Advertisement

Topics

BioWatch News - Corcept Therapeutics - Ovarian Cancer Program - ASCO 2019 Primer

20:09 EDT 16 May 2019 | Biotech Watcher

Introduction

Corcept Therapeutics (CORT) and the University of Chicago have launched several early-& mid-stage solid-tumor trials. Many tumors utilize the GR-pathway to enable treatment-resistance. Corcept’s GR-blocking drugs remove this avenue of escape, and restore the original, pre-resistance efficacy.

Corcept’s drugs target difficult-to-treatcancers, although “difficult” understatesthe situation. These include:

Triple-negative Breast Cancer
Multiple-relapsed Pancreatic Cancer
Platinum-resistant Ovarian Cancer

Corcept is pairing its relacorilantwith Celgene’s Abraxane. It has two relevant cancer trials:


Corcept investigators will present updated ovarian and pancreatic results from its Phase 2a trial in solid tumors on Monday morning, June 3, 2019 as the Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, IL. The study is in good hands.

You can already find online introductionsto ovarian cancer. We will review Corcept’s ovarian cancer program and prep for evaluating its upcoming ASCO results.

Earlier Results


Responses and High GR+ Immunohistochemistry (IHC)





GR IHC
Cancer
Type
Prior
Taxane
Time to
Progression
(Days)
RECIST
(CR, PR, SD, PD)
Dose:
Rela / Abrax
% GR+
Cells
% at 2+ or above
H-Score
Ovarian
Y
294a
SD
200/100
100
100
300
Ovarian
Y
119a
SD
150/80
100
100
290
Ovarian
Y
196a
CR
100/80
95
80
225
aPatient was still in study and hadn’t yet progressed.

In a recent pilot study of relacorilant + Abraxane, Corcept reported 4 of 7 ovarian cancer patients responded with durable disease control (CR, PR, or SD). There was 1 CR and 1 PR. Furthermore, all patients had aggressive metastatic disease and taxane-resistance. These patients were difficult to treat with several prior lines of therapy. Patient response appears stronger for the segment with high GR++. The other 4 ovarian cancer patients had lower GR tumor expression.

Ovarian Cancer Response by GR IMC

GR IHC
Complete Response
Partial Response
Stable Disease
Progressive
Disease
High
1
0
2
0
Other
0
1
0
3

While the sample size is small, it is still impressive. The times to progression and response rate are eye-catching. These compare well to the response rate for 4th and 5th-line, platinum-resistant, taxane-resistant patients: which we guesstimated into the single-digit percentages. We also said that the typical time to progression was within weeks, not months.

ASCO Forecast


We expect the updated results will be similar. This dataset will be included.

We’re unsure whether there will be a straight-line extrapolation: it’s unreasonable to expect every patient to have stable disease or better. This is a notably treatment resistant group. Nevertheless, the ongoing data had to be promising or else Corcept would not have launched a subsequent trial.

Ovarian Cancer Trial


Corcept launched an open-label, randomized, and controlled, Phase 2 trial of relacorilant plus Abraxane in metastatic, platinum-resistant ovarian cancer(and fallopian tube and peritoneal cancer). As with Corcept’s other cancer targets, this is an extraordinarily difficult treatment situation.


Ovarian Cancer Program
Relacorilant + Abraxane - 177 pts with platinum resistant cancer
TBA
Relacorilant + Abraxane - 177 pts with platinum resistant cancer
Q2-2023*

Study Design


Patients are randomized 1:1:1 to one of the three treatment arms. Patient randomization is stratified by the: 1) treatment-free interval from the most recent taxane including Abraxane (< 6 months versus ≥ 6 months) and; 2) presence of ascites.[1]

Arm A (Continuous): Relacorilant 100mg, once daily in combination with Abraxane.
Arm B (Intermittent): Relacorilant 150mg, administered on the day before, the day of, and the day after Abraxane on Days 1, 8, and 15 of each 28-day cycle.
Arm C (Comparator): Abraxane treatment only.

Patients in Arm Cwith definite progressive disease are offered the full treatment.

Endpoints


The primary endpoint is Progression-Free Survival (PFS).
The secondary endpoints include: Response Rate; Response Duration; Overall Survival.

Patients


177 patients with recurrent, platinum-resistant cancer. All had prior platinum therapy with persistent disease or disease progression. As before, we expect most patients to have failed two or more prior therapies.

