Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial

doi:10.1016/S1470-2045(18)30365-6

The Lancet Oncology

Volume 19, Issue 7, July 2018, Pages 975-986

https://doi.org/10.1016/S1470-2045(18)30365-6 Get rights and content

Summary

Background

Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status.

Methods

We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients.

Findings

Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8–20·4) with olaparib and abiraterone and 8·2 months (5·5–9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44–0·97, p=0·034). The most common grade 1–2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group.

Interpretation

Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer.

Funding

AstraZeneca.

Introduction

Prostate cancer is the fifth leading cause of cancer-associated deaths in men worldwide.¹ The standard of care for metastatic castration-resistant prostate cancer includes taxane chemotherapy (eg, docetaxel or cabazitaxel), second-generation antihormonal drugs (eg, abiraterone or enzalutamide) that target the androgen-receptor pathway, or radium-223. However, treatment response is often short-lived because patients develop tumour resistance, and thus improved therapeutic options are needed for men with metastatic castration-resistant prostate cancer.²

Research in context

Evidence before this study

Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that is approved in ovarian and breast cancer indications. Other PARP inhibitors in clinical development include niraparib, pamiparib, rucaparib, talazoparib, and veliparib. Abiraterone is an androgen synthesis inhibitor, which is the standard of care for metastatic castration-resistant prostate cancer. We searched PubMed and the databases of the American Society of Clinical Oncology and European Society for Medical Oncology for journal publications and meeting abstracts published between Jan 1, 2012, and March 1, 2018, using the search terms “poly(ADP-ribose) polymerase” or “PARP” and “inhibitor” or “inhibition” and “prostate cancer”. No language restrictions were applied. In a previous phase 2 study, the efficacy of olaparib monotherapy in patients with advanced prostate cancer was almost exclusively limited to patients with a homologous recombination repair mutation. A phase 2 trial of veliparib in combination with abiraterone in patients with metastatic castration-resistant prostate cancer found no significant efficacy benefit with this combination treatment when compared with abiraterone alone.

Added value of this study

To our knowledge, our data are the first to show a significant improvement in radiographic progression-free survival (rPFS) for men with metastatic castrate-resistant prostate cancer treated with the combination of a PARP inhibitor and androgen synthesis inhibitor compared with an androgen synthesis inhibitor alone. Additionally, and in contrast to the results of previous studies of olaparib monotherapy for this indication, the rPFS benefit was observed for patients with metastatic castration-resistant prostate cancer given olaparib and abiraterone, regardless of homologous recombination repair mutation status, which has not previously been reported. In our study, more patients treated with olaparib and abiraterone had grade 3 or worse adverse events and serious adverse events than those treated with abiraterone alone; however, the increased duration of exposure in the olaparib and abiraterone group suggests that this tolerability risk might be offset by the observed efficacy benefit. No detriment to health-related quality of life was recorded with the combination compared with abiraterone alone.

Implications of all the available evidence

The significant improvement in rPFS observed in patients with metastatic castration-resistant prostate cancer treated with olaparib plus abiraterone compared with abiraterone alone suggests that these patients, who were not selected on the basis of biomarker criteria, might benefit from the combination treatment irrespective of homologous recombination repair mutation status. This result, which suggests that the treatment could provide clinical benefit for a broader patient population, is consistent with preclinical data that indicate a synergy between olaparib and drugs inhibiting androgen synthesis or function, potentially caused by PARP inhibition of androgen-receptor-dependent transcription or creation of a phenotype similar to that of the BRCAness phenotype that is susceptible to PARP inhibition. Larger studies are needed to confirm the results of this trial; however, our data suggest that the combination of olaparib and abiraterone has the potential to provide additional and practice-changing therapeutic options for men with metastatic castration-resistant prostate cancer.

In a preliminary phase 2 study,³ patients with metastatic castration-resistant prostate cancer who were pretreated with chemotherapy (most of whom had also previously received a second-generation antihormonal drug such as abiraterone or enzalutamide) were given the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. Treatment response was markedly improved in patients with tumours carrying a homologous recombination repair (HRR) mutation (based on a 113-gene panel test) compared with patients with tumours without an HRR mutation.³ These clinical data are supported by preclinical studies investigating the mechanism of action of olaparib, which was found to trap PARP at sites of DNA damage, causing an accumulation of DNA double-strand breaks.⁴ Synthetic lethality is observed when PARP is trapped in HRR-deficient cells, which depend on low-fidelity pathways for repairing DNA double-strand breaks.5, 6

Preclinical data7, 8 have indicated synergy between olaparib and drugs that affect the androgen receptor pathway, regardless of HRR mutation status. Therefore, we carried out this phase 2 randomised trial to assess the efficacy and tolerability of olaparib in combination with abiraterone compared with placebo plus abiraterone in patients with metastatic castration-resistant prostate cancer, irrespective of their HRR mutation status.

Section snippets

Study design and participants

We carried out this double-blind, randomised, placebo-controlled, phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America (appendix p 1). The trial comprised an open-label safety run-in phase, followed by a randomised, double-blind treatment phase.

Eligible male patients were aged 18 years or older with histologically or cytologically proven metastatic castration-resistant prostate cancer. Metastatic castration-resistant prostate cancer was defined as an

Results

The results of the open-label safety run-in phase are described in the appendix (p 3). In brief, no patients reported dose-limiting toxicities during the dose-escalation, and olaparib 300 mg twice daily was established as the recommended phase 2 dose for the randomised phase. Pharmacokinetic analyses showed no obvious drug–drug interactions between olaparib and abiraterone (appendix pp 10–11).

