21 April 2025 saw two significant developments in the clinical research space. One involves a major readout in breast cancer, the other emerges from promising preclinical work in lymphoma. Each could shape future treatment options for patients facing difficult-to-treat cancers.

Enhertu plus Pertuzumab Improves Progression-Free Survival in HER2-Positive Metastatic Breast Cancer

AstraZeneca and Daiichi Sankyo released high-level interim results from the DESTINY-Breast09 Phase III trial. In this global, multicenter study the combination of Enhertu (trastuzumab deruxtecan) with pertuzumab was compared against the standard THP regimen (taxane + trastuzumab + pertuzumab) as first-line treatment for patients with HER2-positive metastatic breast cancer.

Key findings include:

• The Enhertu + pertuzumab arm showed a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard THP.
• Improvement in PFS was consistent across all pre-specified patient subgroups.
• Overall survival (OS) data are not yet mature, though an early trend favoring the Enhertu combination has been observed.
• A separate arm of the trial, comparing Enhertu monotherapy versus THP, remains blinded. Investigators are continuing follow-up.

If final OS and safety data continue to support these early results, the Enhertu + pertuzumab combination may become a new standard for first-line HER2-positive metastatic breast cancer. For patients, this could translate into longer duration of disease control with possibly different toxicity profiles.

ARV-393 PROTAC BCL6 Degrader Gains Traction in Lymphoma Models

On the same date Arvinas, a company focused on targeted protein degradation technologies, announced new preclinical combination data for ARV-393. The molecule is a PROteolysis TArgeting Chimera (PROTAC) designed to degrade B-cell lymphoma 6 protein (BCL6), a transcriptional repressor that is a known driver in many B-cell lymphomas.

Highlights from the announcement:

• ARV-393 when combined with standard of care therapies in diffuse large B-cell lymphoma models produced tumor regressions.
• The data will be presented at the American Association for Cancer Research (AACR) Annual Meeting (April 25-30, 2025).
• ARV-393 is currently in a Phase I clinical trial for relapsed or refractory non-Hodgkin lymphoma. The preclinical results provide needed rationale for how it might be used in combination regimens.

The promise of a BCL6 degrader lies in attacking what has historically been a difficult target via traditional inhibitors. If ARV-393 continues to show good safety and tolerability, it could open up novel options for patients who do not respond to or relapse after existing therapies.

Why These Matter

These two stories illustrate how cancer clinical research is pushing both incremental and innovative edges improving existing therapy combinations and developing new mechanism-based modalities like PROTACs. Some of the implications:

• The Enhertu combo may reframe standard first-line therapy for HER2-positive metastatic patients. As survival trends and subgroup data mature, oncologists will watch for how tolerability and quality of life compare with existing regimens.
• The ARV-393 data mark further validation of targeted protein degradation as a feasible strategy in oncology, especially for transcription factors like BCL6 that are not easily druggable by classical small molecules or antibodies.
• Both studies reinforce the importance of combination strategies: combining new agents with established therapies to extend benefit or overcome resistance.

These developments also raise questions that researchers will need to answer:

• What will the safety profiles look like, particularly when combining potent ADCs like Enhertu with other agents over longer follow-up?
• How durable will responses be? Do PFS gains translate into meaningful overall survival and improved patient experience?
• For ARV-393 and similar PROTACs, can the preclinical activity be replicated in human studies, and will off-target effects or degradation of unintended proteins be an issue?

Given their timing and potential, these studies are likely to influence regulatory submissions, guideline revisions, and further clinical trial designs. They are also reminders that oncology research continues to move on multiple fronts: large trials refining standards of care, as well as early-stage work that could chart entirely new directions.