Corcept Therapeutics’ Phase III trial investigating relacorilant in third-line (3L) pancreatic ductal adenocarcinoma (PDAC) drew expert pause on the forthcoming data’s clinical value. This is mostly due to the trial design lacking the trademarks of a late-phase investigation, they explained. Specifically, while the Phase III is a single-arm trial with a primary endpoint of overall response rate (ORR), it should have had a comparator arm with a clinically relevant endpoint like disease-free survival (DFS), they added.

The Phase III trial’s resemblance to an early-phase trial is good because its mechanism as a glucocorticoid receptor antagonist is yet to demonstrate clinical value in PDAC, with many mechanism blanks, experts said. The value of modulating cortisol and the way blocking glucocorticoid receptors can improve chemotherapy efficacy still needs to be understood, they added.

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The 80-patient, Phase III RELIANT trial is investigating two doses of relacorilant in combination with ­Celgene’s Abraxane (nab-paclitaxel). An analyst report notes interim data from the first 40 patients is expected 1H21. Positive Phase I/II results could support accelerated approval, according to the report. Corcept, which did not respond to a comment request, has a market cap of $3.16bn.

Phase III designed to justify mechanism, not clinical value

The Phase III relacorilant/Abraxane trial does not have the typical design elements seen in similar late-phase trials, experts said. The Phase III is a single-arm trial, but it should have had an active comparator, added Dr Richard Burkhardt, assistant professor of surgery, Johns Hopkins Hospital, Baltimore, Maryland.

There are no perfect therapeutic combinations in 3L, added Dr John Neoptolemos, professor of surgery, University of Heidelberg, Germany. However, its potential active comparators would be Ipsen’s Onivyde (irinotecan liposome) or chemotherapy combinations such as those featuring 5-fluorouracil plus oxaliplatin, Neoptolemos noted. Therapies used in 3L depend on what the patients have taken in prior lines of therapy, because PDAC patients develop resistance, said Dr Elisa Giovannetti, head, Molecular Mechanisms of Drug Activity, Department of Medical Oncology, VU University Medical Centre Amsterdam, Netherlands.

The Phase I/II is recruiting patients who have progressed from at least one prior gemcitabine-based therapy and prior fluoropyrimidine-based therapy. The 1L standard-of-care chemotherapy cocktail FOLFIRNINOX features the fluoropyrimidine-based 5-fluorouracil. In patients who progress from FOLFIRINOX, gemcitabine plus Abraxane is then considered, Neoptolemos added. Onivyde was FDA-approved in 1996 in PDAC patients who progress following gemcitabine-based therapy.

The Phase III has an ORR primary endpoint, but this measure may be inappropriate in a late-stage trial, Neoptolemos noted. ORR is used as a primary endpoint in early-phase trials because it can provide quick information about whether or not the drug under investigation offers some degree of efficacy for the asset to move to a later, riskier phase, Burkhardt said. In an early-phase trial, any signal in the ORR endpoint is ideal for further exploration, particularly with a new mechanism, added Dr Carlos Fernández-del Castillo, director, Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Boston.

In a Phase I/II trial (NCT02762981) investigating relacorilant/Abraxane recruiting both ovarian cancer and PDAC patients, data show four out of 25 PDAC patients report having partial response, eight have stable disease (SD), and 13 have progressive disease (PD), according to a poster presented at the 2019 American Society of Clinical Oncology (ASCO) annual meeting (abstract no. 4130). Based on these results, it is unclear how relacorilant/Abraxane would perform in later stages, Neoptolemos said. In ORR, the patient is classified as PD if the PDAC shrinks by 25%, and there is therapeutic response if it reduces by 50%, he explained. If the tumour is within this range, the patient is classified as having SD, he added.

The limitation of ORR, particularly for use in a Phase III trial, comes from it being a flawed measure of finding out whether the tumour has shrunk, Neoptolemos said. The patient could have edema, where the tumour is surrounded by fluids, which obscures accuracy in measuring tumour size, he noted, adding this can make it hard to distinguish between cancer and noncancer.

In the Phase III, perhaps a better endpoint would have been DFS to more clearly show the therapy’s impact on the disease, and to allow insight into how long the patient progresses, Neoptolemos said. It is better to use overall survival (OS) as an endpoint in the 1L setting, as in the later lines the patient already has recurrent disease, he added. However, DFS might be better suited in the adjuvant setting as there is no evidence of disease, Burkard noted. DFS is not an endpoint the Phase I/II and Phase III trials.

Experts noted it is challenging to succeed in the 3L PDAC setting. In general, 30% of all PDAC patients are older, have advanced disease, or have comorbidities by the time they take 1L therapies, Neoptolemos said. This means palliative care might be the best option even at this early stage, he explained. While the 3L market is smaller, it is still notable as patients quickly progress from 1L and 2L, Burkard added.

Mechanism still has many question marks

Relacorilant is a cortisol modulator. It functions by binding to the glucocorticoid receptor. Still, any receptor blockade mechanism is yet to draw enthusiasm in PDAC, Burkhardt said.

Modulating cortisol has been shown to be an immunosuppressor, as evidenced by various preclinical research showing cortisol stands in the way of immunotherapy, added glucocorticoid researcher Dr Onno Meijer, professor, Division of Endocrinology, Leiden University Medical Centre, the Netherlands. Immunotherapy does not work in pancreatic cancer as the tumour microenvironment is very immunosuppressive, Burkhardt said. However, it is still unclear how cortisol is an immunosuppressor in cancer, Meijer noted.

Glucocorticoid receptors have been theorised to lead to chemotherapy resistance, Neoptolemos said. Corcept has in vivo data in pancreatic cancer showing relacorilant restores sensitivity to paclitaxel in a xenograft model, the ASCO poster shows. However, there is limited information available to fully establish this link, Neoptolemos added. Relacorilant could potentiate chemotherapy but it is still ambiguous if it does so via immune-potentiation or via signalling pathways in the tumour, Meijer noted.

More clarification is needed about whether relacorilant targets the glucocorticoid receptors in the immune system or others in the tumour or both, Meijer added. The Phase III trial does not measure patient receptor levels. There may be a spectrum of sensitivity to different people with relacorilant’s mechanism, he said. Due to the high unmet need in this space, younger, relatively fitter patients are recruited in clinical trials, so trials would typically be designed to search for biomarkers, Giovannetti explained.

Glucocorticoid receptors have not shown concerning mechanism-specific side effects so far, Meijer said. In theory, they could lead to Addisonian-like crisis, but this is yet to be seen, he added. The inability to increase cortisol production with stress causes an Addisonian crisis. In the Phase I/II basket trial with Abraxane, the most common treatment-emergent Grade 3 or higher adverse events were neutropenia, abdominal pain, anaemia, and hyponatremia, among others.

Relacorilant is in the most advanced stage in development in PDAC, with the asset also under investigation in ovarian and castration-resistant prostate cancers, as well as in adrenocortical cancer with glucocorticoid excess. Prostate cancer is driven by the androgen receptor, which is comparable with glucocorticoid receptors, Meijer added. At some point, the glucocorticoid receptor takes over the androgen receptor as the driver of cancer, he said. In adrenal cancer, it is surrounded by cortisol, he noted.

Reynald Castaneda is Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.