Between Nov 25, 2014, and July 14, 2015, 171 patients were enrolled in the randomised phase and

Discussion

The results of this randomised phase 2 study show that the addition of olaparib to abiraterone therapy results in a significant rPFS benefit for patients with metastatic castration-resistant prostate cancer, with a significantly longer rPFS in the olaparib and abiraterone group than in the placebo and abiraterone group. Although patients given olaparib had more adverse events than did those who received placebo, median treatment duration was longer for patients treated with olaparib, and

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Le but de cette revue générale est de proposer un état de l’art sur la prise en charge du cancer de la prostate métastatique.
Une revue narrative de la littérature et des dernières recommandations a été réalisée concernant les éléments de prise en charge thérapeutique du cancer de la prostate métastatique ou résistant à la castration.
La suppression androgénique reste le traitement pivotal depuis plus de 50 ans. Néanmoins, le socle de la première ligne de traitement repose désormais sur l’intensification systémique, en associant une hormonothérapie de nouvelle génération, voire un triplet en ajoutant une chimiothérapie par docétaxel, devant les bénéfices importants en survie globale. Les lignes ultérieures sont basées sur un raisonnement de séquences, selon les caractéristiques de la maladie, du patient, et du traitement précédent. L’ère de la médecine personnalisée, et son pendant du testing moléculaire, débute avec l’arrivée des inhibiteurs de PARP et la radiothérapie interne vectorisée, de manière isolée ou combinée. Une individualisation de la prise en charge selon un ensemble de facteurs, pouvant intégrer le statut génomique tumoral, représente la voie d’avenir d’un cancer qui reste létal, mais dont l’espérance de vie au diagnostic des métastases a augmenté de façon remarquable grâce aux améliorations thérapeutiques.
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The aim of this general review is to provide a state of the art on the management of metastatic prostate cancer.
A narrative review of the literature and the latest recommendations was carried out concerning the elements of therapeutic management of metastatic or castration-resistant prostate cancer.
Androgen deprivation has remained the pivotal treatment for more than 50 years. However, first-line treatment is now based on systemic intensification, by combining new generation hormonal therapy, or even a triplet by adding chemotherapy with docetaxel, given the significant benefits in overall survival. Subsequent lines are based on sequences, depending on the characteristics of the disease, the patient, and the previous treatment. The era of personalized medicine and its counterpart of molecular testing, begins with the arrival of PARP inhibitors and vectorized internal radiotherapy, in isolation or in combination. Individualization of treatment according to several factors, including tumor genomic status, is driving the current management of this cancer which remains lethal, but whose life expectancy at diagnosis of metastases has increased remarkably during the last decade thanks to therapeutic improvements.
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Poly (ADP-ribose) polymerase inhibitors (PARPi) represent an option in selected cases of metastatic castration-resistant prostate cancer (mCRPC). The aim of the present systematic review and meta-analysis is to evaluate the efficacy and safety of approved (Olaparib, Rucaparib) and investigational (Talazoparib, Niraparib, Veliparib) PARPi in mCRPC patients. Three databases were queried for studies analyzing oncological outcomes and adverse events of mCRPC patients receiving PARPi. Primary outcome was a PSA decline ≥ 50% from baseline. Secondary outcomes were objective response rate, progression-free survival (PFS), radiological PFS, overall survival (OS), conversion of circulating tumor cell count, and time to PSA progression. The number and rate of any grade adverse events (AEs), grade ≥ 3 AEs, and most common grade ≥ 3 AEs were registered. A subanalysis of outcomes per mutation type, prospective trials, and studies adopting combination therapies was performed. Overall, 31 studies were included in this systematic review, 28 of which are available for meta-analysis. The most frequently investigated drug was Olaparib. The most frequent mutation was BRCA2. A PSA decline rate of 43% (95% CI 0.32-0.54) was observed in the overall population. Mean OS was 15.9 (95% CI 12.9-19.0) months. In BRCA2 patients, PSA decline rate was 66% (95% CI 0.57-0.7) and OS 23.4 months (95% CI 22.8-24.1). Half of the patients suffered from grade 3 and 4 AEs (0.50 [95% CI 0.39-0.60]). Most common AEs were hematological, the most frequent being anemia (21.5%). PARP inhibitors represent a viable option for mCRPC patients. Current evidence suggests an increased effectiveness in homologous recombination repair (HRR) gene mutation carriers, especially BRCA2.
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ArticlesOlaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Genet Med

Cell

Cancer Treat Rev

GLOBOCAN 2012 v1.1, cancer incidence and mortality worldwide: IARC CancerBase No. 11

Abiraterone and increased survival in metastatic prostate cancer

N Engl J Med

DNA-repair defects and olaparib in metastatic prostate cancer

N Engl J Med

Trapping of PARP1 and PARP2 by clinical PARP inhibitors

Cancer Res

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

Nature

Specific killing of BRCA2-deficient tumors with inhibition of poly(ADP-ribose) polymerase

Nature

Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer

Nat Commun

Dual roles of PARP-1 promote cancer growth and progression

Cancer Discov

Global policy

ZYTIGA (abiraterone acetate) prescribing information

Articles
Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial