Adding Cediranib to Olaparib Increases Treatment Efficacy, But Raises Toxicity Concerns, in mCRPC

Joseph W. Kim, MD

Adding cediranib to olaparib (Lynparza) led to significant improvements in radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in a phase 2 trial (NCT02893917). However, the findings, which were published in the Journal of Clinical Oncology, show that the increase in efficacy was also met with an increased rate of adverse events (AEs) in the experimental arm.

At a data cutoff of October 1, 2020, and a median follow-up of 26.1 months, of the 90 patients in the intention-to-treat (ITT) population, the median rPFS was 8.47 months (95% CI, 5.37-12.00) in patients who received the combination vs 3.97 months (95% CI, 3.23-8.47) in patients who received olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392-0.969; P = .0359).

“Our randomized study evaluated whether combining an antiangiogenic agent, cediranib, with olaparib can improve the outcomes of patients with mCRPC,” lead study author, Joseph W. Kim, MD, of Yale School of Medicine and Yale Cancer Center in New Haven, Connecticut, and colleagues, wrote.

PARP inhibition is a standard treatment option for patients with mCRPC with deleterious homologous recombination repair (HRR) gene mutations. Preclinical studies in prostate, breast, and lung cancer cell lines have shown that a hypotoxic tumor microenvironment downregulates HRR gene expression, thereby increasing PARP inhibition sensitivity.

Olaparib has previously demonstrated improvements in rPFS and overall survival (OS) compared with abiraterone acetate (Zytiga) or enzalutamide (Xtandi). Cediranib, a pan-vascular EGFR inhibitor, has been shown in preclinical models to suppress HRR gene expression and increase sensitivity to PARP inhibition.

Eligible patients for this phase 2 trial included those at least 18 years of age with histologically confirmed prostate adenocarcinoma that was metastatic, progressive, and castration-resistant by Prostate Cancer Working Group 3 criteria. Patients needed to have received at least 1 prior therapy for mCRPC, and they were required to have an ECOG performance status of 1 or less, a Karnofsky score of at least 70%, and adequate organ function.

Patients were excluded if they had received prior PARP inhibitors, although prior platinum-based chemotherapy was allowed.

This trial had a primary end point of investigator-assessed rPFS in the ITT population. Secondary end points included rPFS in patients with HRR-deficient and HRR-proficient mCRPC, OS, overall response rate (ORR) in patients with measurable disease by RECIST v1.1 criteria, prostate-specific antigen 50 (PSA50) response rate, and toxicity.

Between August 2017 and February 2019, 90 patients with mCRPC were randomized 1:1. Arm A (n = 45) received cediranib orally at 30 mg once daily plus olaparib orally at 200 mg twice daily. In this arm, cediranib dose reductions to 20 mg and 15 mg once daily and olaparib dose reductions to 150 mg and 100 mg twice daily were permitted.

Arm B (n = 45) received oral olaparib alone at 300 mg twice daily. In this arm, 2 dose reductions of olaparib, to 250 mg and 200 mg twice daily, were allowed. Patients in arm B had the option to cross over to arm A upon radiographic progression. In total, 38% (n = 17) of patients in arm B crossed over to arm A upon radiographic progression.

Patients continued study treatment until radiographic disease progression, grade 3 to 4 treatment-related adverse effects (TRAEs) that did not resolve to grade 1 or less by 14 days, or withdrawal of consent.

In each arm, 22% of patients (n = 10) had liver metastases. A total of 44% (n = 20) and 26% (n = 12) of patients in arms A and B, respectively, had received at least 2 prior cytotoxic chemotherapies.

All patients underwent tumor biopsies at baseline and during week 4 of treatment. Patients also provided a whole-blood sample for germline DNA. Tumors were determined to be homologous recombination deficient (HRD) if they had a biallelic loss or deleterious mutation in the ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12 (somatic mutations only), NBN, PALB2, RAD51C, and RAD51D genes. Tumors without these mutations were classified as HRR-proficient.

A total of 93% (n = 84) of patients had sufficient tumor samples for HRR gene sequencing with BROCA homologous recombination assay. This sequencing showed that 29% (n = 26) of these patients had tumors with at least 1 deleterious HRR gene mutation and were classified as having HRD-positive disease. Of these patients, 26% (n = 12) and 31% (n = 14) were in arms A and B, respectively.