Intellectual Property


The composition of matter patents protects Corcept’s drugs. There are many new glucocorticoid receptor drugs being developed. The combination of Use Patents with Composition of Matter Patents is important, as well as other forms of protection (e.g. Hatch-Waxman, Orphan). With ovarian cancer, Corcept’s main protection will arise from its composition of matter patents that cover its drugs.

Use Patent Application


We have our doubts that Corcept can file a use patent onto ovarian cancer alone, but we are happy to be wrong. It filed a patent application that might cover metastaticovarian cancer and certainly cervical cancer.


Composition of Matter


The following intellectual property covers the two most applicable Corcept drugs for treating ovarian cancer: relacorilant and CORT125281.

CORT125134 is a Heteroaryl-Ketone Fused Azadecalin glucocorticoid receptor drug with awide range of applications. CORT125281 is an example of an Octahydro Azadecalin glucocorticoid receptor drug, with potential for treating cancer.

This should protect against potential generics arising from 2032 to 2037. If the patent applications are granted, then relacorilant and CORT125281 should be protected until 2038.

Patents



Patent Applications



Ovarian Cancer Treatment Review


Platinum Resistant Ovarian Cancer


Epithelial ovarian cancer (EOC) is the most common type, with the combined 5-year survival for all stages around 45%. Between 55% to 75% of responders to first-line therapy experience relapse within two years.

1. Platinum sensitivity (or resistance) largely determines progression-free (PFS) and overall survival (OS). The incumbent 1st-line treatment is primary surgery followed by platinum-based chemotherapy. Paclitaxel is the oft-chosen partner for carboplatin.

2. Treating platinum-resistant patients is tough: the response rate is 10% to 15%, and average overall survival is only 12 months.[2]The holy grail is to increase efficacy without acquiring overwhelming toxicity.[3]

3. 3rd-line chemotherapy yields a response rate of ~12%, although this may include a few platinum sensitive patients. In Corcept’s case, most patients will be on 4th and 5th line chemotherapy. The usual response rate is in the low-single digits (i.e. < 5%). The progression-free survival (PFS) will be tiny. Even for 2nd-line therapy, the median PFS for platinum-resistant patients is only 4 to 6 months.[4]

4. In recurrent platinum-resistant or refractory EOC, sequential single-agent salvage chemotherapy is superior to multiagent chemotherapy. Multiagent regimens increase toxicity without clear benefit; however, no preferred sequence of single agents is recommended.[5]Single-agent options includes: paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan.

Targeted Therapies


First, Targeted therapies are largely dismal failures. Except for one agent, their addition to the incumbent 1st-line therapy has not helped.[6]

Second, Avastin (bevacizumab) has shown the most promise with improved PFS and response rate in the recurrent, platinum-resistant setting.[7]This efficacy suggests that late-stage ovarian tumors have well-incorporated angiogenesis.

In June 2018, Avastin was approved for front-line therapy for ovarian cancer:
Avastin + carboplatin + paclitaxel…followed by
Avastin monotherapy

Third, PARP inhibitors have created improved PFS and a positive trend for OS in BRCA-mutated, platinum-sensitive patients. This however says little about its efficacy for resistantpatients.

Fourth, the checkpoint inhibitors have brought improvements that are “modest at best”. [8]

Corcept seeks to provide an effective treatment, by targeting GR++ resistant ovarian cancers.

The Case for Anti-Glucocorticoid Therapy


We summarized the readings into a few bullet points.

- Dysregulated glucose uptake increases proliferation and metastatic processes.[9]It’s no surprise that metformin increases survival in type 2 diabetics with ovarian cancer.[10]First, this immediately points to relacorilant’s ability to dampen hyperglycemic processes.

- Abnormal daily cortisol rhythms relate to decreased survival and increased inflammation around the tumor. Second, relacorilant is among Corcept’ss drugs that reset the abnormal rhythm into normalcy.[11]

- GR receptor activation upregulates anti-apoptotic processes (death prevention) in ovarian cancer cells. Third, relacorilant restored death in a xenograft model of GR+ ovarian cancer.[12]

Cancer Treatment Milestones


Corcept Sponsored Trials
Cancer Program Comments

Cortisol modulation may play a role in treating solid tumors through two mechanisms.

First, in cancers where the tumors express GR, such as pancreatic, triple negative breast, and ovarian cancer, cortisol stimulates genes that retard apoptosis– the programmed suicide of dysfunctional cells.

Chemotherapies aim to provoke apoptosis, but cortisol is an opposing force.

