Same Pathway, Different Profiles: Clinical Considerations for Alpelisib, Capivasertib, and Inavolisib

Alpelisib (Piqray; Novartis Pharmaceutical Corporation) is a first-in-class PIK3CA-targeting kinase inhibitor approved by the FDA in combination with fulvestrant (Falsodex; AstraZeneca) in patients with hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated metastatic breast cancer in 2019.¹ Following that approval, the FDA approved capivasertib (Truqap; AstraZeneca) with fulvestrant in the same population of as alpelisib but who harbor 1 or more mutations in the PIK3CA/AKT/PTEN pathway in 2023.² Additionally, the FDA approved in 2024 inavolisib (Itovebi; Genentech) with palbociclib (Ibrance; Pfizer Inc) and fulvestrant in the same population as alpelisib and capivasertib (Truqap; AstraZeneca) with those who have a PIK3CA mutation.³ Each agent has a unique place in therapy for those who have the mutation, but there are similarities and differences that should be considered prior to initiation.

Mechanism of Action:

PIK3CA, AKT, and PTEN mutations represent some of the most common genetic aberrations in breast cancer and are present in about one-third of cases.³ Mutational activity in the PIK3CA gene, which codes for the catalytic subunit p110a of PI3K, causes the constitutive activation of P13K, leading to endocrine resistance in HR-positive breast cancer.^3,4 This appears to be a negative prognostic and predictive factors for chemotherapy treatment in patients who have estrogen receptor/progesterone receptor-positive and HER2-negative disease.^3,4 Downstream from PI3K is AKT, which is involved in cell survival and proliferation.^3,4 In contrast, PTEN is a tumor suppressor gene that acts as a brake on the PI3K/AKT pathway by dephosphorylating PIP3, thereby limiting AKT activation.^3,4 Loss of PTEN results in increased AKT activation and uncontrolled growth.⁴ Alpelisib inhibits PI3K-alpha which blocks signaling leading to cell death.⁶ Inavolisib inhibits PI3K-alpha and blocks signaling, as well, but also leads to degradation of PI3K, resulting in cell death. This allows alpelisib to overcome resistances seen with older PI3K inhibitors.⁷ In contrast, capivasertib is a pan-AKT inhibitor which blocks all major forms of AKT (1, 2 and 3) and halts downstream signaling of PI3K.⁸

Dosing and Administration:

Table 1 depicts the dosing, administration, and concomitant medications for each of the PIK3CA inhibitors.

Clinical Data

Alpelisib was studied in a phase 3, randomized, double-blind placebo-controlled trial evaluating postmenopausal women and men with HER2-negative and HR-positive breast cancer (NCT02437318)⁹ Patients were enrolled into 2 cohorts on the basis of tumor-mutation status (PIK3CA-mutated versus not PIK3CA mutated).^9,10 In each cohort, patients were randomly assigned in a 1:1 ratio to receive alpelisib at 300 mg per day with fulvestrant or placebo with fulvestrant. The primary end point for this trial was progression-free survival (PFS) in the PIK3CA-mutated cohort with overall survival (OS) and response rate as secondary end points. The median PFS (mPFS) in the alpelisib group was 11.0 months in comparison to 5.7 months (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P < .001). The exploratory median OS (mOS) in the trial was 39.3 months in the alpelisib plus fulvestrant group.¹⁰

Following this trial, a phase 2 trial had 3 different cohorts based on recent therapy (NCT03056755).¹¹ Cohort A included patients previously treated with a CDK4/6 inhibitor plus an aromatase inhibitor; among them, 50.4% remained progression-free at 6 months with alpelisib and fulvestrant. Cohort B included patients who progressed on a CDK4/6 inhibitor plus fulvestrant and were subsequently treated with alpelisib plus letrozole, which yielded a mPFS of 5.7 months. Cohort C included patients who had received other therapies, with a mOS of 5.6 months.¹²