Among all 84 patients with sequenced tumors, the most common HRR gene mutations were in BRCA2 (18%; n = 16), CDK12 (9%; n = 8), and ATM (3%; n = 3). Of the patients with BRCA2 mutations, 9 were in arm A and 7 were in arm B. Two patients in each arm had germline BRCA2 mutations. One patient, whose best overall response was progressive disease, had a BRCA2 reversion mutation.

Among the patients with HRD-positive disease, a descriptive analysis showed a median rPFS of 10.63 months (95% CI, 5.90-not assessed [NA]) in arm A and 3.83 months (95% CI, 2.33-NA) in arm B (HR, 0.65; 95% CI, 0.272-1.504). Among patients with BRCA2-mutated disease, a descriptive analysis showed a median rPFS of 13.8 months (95% CI, 3.3-NA) and 11.3 months (95% CI, 3.8-NA) in arms A and B, respectively (HR, 0.98; 95% CI, 0.321-2.988).

In patients with HRR-proficient disease, the median rPFS 5.47 months (95% CI, 3.73-11.77) and 4.03 months (95% CI, 3.73-8.47) in arms A and B, respectively (HR, 0.777; 95% CI, 0.448-1.348).

At the median follow-up, 42 patients had died. The median OS was 11.77 months (95% CI, 10.33-NA) and 17.37 months (95% CI, 15.5-NA) in arms A and B, respectively (HR, 1.30; 95% CI, 0.705-2.399).

A total of 71% (n = 64) of patients were evaluable for objective response by RECIST v1.1 criteria. The ORRs were 19% (n = 6/31) and 12% (n = 4/33) in arms A and B, respectively. Of the patients with HRD-positive disease, the ORRs were 14% (n = 1/7) and 22% (n = 2/9) in arms A and B, respectively. Of the patients with HRR-proficient disease, the ORRs were 24% (n = 5/21) and 9% (n = 2/23) in arms A and B, respectively.

The median durations of response were 4.3 months (range, 1.9-17.7) and 5.8 months (range, 2.8-21.4) in arms A and B, respectively.

The PSA50 response rates were 20% (n = 9/45) in arm A and 13% (n = 6/45) in arm B. Of the patients with HRD-positive disease, the PSA50 response rates were 42% (n = 5/12) and 36% (n = 5/14) in arms A and B, respectively. Of the patients with HRR-proficient disease, the PSA50 response rates were 10% (n = 3/29) and 3% (n = 1/29) in arms A and B, respectively.

Safety analyses with the combination were consistent with previous reports in other tumors, and safety analyses with the monotherapy were consistent with previous reports in prostate cancer. Of the 90 patients enrolled to the study, 89 received at least 1 dose of study treatment and were included in the safety analysis. In total, 94% (n = 84) experienced TRAEs. The frequency of TRAEs was similar between the 2 arms, at 95% and 93% in arms A and B, respectively.

The incidence of grade 3 to 4 AEs was 61% in arm A and 18% in arm B. Grade 3 and 4 AEs in arm A included hypertension (23%), fatigue or asthenia (16%), and diarrhea (9%). There was also an increased incidence of other all-grade AEs in arm A, such as anorexia (48%) and weight loss (25%).

AEs were manageable with supportive care but contributed to dose interruption. In total, 84% (n = 37) of patients in arm A and 36% (n = 16) of patients in arm B required dose reductions because of an AE. Additionally, 25% of patients in arm A discontinued treatment because of an AE.

No acute myeloid leukemia or myelodysplastic syndrome was reported.

One patient in arm A experienced a fatal treatment-related intracranial hemorrhage. This patient had a history of fall prior to enrollment and died from subdural hematoma on day 5 of the study.

“To our knowledge, this is the first study to demonstrate the potential efficacy of combining an antiangiogenic agent with a [PARP] inhibitor for patients with mCRPC. Further correlative studies are needed to elucidate the mechanism of synergy between these 2 agents in prostate cancer and to provide a clearer direction for the clinical development,” the study authors concluded.

Reference

Kim JW, McKay RR, Radke MR, et al. Randomized trial of olaparib with or without cediranib for metastatic castration-resistant prostate cancer: the results from national cancer institute 9984. J Clin Oncol. Published online October 18, 2022. doi:10.1200/JCO.21.02947