Biomarker Analysis from a Randomized Study of Olaparib With or Without Cediranib in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC)- Rana Mckay

February 25, 2021

The field of advanced prostate cancer has rapidly progressed. Prior to the publication of TAX-327, in 2004 there were no proven life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC). Since that time there have been many new agents that have proven survival benefits including taxane-based chemotherapy, agents targeting the androgen axis, and bone-targeting agents. Most recently, there has been progress in developing targeted therapies. Among patients with homologous recombination repair (HRR) mutations, the use of poly (ADP-ribose) polymerase (PARP) inhibitors (including olaparib and rucaparib) has proven benefit. However, despite all these advances, mCRPC remains an uncurable disease state, and there remains an unmet need.  Rana R. McKay, MD joins Alicia Morgans, MD, MPH in a discussion on the randomized, phase II study she presented at ASCO GU 2021 about the combination of cediranib and olaparib for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).  Cediranib is an oral ATP-competitive tyrosine kinase inhibitor of VEGF receptor 1-3.  Cediranib can induce a hypoxic tumor environment which results in downregulation of homologous recombination genes. There is both a rationale, as well as preclinical data, to support the combination of cediranib and olaparib.  Here Dr. McKay discusses the study findings.


Rana R. McKay, MD, Medical Oncologist, Assistant Professor of Medicine, UC San Diego Health

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans, a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a great friend and colleague, Dr. Rana McKay, who's an Associate Professor of Medicine and a GU medical oncologist at the University of California, San Diego. Thank you so much for being here with me today, Dr. McKay, to talk about your GU ASCO 2021 presentation on the combination of cediranib and olaparib in patients looking at not only an updated look at their outcomes, but also the biomarker analysis from that work. Thank you again, Dr. McKay.

Rana McKay: Thank you so much for having me, Alicia. It's really great to be able to present our updated data, and really be able to delve into the biomarker status from patients who are enrolled in this study.

Alicia Morgans: Wonderful. Can you give us a little bit about the study schema for the trial, and then tell us what you found?

Rana McKay: Perfect, yeah. The treatment landscape for advanced prostate cancer has been rapidly evolving, as we know, over the last couple of years. Over 2020, with the approvals of two PARP inhibitors in prostate cancer, it's really revolutionized the way we treat men with advanced disease, in that it's one of the first biomarker-driven strategies for patients with advanced disease. We know that homologous recombination repair alterations are found in about 25 to 30% of patients with advanced disease. Data from the TOPARP study and also the TRITON2 study have demonstrated improvements in outcomes with PARP inhibitors for these individuals. Cediranib is an oral ATP competitive tyrosine kinase inhibitor of VEGF receptors one to through three, and anti-angiogenic agents can induce a hypoxic tumor microenvironment, resulting in downregulation of homologous recombination genes. Pre-clinical and clinical studies have demonstrated the anti-tumor activity of the combination of cediranib and olaparib.

So we actually had prophesied that the combination of cediranib and olaparib compared to olaparib alone will result in improved radiographic progression-free survival in men with metastatic CRPC independent of homologous recombination gene status. This trial was a randomized Phase II study enrolling men who had progressive metastatic castration-resistant prostate cancer, who had received at least one line of prior therapy for metastatic CRPC and had an ECOG performance status of zero to one. And patients were randomized one-to-one to receive the combination of cediranib plus olaparib versus olaparib alone. And cediranib was dosed at 30 milligrams daily, combined with olaparib 200 milligrams twice daily, versus olaparib 300 milligrams twice daily. The primary endpoint was radiographic progression-free survival. Key secondary endpoints included radiographic progression-free survival by somatic baseline and germline homologous recombination deficiency status.

So, to go through the baseline characteristics for the patients that were enrolled on the trial, about 70% or so of patients had measurable disease, rates of liver metastases were about 20%, about 80% of patients had received prior abiraterone, about 50% of patients had received prior enzalutamide, a fairly significant number of patients had actually received prior docetaxel as well, on the order of around 70% when we take the entire cohort.

