Concordance between disease progression by Cancer Antigen 125 and computerized tomography (CT) progression in patients with relapsed advanced ovarian cancer treated with poly(adenosine diphosphate [ADP]–ribose) polymerase inhibitor: a pooled analysis

Lead Investigator: Angelina Tjokrowidjaja, University of Sydney
Title of Proposal Research: Concordance between disease progression by Cancer Antigen 125 and computerized tomography (CT) progression in patients with relapsed advanced ovarian cancer treated with poly(adenosine diphosphate [ADP]–ribose) polymerase inhibitor: a pooled analysis
Vivli Data Request: 7156
Funding Source: None
Potential Conflicts of Interest: Dr. Lee reports: Previous honoraria and research funding from AstraZeneca – both for separate research projects. This will be managed with CoI disclosure and non-involvement of the company in findings and manuscript preparation.

Summary of the Proposed Research:

Women with relapsed advanced ovarian cancer are typically treated with chemotherapy. After completing chemotherapy, these women are usually followed up with blood tests, including the tumour marker Cancer Antigen 125 (CA-125). Computerized tomography (CT) scans are usually triggered when the CA-125 rises or doubles, or if women experience symptoms suggesting that the cancer has returned.

In recent years, PARP inhibitor therapy following chemotherapy has improved outcomes for certain groups of women with advanced ovarian cancer and is now widely used. PARP inhibitor therapy block PARP enzymes in cancer cells. PARP enzymes help repair DNA damage. Blocking PARP enzymes prevent cancer cells from repairing DNA damage and as a result, these cancer cells die. However, there is limited knowledge on the best way to monitor women on PARP inhibitor therapy. The studies of PARP inhibitor therapy used regular CT scans to detect cancer progression but in clinical practice, these women are usually followed up with blood tests, including CA-125, and CT scans are only performed when the CA-125 rises or there are symptoms of concern.

We analysed whether CA-125 is a reliable marker for cancer progression as detected by CT by using the data from the SOLO2/ENGOT-Ov21 clinical trial. We found that doubling of CA-125 reliably predicts for cancer progression as detected by CT. However, we found a considerable proportion of patients with a normal CA-125 still experience cancer progression as seen on a CT scan. Our findings raise the question of whether we need to consider regular CT scans in women treated by PARP inhibitor therapy. Detecting cancer progression is important to avoid unnecessary side effects and consider alternative treatment options for these women.

It is important to confirm our findings by pooling data from other studies of women with advanced ovarian cancer treated with PARP inhibitor therapy. Pooling data from other studies allows us to assess the reliability of CA-125 in determining cancer progression with more certainty and in a broader group of women. Our work has the potential to change existing guidelines and improve on the way we monitor women treated with PARP inhibitor therapy.

Statistical Analysis Plan:

Unpublished summary data for disease progression (PD) by Response Evaluation Criteria in Solid Tumors (RECIST) and Cancer Antigen 125 (CA-125) PD by GCIG criteria provided by the study sponsors will be sought. For each trial, we will compare data on investigator-assessed tumour PD by RECIST and CA-125 PD by GCIG criteria as the primary analysis. Blinded independent central review (BICR) RECIST assessment will be used as sensitivity analysis. We will also perform a sensitivity analysis to assess for heterogeneity among the patient characteristics by matching the SOLO2 data to NOVA and ARIEL, stratified according to response to last prior platinum chemotherapy and ECOG status, and proceeded to pooled analysis if the concordance was similar for both matched and unmatched data.

To determine the concordance between CA-125 PD and RECIST PD, we will categorize patients into the following 4 groups:

1. CA-125 and RECIST non-PD concordant (i.e. participants without PD by both GCIG CA-125 and RECIST);
2. CA-125 and RECIST PD concordant (i.e. participants with both Gynecologic Cancer InterGroup (GCIG) CA-125 and RECIST PD);
3. CA-125 PD and RECIST non-PD discordant (i.e. participants with GCIG CA-125 PD but not RECIST PD); and
4. CA-125 non-PD and RECIST PD discordant (i.e. participants with RECIST PD but without GCIG CA-125 PD).

We will summarize baseline categorical variables as frequency (percentage) and continuous variables as median interquartile range (IQR). To assess the concordance of CA-125 PD with RECIST PD, we computed the positive predictive value (PPV), which is defined as the probability that patients with CA-125 PD also had RECIST PD; and the negative predictive value (NPV), defined as the probability that patients without CA-125 PD also did not have RECIST PD.

Amongst those with RECIST PD but normal CA-125 measurements, we will further subdivide into (i) ‘rising CA- 125’ (CA-125 at time of RECIST PD >50% baseline); (ii) ‘stable CA-125’ (CA-125 within the range of up to 15% below and 50% above baseline); or (iii) ‘falling CA-125’ (CA-125 < 15% below baseline). We will display the CA-125 values of these three groups as spider plots and summarize the median (IQR). We will also subclassify RECIST PD as ‘early PD’ (<=12 weeks after randomisation) or ‘late PD’ (>12 weeks), and compare the concordance separately in these two groups.

Requested Studies:

Assessment of Efficacy of AZD2281 in Platinum Sensitive Relapsed Serous Ovarian Cancer
Data Contributor: AstraZeneca
Study ID: NCT00753545

Public Disclosures:

Tjokrowidjaja, A., Friedlander, M.L., Ledermann, J.A., Coleman, R.L., Mirza, M.R., Matulonis, U.A., Pujade-Lauraine, E., Lord, S.J., Scott, C.L., Goble, S. and York, W., 2024. Poor Concordance Between Cancer Antigen-125 and RECIST Assessment for Progression in Patients With Platinum-Sensitive Relapsed Ovarian Cancer on Maintenance Therapy With a Poly (ADP-ribose) Polymerase Inhibitor. Journal of Clinical Oncology, JCO-23. Doi: 10.1200/JCO.23.01182