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Discover more about the efficacy of PIQRAY® + fulvestrant from the BYLieve Phase II clinical trial and the SOLAR-1 Phase III clinical trial.1,2,5,7

BYLieve, the first prospective study to assess PIQRAY® + fulvestrant solely in the post-cyclin-dependent kinase 4/6 inhibitor setting.

BYLieve study design2

A Phase II, multicentre, open-label, three-cohort, non-comparative study assessing the safety and activity of PIQRAY® in combination with endocrine therapy (either fulvestrant or letrozole*).

  • 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide

Inclusion criteria

  • Women and men aged 18 years or older, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less with HR-positive, HER2-negative advanced breast cancer not amenable to curative therapy
  • A confirmed PIK3CA mutation determined by local or central laboratory testing
  • Disease progression on or after prior treatment, including a CDK4/6 inhibitor. Patients could have had no more than two previous anticancer therapies and no more than one previous chemotherapy regimen in the advanced or metastatic setting


Patients were assigned to one of three cohorts based on their most recent therapy:2,3


  Cohort A Cohort B Cohort C
Most recent prior therapy Any CDK4/6i plus aromatase inhibitor (AI) CDK4/6i plus fulvestrant Patients who failed prior AI-based therapy and most recently received systemic chemotherapy or endocrine therapy
Treatment received PIQRAY® (300 mg orally, once daily) plus fulvestrant (500 mg intramuscularly on Day 1 of each 28-day cycle and Day 15 of Cycle 1)

PIQRAY® (300 mg orally, once daily) plus letrozole* (2.5 mg orally, once daily)

Men and premenopausal women also received goserelin (3.6 mg by injectable subcutaneous implant, once every 28 days) or leuprolide (7.5 mg by injectable intramuscular depot, once every 28 days)

PIQRAY® (300 mg orally, once daily) plus fulvestrant (500 mg intramuscularly on Day 1 of each 28-day cycle and Day 15 of Cycle 1)

*PIQRAY® is not indicated for use in combination with letrozole.

Treatment crossover between cohorts was not permitted in this study.

This study reported results from Cohort A (data cut-off: December 17, 2019).2


cohort-a-study flowchart

Figure adapted from Rugo et al. 2021.2


Primary endpoint2 Secondary endpoints2
  • Assess the proportion of patients who were alive without disease progression at 6 months based on local investigator assessment as per RECIST v1.1 criteria
  • Analysis of the primary endpoint was to be performed separately for each cohort
  • Progression-free survival based on local investigator assessment
  • Progression-free survival after next-line treatment
  • Overall response based on local investigator assessment
  • Clinical benefit rate based on local investigator assessment
  • Duration of response
  • Overall survival
  • Safety and tolerability


Baseline characteristics of Cohort A2

Characteristic PIQRAY® + fulvestrant (n=127)
Median age, years (range) 58 (48–65) 
Caucasian, n (%) 81 (64)
Asian, n (%) 12 (9)
Other,* n (%) 34 (27)
ECOG performance status
0, n (%) 79 (62)
1, n (%) 41 (32)
2, n (%) 2 (2)
Missing 5 (4)
Metastatic sites
Breast metastasis, n (%) 5 (4)
Visceral site  
    Lung metastasis, n (%) 43 (34)
    Liver metastasis, n (%) 59 (46)
Bone-only disease, n (%) 24 (19) 
Lines of previous endocrine therapy in the metastatic setting
0, n (%) 15 (12)
1, n (%) 98 (77)
2, n (%) 14 (11)
Endocrine resistance status
Primary resistance, n (%)  26 (21)
Secondary resistance, n (%) 76 (60)
Endocrine sensitivity, n (%) 1 (1)

Table adapted from Rugo et al. 2021.2

*Includes black, pacific islander and other races as well as patients with race missing or unknown.2
Ten patients received a CDK4/6 inhibitor in the adjuvant setting, three patients in the neoadjuvant setting, and one patient in the palliative setting. One patient received medication in the metastatic setting, but was classified as having received zero lines of previous medical therapy in the metastatic setting due to inappropriate regimen coding.2
If sufficient data were not available to determine endocrine status, patients were not coded.2 


BYLieve study profile2

Treatment continued until:

  • Disease progression
  • Unacceptable toxicity
  • Death
  • Discontinuation from study treatment due to any other reason

For patients unable to tolerate PIQRAY® due to adverse events, a maximum of two dose reductions of PIQRAY® were allowed (dose level –1 250 mg/day; dose level –2 200 mg/day).


