instability-high/mismatch repair-deficient tumors, unless patients were ineligible for immune checkpoint inhibitors; and RAS-mutated disease.

Investigators randomly assigned 637 patients fashion to receive Braftovi plus Erbitux alone (158 patients); Braftovi in combination with Erbitux and chemo (236 patients); or standard-of-care (243 patients). Enrollment to the Braftovi/Erbitux alone cohort was stopped following a protocol amendment and subsequently enrolled patients were randomly assigned between the other two arms.

Treatment in the standard-of-care arm included mFOLFOX6, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin and irinotecan), or CAPOX (capecitabine and oxaliplatin) with or without Avastin (bevacizumab).

Stratification factors included region (United States/Canada versus Europe versus rest of world) and ECOG performance status (0 versus 1).

Overall response rate and progression-free survival per blinded independent central review served as the trial’s dual primary end points. Overall survival was a key secondary end point.

Data from the cohort of patients who received Braftovi plus Erbitux without chemo showed that the median progression-free survival was 6.8 months and the median overall survival was 19.5 months.

Updated response data demonstrated that the overall response rate for Braftovi plus Erbitux and chemo was 65.7%; the rates of complete response, partial response, stable disease  and progressive disease in this arm were 4.7%, 61.0%, 21.2% and 3.4%, respectively. In the standard-of-care arm, the overall response rate was 37.4% (95% CI, 31.6%-43.7%) with a complete response rate of 3.3%, a partial response rate of 34.2%, a stable disease rate of 35.0% and a progressive disease rate of 8.6%. In the Braftovi/Erbitux alone arm, the ORR was 45.6% with complete, partial response, stable disease and progressive rates of 1.9%, 43.7%, 36.1% and 7.6%, respectively.

The median time to response was 7.0 weeks (range, 5.1-103.6) for Braftovi/Erbitux/mFOLFOX6, 7.3 weeks (range, 5.4-48.0) for standard-of-care and 6.6 weeks (range, 4.3-86.4) for Braftovi/Erbitux. The median duration of response was 13.9 months, 10.8 months and 7.0 months, respectively.

In the Braftovi/Erbitux/chemo arm, the 6- and 12-month duration of response rates were 71.0% and 34.8%, respectively. These respective rates were 41.8% and 17.6% in the standard-of-care arm; they were 40.3% and 20.8%, respectively, for Braftovi/Erbitux alone.

At data cutoff, 28.4% of patients in the Braftovi/Erbitux/chemo arm remained on treatment compared with 6.6% in the standard-of-care arm and 7.6% of patients in the Braftovi/Erbitux arm. Subsequent therapy was administered to 63.9% of patients in the Braftovi/Erbitux/chemo group versus 61.2% in the standard-of-care group and 73.3% in the Braftovi/Erbitux group. A BRAF inhibitor–based regimen was given as subsequent therapy to 71.9% of the 139 patients in the standard-of-care arm who received additional treatment.

The median time to second disease progression or death was 20.7 months in the Braftovi/Erbitux/chemo arm, 12.7 months in the standard-of-care arm and 14.3 months in the Braftovi/Erbitux arm.

Regarding safety, the Braftovi plus Erbitux and chemo regimen was generally tolerable with a consistent safety profile. No substantial increases in chemotherapy dose reductions or discontinuation were observed compared with the standard-of-care arm.

Any-grade side effects were reported in all patients in the Braftovi/Erbitux/chemo arm, 99.1% of patients in the standard-of-care arm and 97.4% of patients in the Braftovi/Erbitux arm. The rates of grade 3 (severe) or grade 4 (life-threatening) side effects were 81.5%, 66.8% and 42.5%, respectively. The respective rates of grade 5 (death) events were 4.3%, 4.4% and 2.6%. One grade 5 side effect in the standard-of-care arm was deemed treatment related.

The most common grade 1/2 side effects included nausea (combination, 51%; standard-of-care, 46%), anemia (31%; 21%), diarrhea (41%; 46%), decreased appetite (35%; 26%), vomiting (32%; 20%), decreased neutrophil count (15%; 12%), arthralgia (29%; 5%), rash (29%; 4%), asthenia (24%; 14%), pyrexia (27%; 15%), peripheral neuropathy (20%; 20%), constipation (27%; 22%), peripheral sensory neuropathy (20%; 20%) and fatigue (24%; 24%).

The most frequently reported grade 3/4 side effects included nausea (combination, 3%; standard-of-care, 4%), anemia (15%; 4%), diarrhea (1%; 5%), decreased appetite (2%; 1%), vomiting (4%; 2%), decreased neutrophil count (19%; 17%), arthralgia (3%; <1%), rash (1%; 0%), asthenia (5%; 1%), pyrexia (2%; <1%), peripheral neuropathy (8%; 4%), constipation (<1%; <1%), peripheral sensory neuropathy (7%; 4%) and fatigue (3%; 4%).

Side effects led to permanent discontinuation of any study treatment in 26.7% of patients in the Braftovi/Erbitux/chemo arm, 17.5% of patients in the standard-of-care arm and 13.1% of patients in the Braftovi/Erbitux arm. Side effects led to dose reductions of any treatment in 65.5%, 54.1% and 10.5% of patients, respectively. The rates of side effects leading to dose reductions were 59.9% in the Braftovi/Erbitux/chemo arm and 54.1% in the standard-of-care arm. Side effects led to the discontinuation of chemotherapy (with or without Avastin) in 20.7% of the patients in the Braftovi/Erbitux/chemo group versus 17.5% in the standard-of-care group.

Elez E, Yoshino T, Shen L, et al. First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): progression-free survival and updated overall survival analyses. 

. 2025;43(suppl 17):LBA3500. doi:10.1200/JCO.2025.43.17_suppl.LBA3500

Elez E, Yoshino T, Shen L, et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. 

. Published online May 30, 2025. doi:10.1056/NEJMoa2501912

The phase 3 BREAKWATER trial demonstrated that combining Braftovi (encorafenib) and Erbitux (cetuximab) with mFOLFOX6 chemotherapy significantly improved progression-free survival in patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutations compared to standard-of-care. The combination also showed a median overall survival of 30.3 months versus 15.1 months for standard treatment. The regimen was well-tolerated, with manageable side effects. The FDA granted accelerated approval for this combination in December 2024, establishing it as a new standard-of-care for this patient population.

Braftovi and Erbitux plus chemotherapy improved survival without progression over standard therapy in BRAF V600E-mutant mCRC in the first-line setting.

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Braftovi and Erbitux Plus Chemo Improves Outcomes for BRAF V600E+ mCRC

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