Precision in practice: a new standard in early-relapsing HR+ breast cancer

While notable advances have been made for the treatment of early-stage hormone-receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, early-relapses remain a significant area of unmet clinical need. PIK3CA mutations, present in 35–40% of advanced HR+/HER2− breast cancers, are among the key molecular drivers of endocrine resistance in advanced disease (1). Notably, these tumours are often associated with a worse prognosis, presenting with early relapses following adjuvant therapy, rapid clinical deterioration and a high attrition rate for receiving therapy in the 2^nd line and beyond (2).

The phase III INAVO120 trial was designed to evaluate whether the addition of the next-generation PIK3CA inhibitor inavolisib to standard endocrine therapy and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition could meaningfully improve outcomes in a selected high-risk early-relapse patient population (3). As biomarker-driven strategies increasingly shape breast cancer treatment, INAVO120 highlights critical clinical and translational considerations, including the importance of patient selection, timing of molecular assessment and real-world implementation of targeted therapies with notable challenges in translating biomarker-guided advances into equitable, accessible, personalized cancer care.

Among oncogenic drivers with prognostic and therapeutic relevance in HR-positive, HER2-negative breast cancer, PIK3CA mutations are among the most frequent (4). These alterations promote endocrine resistance (4) and have driven the development of agents such as alpelisib (5) and more recently capivasertib (6) and ipatasertib (7), which demonstrated benefit in biomarker-selected populations. However, their broader clinical use has been limited by substantial on-target toxicities, which presents challenges for real-world implementation (8). In contrast, inavolisib, a next-generation PI3Ka inhibitor, was designed to be more selective, with increased specificity for the mutant PIK3CA allele, resulting in a more favourable tolerability profile and an improved therapeutic window (9,10).

Beyond tolerability, understanding the timing and evolution of PIK3CA mutations may further inform early testing strategies and targeted interventions, particularly in the early-relapsing population. Existing data suggest that the majority of PIK3CA alterations are truncal, meaning they occur early in tumour development and are present in both the primary and metastatic sites (11). This supports the clinical feasibility of testing either archived primary tumour tissue or metastatic biopsies. However, emerging tools including ctDNA profiling, variant allele frequency (VAF) and their dynamics, could offer deeper insights into the clonal architecture and temporal evolution of these mutations during or shortly after adjuvant therapy. These questions are especially pertinent in understanding the biology of early relapse, including how early PIK3CA mutations can be identified, whether ctDNA dynamics could help predict relapses during adjuvant therapy and how genomic features in early relapse differ from those in primary-tumour focused datasets such as The Cancer Genome Atlas (TCGA). Addressing these questions may open avenues for earlier intervention, potentially leading to earlier next-generation sequencing (NGS) testing and enhanced surveillance in the adjuvant setting for patients with PIK3CA mutations deemed at high risk of relapse. However, practical challenges remain, including the cost-effectiveness, scalability and equity of such an approach, particularly given the high global incidence of HR positive breast cancer.

The INAVO120 clinical trial was a phase III randomized double-blind, placebo-controlled trial enrolling patients with HR-positive HER2-negative, PIK3CA-mutated advanced breast cancer whose disease had recurred during or within 12 months of completing adjuvant endocrine therapy (3,12). Testing for PIK3CA mutations was determined by liquid biopsy using the FoundationOne Liquid CDx assay. Patients were randomized 1:1 to the intervention arm of inavolisib in combination with an intramuscular selective estrogen receptor degrader (SERD), fulvestrant and the CDK4/6 inhibitor palbociclib, or placebo with fulvestrant and palbociclib alone, which at the time of the trial design represented the standard of care based on findings from the PALOMA-3 clinical trial.