  • Using a data cut-off date of 17 December 2019, data for Cohort A are available
  • The primary analysis was performed for the modified full analysis set (mFAS), defined as all subjects in Cohort A with a PIK3CA mutation confirmed by a Novartis-designated central laboratory who received one dose of study treatment (n=121)2,3

Progression-free survival2

PIQRAY® + fulvestrant is an active treatment option for patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in the post-CDK4/6 inhibitor plus aromatase inhibitor setting



Figure adapted from Rugo et al. 2021.2

Censoring date was date of last adequate tumour assessment before the cut-off date. Censoring is shown with circles.2

In the modified full analysis set, median progression-free survival per local investigator assessment of patients in Cohort A was 7.3 months (95% CI 5.6–8.3).1,2



*121 of 127 patients in Cohort A had a centrally confirmed PIK3CA mutation (modified full analysis set).

SOLAR-1 was the first Phase III trial of PIQRAY® + fulvestrant in patients with HR+/HER2– advanced breast cancer harbouring a PIK3CA mutation.4,5

SOLAR-1 study design5

A randomised, double-blind, placebo-controlled, multicentre, Phase III trial in HR+/HER2− patients with advanced breast cancer. A total of 572 patients were enrolled in the trial, including 341 patients whose tumour harboured a PIK3CA mutation. These patients were randomised to receive either PIQRAY® + fulvestrant or placebo + fulvestrant.

A total of 231 patients with PIK3CA wild-type tumours were included in SOLAR-1, and randomised to receive either PIQRAY® + fulvestrant or placebo + fulvestrant, as a separate proof-of-concept cohort. The proof-of-concept criteria for this cohort were not met, hence PIQRAY® + fulvestrant is not licensed for PIK3CA wild-type HR+/HER2– advanced breast cancer,1 and this cohort will not be discussed further.

Patients were stratified by:

  • Presence/absence of liver or lung metastases
  • Prior CDK4/6 inhibitor treatment

Diagram of the SOLAR-1 study design

aMore than 90% of patients had their mutational status identified from archival tissue.
bAt least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors [RECIST] v1.1.5
cFulvestrant given on Day 1 and Day 15 of the first 28-day cycle, then Day 1 of subsequent 28-day cycles.5


Baseline characteristics table

  • All patients (N=341) included in the table progressed on ET.

aOne man was enrolled in the PIQRAY® + fulvestrant arm. All other study participants were postmenopausal women.

bOne patient randomised to placebo was not treated.

cEastern Cooperative Oncology Group (ECOG) performance-status scores are assessed on a scale from 0 to 5, with higher numbers indicating greater disability.

dIn the PIQRAY® + fulvestrant arm there were 0 patients with 0 metastatic sites, 63 (37.3%) with 1 metastatic site, 58 (34.3%) with 2 metastatic sites and 48 (28.4%) with ≥3 metastatic sites. In the placebo + fulvestrant arm there was 1 patient (0.6%) with 0 metastatic sites, 52 (30.2%) with 1 metastatic site, 60 (34.9%) with 2 metastatic sites and 59 (34.3%) with ≥3 metastatic sites.

eIn the SOLAR-1 study, first line was defined as treatment in patients whose disease progressed ≤1 year after (neo) adjuvant ET or whose disease progressed >1 year after (neo) adjuvant ET, and who did not receive prior treatment for aBC. Second line was defined as treatment in patients whose disease progressed >1 year after (neo) adjuvant ET and while on or after one line of ET for aBC or patients with newly diagnosed aBC whose disease progressed while on or after one line of ET. Three patients (two patients in the PIQRAY + fulvestrant group and one in the placebo + fulvestrant group) were excluded because of protocol deviations.

fOne patient in the placebo group received chemotherapy for advanced disease (which was a protocol deviation).

gPrimary endocrine resistance was defined as relapse within 24 months while the patient was receiving adjuvant endocrine therapy or progression within 6 months while the patient was receiving endocrine therapy in the context of metastatic disease. Secondary endocrine resistance was defined as relapse that occurred after ≥24 months while the patient was receiving adjuvant endocrine therapy, relapse that occurred within 12 months after the end of adjuvant endocrine therapy, or progression that occurred after ≥6 months while the patient was receiving endocrine therapy in the context of metastatic disease. After enrollment began, the trial protocol was updated to exclude patients who relapsed ≥12 months after the completion of neoadjuvant or adjuvant endocrine therapy and had not been treated for metastatic disease (endocrine sensitive).