Corcept’s drugs should reverse and downregulate the “apoptosis suppressing genes”.This restores chemotherapies’ original impact.

Second, cortisol modulation may help the immune system fight cancer. A healthy body regularly produces cancer cells, but the immune system identifies and destroys them.Even at normal levels, cortisol suppresses the immune system. Unfortunately, the stress of cancer and its treatment raise cortisol activity above normal levels and creates even greater immunosuppression. Cortisol modulators counter this effect by mitigating cortisol’s effects, thus freeing the immune system to act more potently.

Corcept’s oncology program builds on preclinical and clinical research at the University of Chicago and confirmed by researchers at Sloan Kettering. There is robust interest in immune system modifiers to fight cancer. Corcept’s drugs additionally have a mild side effect profile. This makes for strong combination therapy candidates.
Solid Tumors
CORT125134 (relacorilant) is in a Phase I/II trialto treat solid tumors including breast and ovarian cancer. In the Phase I part, CORT125134 is paired with Abraxane. Dose cohorts are employed to seek the maximum tolerated dose (MTD).

Corcept expects to open additional expansion cohorts in patients with other tumor types, most likely ovarian and triple-negative breast cancer in 2018. Corcept is opening a cohort of pancreatic cancer patients. Given the preclinical animal results, we aren’t surprised.

Relacorilant has shown potential. Besides lacking a couple side effects associated with Korlym, the animal models andearly clinical datafor treating solid tumors looks good, especially for pancreatic and ovarian cancers.

Relacorilant appears to perform better than Korlym in mouse models of TNBC and castration-resistant prostate cancer. It also demonstrated good results with ovarian cancer cells in the lab. It is like Korlym but lacks some of its side effects.
Ongoing Ib Results –Relacorilant (100 mg/ daily) +
Abraxane (80 mg/m2) - 20 Patients with Pancreatic Cancer
ASCO 2019
Early June
Phase IIa Results – Expansion Cohorts (~24 pts per Cohort)
TBA
Ovarian Cancer
Corcept is launched an open-label, randomized and controlled, Phase 2 trial of relacorilant plus Abraxane in metastatic ovarian cancer. The primary endpoint is progression-free survival in patients with recurrent platinum-resistant cancer.

Platinum-resistant ovarian cancer patients are randomized 1:1:1 to one of three treatment arms. Patient randomization will be stratified by treatment-free interval from most recent taxane (<6 months="" vs="">/=6 months) and presence of ascites (yes vs no).
Arm A (Continuous): Relacorilant 100mg, administered orally, once daily every day starting on Cycle 1, Day -7 in combination with nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle.
Arm B (Intermittent): Relacorilant 150mg, administered orally, on the day before, the day of, and the day after nab-paclitaxel, starting on Cycle 1, Day -1, in combination with nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle.
Arm C (Comparator): Abraxane on Days 1, 8, and 15 of each 28-day cycle.

Patients in Arm C with definite progressive disease may be later offered relacorilant + Abraxane. Platinum resistant ovarian cancer has a tough prognosis: the response rate is 10% to 15%, and overall survival is only 12 months. For this trial, the expected length could be even shorter. The holy grail is to increase efficacy without overwhelming toxicity.

In the previous Phase 1b trial of relacorilant + Abraxane, 4 of 7 ovarian cancer patients had durable disease control (CR, PR, or SD). There was 1 CR and 1 PR. Furthermore, all patients had aggressive metastatic disease and were taxane-resistant.
Relacorilant + Abraxane - 177 pts with platinum resistant cancer
TBA
Relacorilant + Abraxane - 177 pts with platinum resistant cancer
2023
Prostate Cancer
CEO Belanoff mentionedexicorilant(CORT125281) stood out with treating rodent models of prostate cancer including castrated animals. There will be close attention from the cancer community on trialsinvolving GR antagonists for treating prostate cancers that are resistant to enzalutamide and abiraterone.