The primary endpoint for the trial was progression-free survival (PFS), which has been previously reported and showed a statistically significant and clinically meaningful improvement, with a PFS of 15.0 months in the inavolisib arm compared to 7.3 months in the placebo arm (hazard ratio 0.43, 95% confidence interval: 0.32–0.59; P<0.0001). Key secondary endpoints included overall survival (OS), objective response rate (ORR), safety and quality of life. The recently published data by Jhaveri et al. in the New England Journal of Medicine demonstrated a notable OS advantage, reported at 34.0 months in the inavolisib group compared to 27.0 months in the control arm (hazard ratio 0.67; P=0.0190) (12). It is important to note that the study did not allow crossover and that only a minority of patients in the control arm received PI3K targeted therapies in subsequent lines. This is particularly relevant given the growing availability of other agents approved globally in the 2^nd line setting, which target the PI3K pathway, including PIK3CA, AKT and PTEN mutations, specifically alpelisib for PIK3CA and capivasertib for PIK3CA, AKT and PTEN mutations. Because INAVO120 did not allow crossover, the observed OS benefit reflects the true effect of PI3K pathway inhibition in PIK3CA-mutated cancers. This strengthens the interpretation of both PFS and OS outcomes, although the limited data on subsequent therapies warrant consideration in the context of evolving treatment landscapes.

The initial reports and most recent publication of the INAVO120 trial highlight a relatively favourable toxicity profile relative to other drugs in its class (Table 1) (8,13). Whereas alpelisib has been associated with higher rates of hyperglycemia (any grade between 60–65%; grade 3/4 of 30–40%), rash, diarrhea and other metabolic disturbances (5), and capivasertib was noted to have a higher prevalence of diarrhea and rash but lower hyperglycemia (6), inavolisib’s adverse event profile appears milder in those respects (10). However, despite the restrictive enrollment criteria for inavolisib requiring a baseline HbA1C <6%, any-grade hyperglycemia was reported in 59% of patients in the inavolisib arm relative to 9% in the control arm, comprising 6% of grade 3 or higher events (12). This raises the question of whether these criteria limit generalisability to real-world populations, many of whom will have worse baseline metabolic control.

Other frequent side effects included stomatitis, diarrhea and rash, though the majority of these were low to moderate grade events. Longer follow-up and broader post-approval experience will be essential to better characterize the durability, cumulative burden and real-world management of these toxicities. Additional limitations include the lack of crossover in INAVO120 at the time of progression and the low rates of subsequent use of a PI3K pathway inhibitor in the control arm. While the improved tolerability of inavolisib is promising, it underscores the importance of careful patient selection, proactive management of adverse events, and implementation science to ensure that oncologists and care teams have accessible and curated resources to adequately address treatment-related toxicities as they arise. Ultimately, these considerations reinforce the importance the importance of carefully weighing efficacy against toxicity in individual patients.

Response rates with the addition of inavolisib in INAVO120 were found to be superior, which may be relevant when a rapid response is needed, particularly in patients with a large burden of disease, significant symptoms or a very rapid pace of disease. In the trial, ORR was 58.4% in the inavolisib arm vs. 25.0% in the placebo arm. It’s important to note that visceral crisis was not permitted, so while these response data are promising, the standard of care for true visceral crisis remains upfront chemotherapy.

While there are agents in development seeking to target specific isoforms, more than 60 PIK3CA mutations were eligible for enrollment based on the INAVO120 inclusion criteria, thereby reflecting the majority of mutations expected in real-world settings (11). Detailed biologic subgroup analysis for certain isoforms or particular mutation variants (ex. Helical vs. kinase domain; VAF subgroups) has not yet been published, though available results show that benefit was observed across demographic and disease subgroups and other agents in this class have not suggested any biological differences in observed activity across isoforms. Mechanistically, tumours harbouring alterations such as PTEN loss or activation AKT mutations may exhibit reduced sensitivity to PIK3CA inhibition, as these changes activate the PI3K/AKT pathway downstream or independently of PIK3CA .

