Ask AI
Back Back
PI3K AKT Therapies for HRpos HER2neg ABC
Where We Are Today and Where We Are Going: Integrating PI3K/AKT Pathway–Directed Therapies Into Clinical Practice for Hormone Receptor–Positive/HER2-Negative Advanced Breast Cancer

Released: July 13, 2026

Giampaolo Bianchini
Giampaolo Bianchini, MD
Cristina Saura Manich
Cristina Saura Manich, MD, PhD
Activity Information

Activity

Continue to Activity
Key Takeaways
  • Earlier testing for PIK3CA/AKT/PTEN alterations, either at diagnosis of advanced/metastatic recurrence or before the next treatment decision, is increasingly important for guiding individualized sequencing as PI3K/AKT pathway–directed therapies expand in HR-positive/HER2-negative advanced breast cancer.
  • In INAVO120, inavolisib plus palbociclib/fulvestrant reduced the risk of progression or death by 57% in patients with PIK3CA-mutated HR-positive/HER2-negative advanced breast cancer.

In this commentary, Cristina Saura Manich, MD, PhD, and Giampaolo Bianchini, MD, discuss the evolving role of PI3K/AKT pathway–directed therapies for patients with hormone receptor (HR)–positive/HER2-negative advanced breast cancer, including current practice and emerging directions. The experts also provide highlights and takeaways from the overall program and share their answers to frequently asked questions from healthcare professionals (HCPs) who participated in the program.

Giampaolo Bianchini, MD:
The treatment landscape for HR-positive/HER2-negative advanced breast cancer has evolved considerably in recent years. Alpelisib established proof of principle that targeting the PI3K pathway could improve outcomes in biomarker-selected patients (SOLAR-1: median progression-free survival [PFS], 11.0 vs 5.7 months with placebo plus fulvestrant; hazard ratio: 0.65; 95% CI: 0.50-0.85; P <.001), and newer data and approvals have expanded treatment options. Today, the key questions are when to intervene, which component of the pathway to target, and how to sequence these therapies with endocrine treatment. 

One important development is the emergence of data supporting earlier integration of pathway-directed therapy. In the phase III INAVO120 study, adding inavolisib to palbociclib and fulvestrant improved PFS in patients with PIK3CA-mutated, endocrine-resistant disease in the adjuvant setting with recurrence on or within 12 months of completing adjuvant endocrine therapy (median PFS: 15.0 vs 7.3 months; hazard ratio: 0.43; 95% CI: 0.32-0.59; P <.001), supporting earlier PI3K pathway inhibition as a strategy to prolong disease control.

Cristina Saura Manich, MD, PhD:
Our approach has changed considerably in recent years. Rather than waiting until disease progression after first-line CDK4/6 inhibitor therapy, I now recommend testing for PIK3CA mutations using archival or metastatic tumor tissue early in the metastatic setting whenever feasible. This identifies patients who may benefit from PI3K pathway-directed therapies and supports treatment planning before progression. At progression, liquid biopsy provides an opportunity to detect newly acquired ESR1 mutations and, in some patients, additional actionable alterations within the PI3K pathway that may influence subsequent treatment decisions. As sequencing becomes more complex, earlier biomarker testing helps us anticipate future therapeutic opportunities rather than react to disease progression.

Implementing PI3K/AKT Pathway–Directed Therapy in Practice

Cristina Saura Manich, MD, PhD:
In practice, these data reinforce the need to align treatment selection with disease biology, prior therapy, and anticipated resistance mechanisms. A proactive testing strategy can help HCPs identify appropriate candidates for pathway-directed therapy while leaving room to adjust subsequent treatment choices as new molecular findings emerge.

Implementation also requires balancing efficacy with practical considerations, including endocrine sensitivity, disease burden, comorbidities, anticipated toxicities, patient preferences, and local access to therapy. Hyperglycemia remains an important adverse event associated with PI3K pathway inhibition, underscoring the value of collaboration with endocrinologists or diabetologists to monitor and manage treatment-related toxicity.

Clinical evidence often evolves more rapidly than access to new therapies, and reimbursement and regulatory differences with approved PI3K pathway inhibitors continue to influence implementation across Europe. These regional differences highlight the need to balance emerging evidence with local availability when developing individualized treatment plans. HCPs can apply these concepts using the accompanying interactive clinical decision support tool, which provides evidence-based guidance for biomarker-driven treatment selection and sequencing in HR-positive/HER2-negative advanced breast cancer.

Over the course of this educational program, learner survey findings showed improvements in familiarity with PI3K/AKT pathway–directed therapies for HR-positive/HER2-negative advanced breast cancer. For instance, participants showed gains in identifying appropriate candidates for PI3K/AKT pathway–directed therapy (47% at baseline to 89% postassessment), incorporating these agents into treatment planning (46% at baseline to 87% postassessment), and understanding the role of biomarkers in treatment selection (82% at baseline to 93% postassessment). However, the results also showed a continued need for education on managing treatment-associated hyperglycemia and on the practical value of partnering with endocrinologists or diabetologists, while noting that newer PI3K/AKT pathway inhibitors have shown improved tolerability.

Emerging Therapies and Ongoing Clinical Trials

Giampaolo Bianchini, MD:
Recent studies continue to build on first-generation PI3K inhibitors. At the ASCO 2026 Annual Conference, investigators presented positive phase III VIKTORIA-1 results showing that gedatolisib-based therapy improved PFS compared with alpelisib plus fulvestrant in patients with PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancer after CDK4/6 inhibitor therapy (median PFS, 11.1 months with gedatolisib plus palbociclib and fulvestrant vs 5.6 months with alpelisib plus fulvestrant; hazard ratio: 0.50; 95% CI: 0.37-0.68; P <.0001). These findings suggest that targeting multiple components of the PI3K/mTOR pathway may offer another therapeutic strategy with a distinct safety profile. Of note, the potential FDA approval decision date for gedatolisib in HR-positive/HER2-negative, PIK3CA wild-type advanced breast cancer, based on the PIK3CA wild-type cohort of VIKTORIA-1, is July 17, 2026.

Clinical development is also progressing with next-generation allosteric PI3Kα inhibitors designed to improve mutant PI3Kα selectivity and reduce wild-type PI3Kα–associated toxicities. In the phase I/II ReDiscover trial, zovegalisib plus fulvestrant showed preliminary activity in heavily pretreated patients with PIK3CA-mutated, HR-positive/HER2-negative metastatic breast cancer after CDK4/6 inhibitor therapy, with a median PFS of 11.1 months and an ORR of 43%; reported safety findings included predominantly grade 1 hyperglycemia, no grade 4/5 hyperglycemia, and treatment-related discontinuation in 6.7% of patients (NCT05216432). Zovegalisib is also being evaluated in the phase III ReDiscover-2 trial after CDK4/6 inhibitor progression (NCT06982521). Tersolisib is being evaluated in a phase III first-line study in PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancer, with efficacy and safety results not yet available (NCT07174336). Ongoing phase III INAVO123 is similarly testing earlier incorporation of PI3K pathway inhibition with inavolisib plus a CDK4/6 inhibitor and letrozole in endocrine-sensitive, PIK3CA-mutated disease (NCT06790693). Together, these studies may further refine how pathway-directed therapies are used in future treatment strategies.

Cristina Saura Manich, MD, PhD:
The future of PI3K/AKT pathway–directed therapy will likely depend on earlier biomarker testing, clearer sequencing strategies, and continued clinical trial data to define which patients benefit most from specific pathway-directed approaches. Ultimately, our goal is to deliver the right therapy to the right patient at the right time, supported by thoughtful sequencing and continued clinical trial participation.

Apply the concepts discussed in this commentary by completing the accompanying interactive case challenge focused on biomarker-guided treatment selection, sequencing, and management of PI3K/AKT pathway–directed therapies in HR-positive/HER2-negative advanced breast cancer.

Your Thoughts
What are your thoughts on incorporating PI3K/AKT pathway–directed therapies into everyday clinical practice for patients with HR-positive/HER2-negative locally advanced or metastatic breast cancer? Answer the polling question and leave a comment to join the discussion. Visit the program page to access related resources and other education associated with this topic.

Continue to Activity

Poll

1.

What is your greatest barrier to using PI3K/AKT pathway–directed therapy in eligible patients?

Submit