This trial pairs exicorilantwith enzalutamide(Xtandi)to treat 80 mCRPC (metastatic, castration-resistant prostate cancer) patients. The study aims to find the maximum tolerated dose (MTD) of the combination therapy. One cohort of patients progressed on prior treatment with enzalutamide or other advanced AR-blocking therapies.
Phase 1/2a Ongoing ResultsExicorilant+ Xtandi
Dose Escalation - 80 Metastatic Castration Resistant (Open Label)
Q4-2019?
Decision to Green Light a Phase 2b Trial
Q4-2019
Phase 1/2a Final ResultsExicorilant+ Xtandi – Dose Escalation
80 Metastatic Castration Resistant Prostate Cancer (Open Label)
Mid-2021*
Pancreatic Cancer Program

In the ongoing Phase 1b trial of relacorilant + Abraxane, 4 of 9 pancreatic cancer patients had durable disease control with a partial responder having progressed earlier on Abraxane combination therapy. Furthermore, all patients had aggressive metastatic disease and were taxane-resistant. Responders tended to have high GR expression.

A hypothesized pivotal trial will recruit a very tough group of patients: we think many, if not most, patients will be abraxane-resistant. We also think this will be the first major study involving several patients with 3+ prior lines of therapy. This is a test of Corcept’s drugs for fighting GR++ resistant cancer. It doesn’t get much tougher than this.
Phase 2b Trial Decision
Relacorilant + Abraxane (Pancreatic Cancer)
ASCO 2019
Early June
*Guesstimate

Independent Investigator Sponsored Trials
Advanced GR+ Triple Negative Breast Cancer
Patients are treated in a randomized, double-blinded, placebo-controlled design.
Phase II Results(University of Chicago) (64 pts)
Korlym + Abraxane
Q4-2019
Advanced HER2-negative Breast Cancer & Checkpoint Inhibitor
The open-label study will include a safety lead in of ten patients. Patients who are deemed eligible and have signed informed consent will be treated with pembrolizumab(Keytruda) at a fixed dose of 200 mg intravenously on day 1 of each 21-day cycle for each dose level. Mifepristone 300mg PO will be administered daily starting the week prior to pembrolizumab.

Pembrolizumab is an approved anti-PD-1 mAb, marketed by Merck.

The first cohort of 10 patients will be evaluated for safety (Phase 1). During dose expansion, the study will include triple-negative breast cancer patients. After successful Phase 1 safety is passes, then both cohorts will be subjected to dose expansion.
Cohort 1: Hormone receptor positive, treatment refractory breast cancer (25 to 34 pts)
Cohort 2: Triple Negative breast cancer (27 to 40 pts)
Pembrolizumab + Mifepristone - (University of Chicago) (74 pts)
Q4-2020*
Prostate Cancer

Mifepristone Study

Patients are given Xtandi vs. Xtandi + Mifepristone. While these patients failed prior therapy, they are naïve to 2nd generation AR antagonists (Xtandi, AR509).

The University of Chicago investigators are often slow to release results. The results are presented at an academic conference.

Relacorilant Study

In the other study, relacorilant is combined with Xtandi to treat metastatic castration resistant prostate cancer (mCRPC) in an open-label design. Enrolled patients will have prior treatment with at least one line of enzalutamide (Xtandi), apalutamide (Erleada), or abiraterone (Zytiga).

24 patients will be enrolled in 6 patient cohorts with a 6+3 design and a 28-day DLT period. Doses of relacorilant, enzalutamide will be adjusted based on safety and pharmacokinetics (PK). Once a safe dose with appropriate drug levels (PK) has been established, the cohort will be expanded to a total of 12 patients to refine safety and PK at the recommended phase II dose (RP2D).
Xtandi ± Mifepristone - (University of Chicago) - 108 pts
1H-2020*
Xtandi + Relacorilant – (University of Chicago) – 24 pts
Mid-2020*
Advanced Non-Small Cell Lung Cancer
This is an open-label design, in patients with metastatic NSCLC who have failed 2+ prior chemotherapies. Mifepristone as a monotherapy must increase the median progression-free survival time past 15 weeks and overall survival > 16 months. We are queasy because we do not view Corcept’s drugs as monotherapies for treating cancer.
Phase II Top-line Results(Cooper Institute) (40 Pts)
300mg/day in 28-day cycles
Q4-2019*

Our Thoughts


The early results showed that 4 of 7 ovarian cancer patients had durable disease control (CR, PR, or SD), including 1 CR and 1 PR. Furthermore, all patients had aggressive metastatic disease and were taxane-resistant with several prior lines of therapy. It is hard to imagine a more difficult group. These results are incorporated into the upcoming presentation for ASCO 2019; additional ovarian cancer patients were recruited into the ongoing solid tumors trial.

Thinking about ASCO 2019


First,the pilot study signaled a strong thumbs up. This was consistent with earlier lab, animal, and clinical resultsfor Corcept’s drugs.