The INAVO120 represents a practice-changing clinical trial which has transformed the treatment for patients with HR-positive HER2-negative breast cancer with PIK3CA mutations who relapse during or within 12 months of adjuvant endocrine therapy. Its initial publication demonstrated a doubling in PFS which led to significant enthusiasm for the triplet regimen for endocrine-resistant disease in the 1^st line setting (3). With the more recent data showing a clinically meaningful OS advantage (12), the case for adopting this regimen as a new standard of care in the early-relapse setting has become even more compelling, as evidenced by the FDA’s approval of the triplet regimen. To this effect, one particularly important observation from the Kaplan-Meier curves is the early and steep separation between treatment arms, with a rapid drop-off in the control group. This suggests that patients with particularly aggressive disease derive clinical benefit from early PI3K pathway targeting, supporting the rationale for upfront use of the triplet regimen rather than deferring PI3K inhibition to later lines of therapy.

Another key consideration for timely access to this therapy is contingent upon early identification of PIK3CA mutations, underscoring the importance of routine NGS at or near the time of metastatic diagnosis or possibly earlier if there is fidelity in these mutations from the primary to the recurrence. This raises real-world concerns about inequities in molecular testing and access to targeted therapies, particularly in regions with limited resources, which could contribute to disparities in outcomes (14). It also raises the question of whether 1 year is key to identify those who may benefit, as historically clinical endocrine resistance has been defined as those relapsing within 2 years of adjuvant therapy. Thus, the question remains as to whether the early-relapse group is truly the only one to benefit from an upfront triplet combination approach or whether expansion beyond the early-relapse population to a broader population could be worthwhile. The optimal sequencing strategies may be further delineated by the ongoing INAVO121 study as we distill the data to understand whether early targeting of the PI3K pathway with or without CDK4/6 inhibition is needed for all.

Moreover, as the inavolisib triplet regimen gains traction as a new standard of care in the first-line metastatic setting, we know that therapies proven to be of benefit in the advanced setting often move up earlier in the sequence of therapy, as has been the case recently with the approval of adjuvant CDK4/6 inhibitors (15,16). Thus, testing in the newly diagnosed setting may present a unique opportunity to identify patients at higher risk of early relapse. Strategies are being explored in the neoadjuvant and adjuvant setting, which may inform more proactive, risk-adapted treatment paradigms in this rapidly evolving therapeutic landscape (Figure 1).

Figure 1 Overview of phase III inavolisib clinical studies for patients with centrally-confirmed PIK3CA mutation. *, ET resistant = relapsing during or within 12 months of adjuvant endocrine therapy (3,12); **, Phesgo = pertuzumab/trastuzumab/hyaluronidase subcutaneous fixed dose combination. Figure adapted from publicly available Roche materials (https://www.roche.com), used for illustrative purposes. Used with permission from Roche. eBC, early breast cancer; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR, hormone receptor.

This question is particularly pressing in early-stage HR-positive HER2-negative breast cancer, where pathologic complete response (pCR) rates remain low and carry less prognostic weight compared to the triple negative and HER2-positive subtypes (17). As such, strategies that alter the natural history of the disease, even in the absence of pCR, are of increasing interest. Hopefully the field will pivot from a reactive paradigm of treating recurrences, to a preventative one, in which patients with biologically high-risk disease are identified upfront and receive targeted therapies before experiencing distant and incurable relapses. However, this remains challenging as studies in the HR positive subtype such as Penelope-B, which evaluated post-neoadjuvant CDK4/6 inhibition with palbociclib in patients with residual disease, failed to show improved outcomes, despite notable PFS advantages in the advanced setting (18). Other approaches would include testing the primary for individuals with high-risk disease or the adoption of a ctDNA-first workflow, whereby patients with high-risk disease could partake in serial ctDNA-based monitoring after completion of adjuvant therapy to identify early molecular relapse and allow early intervention.

Furthermore, the space is becoming increasingly competitive, with trials such as Keynote-756 (19) and CheckMate 7FL (20) exploring the integration of immunotherapy in early HR-positive, HER2-negative disease. These approaches appear to be particularly relevant in the ER-low subgroup, where traditional endocrine therapies and CDK4/6 inhibitors may offer less benefit, and where immune responsiveness could be more pronounced. Ultimately, thoughtful biomarker selection, improved molecular risk stratification and careful trial design will be essential to determine whether early PI3K pathway inhibition can meaningfully alter outcomes without overtreating patients or creating unacceptable toxicity in the curative setting.

