Alpelisib Plus Olaparib in Platinum-resistant/Refractory, High-grade Serous Ovarian Cancer, With no Germline BRCA Mutation Detected

This study will include adult women with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected. Participants will be randomized in a 1:1 ratio to either alpelisib plus olaparib or single agent cytotoxic chemotherapy (paclitaxel or PLD) in this open-label, active controlled study.

Participants will continue to receive study treatment until disease progression, unacceptable toxicity that precludes further treatment, or until discontinuation of study treatment due to any other reason. After treatment discontinuation, all participants will enter in the post-treatment follow-up period, which consists of a safety follow-up visit and a 9-week post-progression visit. Once they complete the post-treatment follow-up, participants will then enter the survival follow-up period.

Primary Outcome Measures

1. Progression Free Survival (PFS) based on Blinded Independent Review Committee (BIRC) assessment using RECIST 1.1 criteria
   Progression-free survival (PFS) was defined as the time from randomization until the first documented disease progression or death from any cause, based on BIRC assessment. Participants without an event were censored at the date of their last adequate tumor assessment. Clinical deterioration without objective radiologic evidence was not considered disease progression in the primary efficacy analysis.

Secondary Outcome Measures

1. Overall survival
   Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive
2. Overall Response Rate (ORR) with confirmed response based on BIRC assessment according to RECIST 1.1 criteria
   Overall response rate (ORR) with confirmed response was defined as the percentage of participants whose best overall response (BOR) was a confirmed complete response (CR) or confirmed partial response (PR), as determined by BIRC according to RECIST 1.1 criteria.
3. Clinical benefit rate (CBR) with confirmed response based on BIRC assessment according to RECIST 1.1
   Clinical benefit rate (CBR) with confirmed response was defined as the percentage of participants whose best overall response was a confirmed CR or PR, or stable disease (SD) maintained for at least 24 weeks. CR, PR, and SD were determined by BIRC according to RECIST 1.1 criteria.
4. Time to response (TTR) based on BIRC assessment and according to RECIST 1.1
   Time to response (TTR) was defined as the interval from randomization to the first documented occurrence of either complete response (CR) or partial response (PR), which was subsequently confirmed (using the date of initial response, not the confirmation date). CR and PR were determined based on tumor response data assessed by BIRC according to RECIST 1.1 criteria.
5. Duration of response (DOR) with confirmed response based on BIRC assessment and according to RECIST 1.1
   Duration of response (DOR) with confirmed response was calculated only for participants whose best overall response was a confirmed complete response (CR) or confirmed partial response (PR), based on tumor response data assessed by BIRC according to RECIST 1.1. The start date was the date of the first documented CR or PR (i.e., the initial response date, not the confirmation date), and the end date was the date of first documented disease progression or death due to underlying cancer. Participants without progression or cancer-related death were censored at the date of their last adequate tumor assessment.
6. Time to definitive deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status (PS)
   Performance status (PS) was evaluated using the ECOG scale, which comprises six grades (0 to 5), where 0 represents fully active and 5 represents death. Time to definitive deterioration in ECOG PS was defined as the interval from randomization to the date when ECOG PS worsened by at least one category from baseline and remained worsened. Deterioration was considered definitive if there was no subsequent improvement to the baseline category or better. Participants were censored if no definitive deterioration occurred before the earlier of: (i) the analysis cut-off date or (ii) initiation of a new anti-neoplastic therapy. The censoring date was the date of the last PS assessment prior to the cut-off or start of new therapy.
7. Number of participants with dose interruptions and dose reductions
   The number of participants with dose reductions/interruptions was assessed and summarized by study treatment.
8. Dose intensity
   Dose intensity was computed as the ratio of actual cumulative dose received to actual duration of exposure and summarized by study treatment.
9. Area under the curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) of alpelisib and olaparib
   The AUCtau will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
10. Area under the curve from time zero to the last measurable concentration sampling time (AUClast)of alpelisib and olaparib
    The AUClast will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
11. Maximum Concentration (Cmax) of alpelisib and olaparib
    The Cmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
12. Time to reach maximum concentration (Tmax) of alpelisib and olaparib
    The Tmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
13. Change from baseline in Function Assessment of Cancer Therapy-Ovarian Trial Outcome Index (FACT-O TOI)
    The Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) combines scores from Physical Well-Being (PWB), Functional Well-Being (FWB), and the Ovarian Cancer Subscale (OCS). Each item is rated on a 0-4 Likert scale (0 = 'Not at all', 4 = 'Very much'). The TOI score is the sum of these subscales and ranges from 0 to 100, with higher scores reflecting better quality of life and physical/functional status. A positive change from baseline indicates improvement in physical/functional well-being and ovarian cancer-specific symptoms, while a negative change indicates deterioration in these domains.