Several studies presented at the recent 2026 ASCO Annual Meeting evaluated biomarker-guided strategies for HR+/HER2- metastatic breast cancer, including PI3K pathway targeting and circulating tumor DNA (ctDNA) monitoring. Komal Jhaveri, MD, FACP, FASCO, discusses how these data may inform treatment after progression on CDK4/6 inhibitor therapy and the evolving role of early treatment switching.

Following these presentations, featured expert Komal Jhaveri, MD, FACP, FASCO, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Jhaveri on these findings are presented here.

In HR+/HER2- metastatic breast cancer, ctDNA-based treatment assignment can be guided by mutational information, including PIK3CA mutations or other alterations in the PI3K/AKT/mTOR pathway. Those alterations comprise approximately 40% of HR+ breast cancer cases, and PIK3CA mutation status is a poor prognostic variable.

The proof of concept for targeting this pathway came with everolimus, followed by alpelisib, an alpha-isoform PI3K inhibitor that was US Food and Drug Administration (FDA) approved in combination with fulvestrant based on the SOLAR-1 study, where we saw a near doubling of progression-free survival (PFS) for tumors with PIK3CA mutations. The challenge with alpelisib has always been toxicity, particularly hyperglycemia, diarrhea, and rash. Capivasertib later added AKT inhibition for PI3K-, AKT-, and PTEN-altered tumors after progression on CDK4/6 inhibitor therapy. The toxicity profiles of these drugs are why we focus on newer generations of PI3K inhibitors. A good example of these newer therapies is mutant-selective inhibitors, where the idea is that if you spare the inhibition of PI3K wild type and focus on the PI3K mutation (the oncogenic driver), then maybe you will have lower rates of hyperglycemia, diarrhea, and rash, and patients can stay on these drugs longer.

That same effort to improve efficacy while managing toxicity is also driving the development of mutant-selective PI3K inhibitors. At ASCO 2026, the mutant-selective PI3Kα inhibitor with updated clinical data was tersolisib. We presented updates from the ongoing phase 1/2 PIKALO-1 trial evaluating tersolisib alone or combined with fulvestrant and triplet strategies with a CDK4/6 inhibitor, tersolisib, and endocrine therapy in pretreated patients with PIK3CA-mutant HR+/HER2- advanced breast cancer (abstract 1072). Results showed that tersolisib alone or with fulvestrant, with or without a CDK4/6 inhibitor, continued to be well tolerated, with PIK3CA-mutant ctDNA reduction observed at all dose levels. With tersolisib, we see low toxicity rates, few grade 3 toxicities, low grades of hyperglycemia, and low grades of diarrhea and rash. We do, however, also see some signal of elevated liver enzymes.

A different approach to PI3K pathway targeting after progression on CDK4/6 inhibitor therapy was evaluated in the PIK3CA-mutant cohort from the VIKTORIA-1 trial and was presented at ASCO 2026 by Sara A. Hurvitz, MD, FACP (abstract LBA1008). VIKTORIA-1 evaluated gedatolisib, a dual PI3K/mTOR inhibitor. Unlike other PI3K, AKT, or mTOR inhibitors, gedatolisib is given intravenously. Alpelisib with fulvestrant gave us a median PFS of 5.6 months, and this nearly doubled to 11.1 months with the gedatolisib, palbociclib, and fulvestrant triplet. The efficacy is appealing, but the regimen is complicated, and there was a signal for stomatitis.

The post-CDK4/6 data have also raised the question of whether PI3K pathway targeting should move earlier, including into first-line triplet strategies with a PI3K inhibitor, endocrine therapy, and a CDK4/6 inhibitor. The rationale was borne out after the FDA approval of inavolisib, an alpha-isoform PI3K inhibitor, based on the INAVO120 trial evaluating inavolisib with palbociclib and fulvestrant compared with fulvestrant and palbociclib in patients with PIK3CA-mutated, HR+/HER2-, locally advanced or metastatic, endocrine-resistant tumors. Not only did we see an improvement in PFS from 7.3 months in the control arm to 15 months in the experimental arm but also, for the first time, we were able to show an overall survival signal.

Beyond using ctDNA to identify mutations and assign therapy, we have appreciated ctDNA for monitoring treatment responses, although this has not become a routine standard. Can we use ctDNA information, identify an emerging alteration, and intercept before radiological progression? That strategy gave us data from the PADA-1 trial. Patients who were started on an aromatase and a CDK4/6 inhibitor were tested for ctDNA. If an ESR1 mutation was identified, patients were randomized to switch to fulvestrant or continue the current standard of care; switching to fulvestrant improved PFS.

The SERENA-6 study did what PADA-1 did but in a larger group and with an oral SERD. If ESR1 mutations emerged without radiological progression, patients were randomized to switch to camizestrant and the same CDK4/6 inhibitor or continue the aromatase and CDK4/6 inhibitors they had started. At ASCO 2026, the final PFS2 and exploratory ctDNA clearance analyses from SERENA-6 were presented by Francois Clement Bidard, MD, PhD (abstract LBA1007). PFS2 was longer with the switch strategy (25.7 months compared with 19.1 months). The question remains whether an early switch to an oral SERD in patients with emerging ESR1 mutations without radiological progression will improve long-term outcomes, or whether we would achieve similar outcomes using an oral SERD or an oral SERD combination at radiological progression, which is what we currently do in clinic.

Ultimately, this leaves us with 3 different strategies. Do we start treatment and delay the emergence of ESR1 mutations? Or, like with SERENA-6, do we track ESR1 mutations during first-line therapy and only act if one emerges? Or do we wait for radiological progression and give therapy for ESR1-mutant disease at the back end? We have FDA approvals for treatments at the back end, and we will see what happens with SERENA-6.