Second, the results must signal no red flags, or else Corcept would not have launched the new trial. We expect the durable control rate to be like the early results, especially since these are incorporated into the updated ASCO presentation

Third, the response rate and OS for platinum-resistant patients: 10% to 15%, and 12 months. That’s for 2nd-line therapy. The baseline comparisons for Corcept’s patients are lower. That’s because it has many patients undergoing their 3rd or 4th course of therapy and may be also resistant to taxanes. This translates to a response rate under 5% and a PFS that is counted in weeks, not months.

Thinking about the New Ongoing Phase 2 Trial


The patients in the new ovarian cancer trial are extraordinarily tough to treat. If relacorilant works here or with pancreatic cancer, then you can just about believe anything about Corcept’s drugs with cancer.

If the results in the new trial mimic what was seen in the pilot results in 2018, then it raises an interesting question: can Corcept file for early approval? It depends upon the future market landscape. If it’s still as dismal as today, we believe this to be the case.

(At the time this was written, one or more BioWatch authors held a long position in CORT)

This blog post is from The Biotech Watcher:



[1]Ascitesis the build-up of abdominal fluid due to the spread of cancer cells into the peritoneal lining. The presence of ascites implies a poorer prognosis.
[2]The response rates vary and may reflect differing definitions for platinum resistance. The Oronosky et al. (2017) articles says the 2nd-line chemotherapy response rates ranged from 6% to 30%.
[3]Many studies focus on platinum-resistance, not prior tries at chemotherapy. We think it makes a difference. The response rate and PFS are abysmal for 4th- and 5th-line resistant patients.
[4]Bruchim I, et al. (2013) Advanced (>second) line chemotherapy in the treatment of patients with recurrent epithelial ovarian cancer. European Journal of Obstetrics & Gynecology and Reproductive Biology, 166, 94-98.
[5]Oronsky B, et al. (2017) A brief review of the management of platinum-resistant/platinum-refractory ovarian cancer. Medical Oncology, 34, 103-108. DOI: 10.1007/s12032-017-0960-z
[6]Kim JY, et a. (2017) Targeted therapy of ovarian cancer inclucing immune check point inhibitor. Korean Journal of Internal Medicine, 32, 798-804.“Although cytoreductive surgery and platinum-based chemotherapy
remain the gold standards of treatment, the recurrence rate of ovarian cancer remains high. Attempts to improve this standard two-drug chemotherapy by adding a third cytotoxic drug have failed to affect either progression-free survival or overall survival and have resulted in an increase in toxic side effects.”
[7]Avastin fails to show a statistically significant advantage in overall survival, although the Avastin groups consistently showed a tiny numerical advantage. In Rossi L, et al. (2017) Bevacizumab in ovarian cancer: A critical review of phase III studies. Oncotarget, 8, 12389-12405.
[8]Oronsky B, et al. (2017) A brief review of the management of platinum-resistant/platinum-refractory ovarian cancer. Medical Oncology, 34, 103-108. DOI: 10.1007/s12032-017-0960-z
[9]Han J, et al. (2015) Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling. Gynecologic Oncology, 138, 668–675.
[10]Wang SB, et al. (2017) Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: A retrospective study. Medicine, 96:29(e7605). http://dx.doi.org/10.1097/MD.0000000000007605
[11]Schrepf A, et al. (2015) Diurnal cortisol and survival in epithelial ovarian cancer. Psychoneuroendocrinology, 53, 256-2678.
[12]Stringer-Reasor EM, et al. (2015) Glucocorticoid receptor activation inhibits chemotherapy-induced cell
death in high-grade serous ovarian carcinoma. Gynecologic Oncology, 138, 656–662.

Original Article: BioWatch News - Corcept Therapeutics - Ovarian Cancer Program - ASCO 2019 Primer

NEXT ARTICLE

More From BioPortfolio on "BioWatch News - Corcept Therapeutics - Ovarian Cancer Program - ASCO 2019 Primer"

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Cancer
  Bladder Cancer Brain Cancer Breast Cancer Cancer Cervical Cancer Colorectal Head & Neck Cancers Hodgkin Lymphoma Leukemia Lung Cancer Melanoma Myeloma Ovarian Cancer Pancreatic Cancer ...

Endocrinology
Diabetes Diabetes Endocrine Disorders Obesity Oxycontin Renal Disease Thyroid Disorders Endocrinology is the study of the endocrine glands and the hormones that they secrete (Oxford Medical Dictionary). There are several g...