Finally, one of the greatest challenges in such a complex and rapidly evolving therapeutic landscape is the disconnect between trial design and contemporary clinical practice. As trials are often designed years prior to results becoming available, the standard of care has often shifted by the time data are presented, complicating the relevance and applicability of the control arm. This is especially relevant in INAVO120, where fulvestrant and palbociclib were selected as the endocrine therapy backbone and CDK4/6 inhibitor, respectively, reflecting standard practice at the time of study design. With the results of Monaleesa-3 demonstrating an OS advantage (21), there is interest in potentially combining inavolisib with ribociclib, as explored by the Morpheus study, which is limited by small numbers but demonstrated preliminary signs of safety and feasibility (22). Similarly, while fulvestrant remains a widely used SERD, the evolving endocrine therapy landscape of oral SERDs and other emerging endocrine agents may offer greater convenience and potentially improved activity, particularly for patients with co-alterations in ESR1 and PIK3CA. Although no clinical data yet support this dual-targeted approach, the biological rationale is compelling and warrants further investigation. As more targeted therapies become available, we must also begin to consider sequencing strategies, not only for CDK 4/6 inhibitors, but potentially also for PI3K pathway inhibition to address emergent resistance mechanisms with continued suppression of the dominant oncogenic driver. Could upstream targeting of the pathway at progression help delay or overcome resistance? Answering this question will require more sophisticated characterization of tumour evolution, including genomic and transcriptomic profiling at the time of progression, to inform the next generation of combinations and sequencing strategies.

To conclude, INAVO120 establishes a new standard of care for patients with HR-positive HER2-negative, PIK3CA-mutated breast cancer who experience relapse following adjuvant endocrine therapy. The demonstrated improvement in both PFS and OS highlights a pivotal opportunity for early intervention to alter the trajectory of disease in this high-risk group in a clinically significant manner. Moreover, this new standard solidifies the critical role of NGS as a routine component of clinical care in breast cancer. Early identification of PIK3CA mutations, particularly in those at high risk of relapse, may allow for closer surveillance and timely access to targeted therapies with the potential to alter long-term outcomes.

While inavolisib is a novel, mutant-selective PIK3CA inhibitor that was specifically designed to enhance tolerability while preserving efficacy through improved molecular targeting, real-world implementation will require careful attention to toxicity management, patient selection and infrastructure to support access to both testing and treatment. As the therapeutic landscape continues to evolve, inavolisib may also prove to be a valuable partner in rational combination strategies or sequencing approaches aimed at overcoming resistance. Ultimately, INAVO120 is more than just a positive trial, it is a paradigm shift, reinforcing the value of precision oncology in HR-positive breast cancers and opening new avenues for earlier and more personalized interventions.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-112/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-112/coif). N.L. reports research funds from Abbvie, Astra Zeneca, Avon Foundation, CIHR, Eli Lilly, Exact Sciences, Gilead, Pfizer, and Roche; consulting fees for serving on advisory boards from Astra Zeneca, Daiichi Sankyo, Eli Lilly, Gilead, Knight Therapeutics, Merck, Novartis, Pfizer, Roche, Seagen, and TerSera; speaker’s honoraria from Astra Zeneca, Daiichi Sankyo, Eli Lilly, Gilead, Merck, Knight Therapeutics, Merck, Novartis, Pfizer, Roche, Seagen, and TerSera; support for attending meetings from Gilead; and leadership or fiduciary roles in Breast Cancer Canada and REAL Canadian Breast Cancer Alliance. K.A.G. reports research funds from Astra Zeneca and BMS; consulting fees for serving on advisory boards from Astra Zeneca, Daiichi Sankyo, Gilead, Merck, Novartis, Pfizer, Celcuity, and City of Hope; speaker’s honoraria from Astra Zeneca and Novartis; and leadership or fiduciary roles in Breast Cancer Canada, REAL Canadian Breast Cancer Alliance, Canadian Breast Cancer Network, and RETHINK Breast Cancer. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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