Capivasertib was studied in a phase 3 trial double-blind, placebo-controlled trial evaluating patients with HR-positive/HER2-negative locally advanced breast cancer (NCT04305496).¹³ Inclusionary criteria included patients who progressed on aromatase inhibitors with or without a CDK 4/6 inhibitor. Capivasertib was given in combination with fulvestrant in this trial. The primary end point was PFS in the PIK3CA, AKT, or PTEN altered population and in the overall population. In the overall population, the mPFS was 7.2 months (HR 0.60 95% CI 0.51 – 0.71 P < .001) and in the AKT-pathway altered population the mPFS was 7.3 months (HR 0.50 95% CI 0.38 – 0.65, p <0.001). Objective response rates were 22.9% favoring capivasertib in the overall population and 28.8% in the AKT-pathway altered population.¹¹ Health-related quality of life—also assessed in this study—showed a median time to deterioration of 24.9 months and OS has not been reached.¹⁴

A phase 3, double-blind, placebo controlled study investigated inavolisib plus palbociclib and fulvestrant in patients with HR-positive/HER2 negative, PIK3CA-mutated breast cancer who progressed during or within 12 months of completing adjuvant endocrine therapy and no prior treatment for metastatic disease (NCT05646862).¹⁵ The primary end point was PFS, which was 15 months in comparison to 7.3 months (HR 0.43 95% CI 0.32 – 0.59 P < .001). The objective response rate was 58% with a median duration of response of 19.2 months favoring inavolisib. The mOS was 34 months based on a median follow-up of approximately 34 months. Time to chemotherapy was 35.6 months and favored inavolisib.^16,17

Adverse Effects

Table 2 shows the most common adverse effects (AEs) reported in the pivotal trials. Alpelisib is most frequently associated with hyperglycemia; however, discontinuation rates were significantly reduced through early intervention strategies, including initiating metformin at the first signs of hyperglycemia, using prophylactic antihistamines to prevent rash, and administering loperamide at the onset of diarrhea.^18,19,20 Capivasertib presented with a hyperglycemia rate of 2.3%. Inavolisib had no reports of grade 3 or 4 rash, but 26% of patients experienced all-grade rash.^14,16

Table 3 displays a comparison of AE management between the 3 medications in addition to the median onset of specified side effects. Alpelisib has more specific guidance on monitoring and management than capivasertib and inavolisib.

Conclusions

PIK3CA inhibitors have greatly expanded options for patients with HR-positive breast cancer. Although all 3 agents act on the AKT pathway, each medication exhibits differences in efficacy and side effect profiles. Alpelisib has clinically meaningful benefits but seemingly higher rates of AEs such as hyperglycemia and dermatologic reactions. Capivasertib includes a broader selection of patients based on biomarkers and is a good alternative for patients who are at risk for developing hyperglycemia. Inavolisib is highly selective for PI3K and provides favorable outcomes but also comes with neutropenia and stomatitis when combined with palbociclib. In clinical practice, selection among these agents should be guided by molecular profiling, prior lines of therapy, comorbidities, and patient preferences. Ongoing head-to-head comparisons are lacking, but real-world data and future trials will be critical to refining the sequencing and optimal integration of these targeted agents in the evolving treatment landscape.

REFERENCES

1. U.S. Food and Drug Administration. FDA approves alpelisib for metastatic breast cancer [Internet]. Silver Spring (MD): FDA; 2019 May 24 [cited 2025 Aug 12]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-metastatic-breast-cancer

2. U.S. Food and Drug Administration. FDA approves capivasertib with fulvestrant for breast cancer [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2023 Nov 16 [cited 2025 Aug 12]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer

3. U.S. Food and Drug Administration. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive breast cancer [Internet]. Silver Spring (MD): FDA; 2025 May 16 [cited 2025 Aug 12]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive

4. Kim R, Kim HJ, Lee H, Choi HJ, Kim SH, Kim JW, et al. PIK3CA mutations and their role in breast cancer: a comprehensive review. Sci Rep. 2024 May 6;14(1):9371. doi:10.1038/s41598-024-62664-1.

5. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Cancers (Basel). August 17, 2020. doi:10.3390/cancers12082132.

6. Novartis Pharmaceuticals Corporation. Alpelisib [package insert]. East Hanover (NJ): Novartis; 2025.

7. Genentech, Inc. Inavolisib [package insert]. South San Francisco (CA): Genentech; 2025.

8. AstraZeneca Pharmaceuticals LP. Capivasertib [package insert]. Wilmington (DE): AstraZeneca; 2025.

9. Study assessing the efficacy and safety of alpelisib plus fulvestrant in men and postmenopausal women with advanced breast cancer which progressed on or after aromatase inhibitor treatment. (SOLAR-1). Updated February 13, 2025. Accessed August 26, 2025. https://clinicaltrials.gov/study/NCT02437318

10. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. May 16, 2019. doi:10.1056/NEJMoa1813904.

11. study assessing the efficacy and safety of alpelisib plus fulvestrant or letrozole, based on prior endocrine therapy, in patients with pik3ca mutant, HR+, HER2- advanced breast cancer who have progressed on or after prior treatments (BYLieve). Updated July 31, 2025. Accessed August 26, 2025. https://clinicaltrials.gov/study/NCT03056755

12. Rugo HS, Im SA, Ciruelos E, Cristofanilli M, Diéras V, Iwata H, et al. Effectiveness of alpelisib plus fulvestrant compared with real-world standard treatments in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer after progression on CDK4/6 inhibitor therapy: the BYLieve trial. Oncologist. July 2021. doi:10.1002/onco.13804.

13. Capivasertib+fulvestrant vs placebo+fulvestrant as treatment for locally advanced (inoperable) or metastatic HR+/​HER2- breast cancer (CAPItello-291). Updated May 30, 2023. Accessed August 26, 2025. https://clinicaltrials.gov/study/NCT04305496

14. Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao Z, et al. Capivasertib plus fulvestrant for advanced hormone receptor-positive, HER2-negative breast cancer: the phase 3 CAPItello-291 trial. Lancet Oncol. May 20, 2023. doi:10.1016/S1470-2045(23)00153-0.

15. A study evaluating the efficacy and safety of inavolisib plus fulvestrant compared with alpelisib plus fulvestrant in participants with HR-Positive, HER2-Negative, PIK3CA mutated, locally advanced or metastatic breast cancer post CDK4/​6i and endocrine combination therapy (INAVO121). Updated July 28, 2025. Accessed August 26, 2025. https://clinicaltrials.gov/study/NCT05646862

16. Bardia A, Loibl S, LoRusso PM, Rugo HS, Oliveira M, Conte P, et al. Inavolisib plus palbociclib and fulvestrant in PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer: the INAVO120 phase 3 trial. N Engl J Med. February 8, 2024. doi:10.1056/NEJMoa2306872.

17. Jhaveri KL, Im SA, Saura C, Loibl S, Kalinsky K, Schmid P, et al. Overall survival with inavolisib plus palbociclib-fulvestrant in PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer. N Engl J Med. July 10, 2025. doi:10.1056/NEJMoa2501796

18. Di Leo A, et al. [abstract]. Ann Oncol. 2024;35(suppl_4):S567-S568.

19. Swissmedic. Inavolisib scientific review [Internet]. Bern (Switzerland): Swissmedic; 2025 [cited 2025 Aug 12]. Available from: https://www.swissmedic.ch

20. Rugo HS, André F, Yamashita T, et al. Management of alpelisib-associated hyperglycemia in patients with PIK3CA-mutated breast cancer: expert panel recommendations. Oncologist. 2021 Jan;26(1):35-44. doi:10.1002/onco.13510.

21. Verret B, Miller K, Modi S, et al. Expert recommendations for the management of alpelisib-associated adverse events in clinical practice. Breast Cancer Res Treat. August 2021. doi:10.1007/s10549-021-06272