So, 90 patients were enrolled on the trial, overall 84 were actually valuable for homologous recombination deficiency status using the BROCA HRD assay with collaborators at the University of Washington with the Liz Swisher lab. Actually of the 90 patients who enrolled, we did baseline biopsies on all 90 patients, but 84 of them actually had tumor that was able to be assessed for HRD status. Thirty-one percent of patients actually had homologous recombination deficiency, 29% in the cediranib and olaparib arm, 33% in the olaparib arm, 6% of patients had germline alterations, not just somatic alterations, and the most common alterations were in BRCA2, CDK12 followed by ATM. With regards to the primary endpoint for the study of overall radiographic progression-free survival, independent of gene of biomarker status, we demonstrate a statistically significant improvement of the combination of cediranib plus olaparib compared to olaparib alone in the total patient population.

We're presenting the updated data at GU ASCO. For the key secondary endpoint of rPFS by homologous recombination gene status, we actually see the signal to be more profound for patients who have homologous recombination deficiency, as opposed to those who were actually proficient, so the homologous recombination deficiency (rPFS) was 10.63 months compared to 3.83 months, which hadn't yet reached statistical significance, but there was definitely a clear trend there that was not seen in the proficient patients. This was the overall finding from the biomarker data. The biomarker data is still ongoing. We did see PSA responses and objective responses for those that had measurable disease, but it did appear that the patients who derive the most benefit were actually the deficient patients, which really opens up the door for investigating this strategy potentially in a biomarker-selected patient population.

Alicia Morgans: It's so important and so interesting. Any way that we can try to augment the power of these PARP inhibitors is going to be something that we want to do, but we're also always trying to, of course, make sure that whatever treatment we choose is going to be tolerable for patients. How did the adverse events look in this trial?

Rana McKay: With regards to adverse events, we clearly saw more adverse events with the combination of cediranib plus olaparib compared to olaparib alone. So rates of grade 3 or more AEs were around 77% with the combination compared to 55% with just olaparib alone. Rates of discontinuation for AEs were about 25% with the combo arm and 16% with olaparib alone. We did see more toxicity with the combination. Most of the toxicity was around diarrhea, hypertension, and fatigue, which was fairly well managed with optimization of antihypertensives and appropriate management of diarrhea with imodium and other oral medications.

Alicia Morgans: Well, I'm definitely glad to hear that these are things that we encounter actually pretty regularly in the treatment of our patients, and these are things that we have strategies to overcome, which is really, really important. One thing I want to make sure that we clarify and understand is the response, if any, in those patients who were wild-type for DNA repair defect mutations. I think when we first heard this data, there was a signal perhaps in those patients as well with the combination of cediranib and olaparib, and it sounds like that signal may not be as strong, certainly as those patients who have the DNA repair defect alterations, but is there any signal there?

Rana McKay: It seems like there didn't appear to be a clear signal in the proficient patients. There were 27 patients in arm A, which is the combination arm, 29 patients in arm B, which is the olaparib alone arm. With regards to the rPFS, it was around 5.3 months for the combo compared to four months for single agent in the proficient group. The signal was definitely not as strong as in the deficient group, but keeping in mind, this is a small study. Even when we look at the deficient patients, it was like 12 and 14 patients in each of the arms, so I do think that this data warrants validation, but I do think that the signal that we observed in the trial was actually that the deficient patients seem to benefit the most from this strategy.

Alicia Morgans: Okay, great. Well, thank you so much for sharing this update and really this more nuanced data with us. We always appreciate hearing about your work, you and the team certainly did a lot of work to try to get all of those biopsies. Impressive, impressive care of these patients and wonderful running of this trial. What would your summary be to those who want to try to get a good take-home message from this analysis?

Rana McKay: I think the big take-home message is that one, we did demonstrate that cediranib plus olaparib, for the primary endpoint of the study, actually did improve radiographic progression-free survival for men with metastatic CRPC. We demonstrate that metastasis biopsy was feasible, and 93% of patients who actually enrolled on the trial were valuable for homologous recombination deficiency status. We demonstrate that the rate of pathogenic HR deficiency alterations were consistent with prior reports, at around 31%. With regards to the subset analysis by biomarker status, I think the data are provocative and point to a signal in the deficient group, but definitely need further data, larger study, to validate these findings.

Alicia Morgans: Wonderful. Well, thank you so much for sharing your expertise and for taking the time. I really appreciate it. Thank you for making it another wonderful GU ASCO. Thank you, Rana.

Rana McKay: Thank you so much, Alicia.