SOLAR-1 study profile5

Treatment continued until:5

  • Disease progression
  • An unacceptable level of toxic effects
  • Withdrawal of consent, loss to follow-up, or death

Primary analysis cut-off:5

  • In the PIK3CA-mutant cohort, the median duration of follow-up from randomisation to data cut-off (June 2018) was 20.0 months (range, 10.7 to 33.3)
  • At the data cut-off, in the cohort with PIK3CA-mutated cancer, the trial intervention was ongoing in 42 patients (24.9%) receiving PIQRAY® + fulvestrant and in 32 (18.6%) receiving placebo + fulvestrant

Progression-free survival5


Progression free survival graph

Figure adapted from Andre F, et al. 2019.5

This represents a 35% reduction in the risk of disease progression or death in favour of treatment with PIQRAY® plus fulvestrant.4,5

A blinded independent review supported the mPFS results for patients with PIK3CA-mutated cancer. Among patients who received PIQRAY® + fulvestrant, mPFS was 11.1 months (n=85; 95% CI: 7.3–16.8), compared with 3.7 months (n=88; 95% CI: 2.1–5.6) among patients who received placebo + fulvestrant (HR, 0.48; 95% CI, 0.32–0.71).5 

Overall survival7

Final inferential analysis of OS in the PIK3CA-mutant cohort of the SOLAR-1 Phase III clinical trial.7

OS* in patients whose tumour harbours a PIK3CA mutation

Figure adapted from André F, et al. 2021.7

*The final OS analysis was conducted using a data cut-off date of 23 April 2020.7

The median follow-up for OS, defined as the time from randomisation to OS event or censoring, was 30.8 months (0.4–53.4 months).7 

In patients with PIK3CA-mutated cancer, median OS was 39.3 months (95% CI, 34.1–44.9) in the PIQRAY® + fulvestrant arm versus 31.4 months (95% CI, 26.8–41.3) in the placebo + fulvestrant arm (HR=0.86; 95% CI, 0.64–1.15; one-sided P=0.15).7

Quality of life8

QoL outcome measures were similar in the PIQRAY® + fulvestrant arm and the placebo + fulvestrant arm

Treatment with PIQRAY® and fulvestrant showed no clinically meaningful difference in global health/QoL status or TTD in EORTC QLQ-C30 global health scale score compared with placebo + fulvestrant (HR=1.03 [0.72–1.48]).

TTD in EORTC QLQ-C30 global health status was defined as time between baseline and first occurrence of ≥10-point worsening of global health status (EORTC QLQ-C30 global health scale score) compared with baseline, with no later improvement above this threshold observed during the treatment period or death due to any cause.

aBC, advanced breast cancer; AI, aromatase inhibitor; CDK, cyclin-dependent kinase; CI, confidence interval; ctDNA, circulating tumour DNA; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment; ET, endocrine therapy; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; HR, hazard ratio;  IM, intramuscular; m, median; mPFS, median progression-free survival; NE, not estimable; OS, overall survival; PFS, progression-free survival; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PO, oral; QLC-C30, cancer health-related quality of life questionnaire 30; QoL, quality of life; TTD, time to deterioration.


  1. PIQRAY® (alpelisib) Summary of Product Characteristics. Novartis Pharma; December 2021.
  2. Rugo HS, et al. Lancet Oncol 2021;22:489–498.
  3. Study assessing the efficacy and safety of alpelisib plus fulvestrant or letrozole, based on prior endocrine therapy, in patients with PIK3CA mutation with advanced breast cancer who have progressed on or after prior treatments (BYLieve). Available at: [Accessed May 2022].
  4. Novartis press release. Available at: [Accessed May 2022].
  5. André F, et al. N Engl J Med 2019;380(20):1929−1940.
  6. André F, et al. Presented at ESMO 2018 Congress; 19−23 October 2018; Munich, Germany.
  7. André F, et al. Ann Oncol 2021:32(2):208–217.
  8. Ciruelos EM, et al. J Clin Oncol 2021;39(18):2005–2015.
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UK | May 2022 | 186027

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