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When a drug is successful in oncology, we tend to want to combine it with other therapies with the goal of further improving its efficacy or, in the case of PARPi, broadening the patient population which can benefit from that therapy.
There are several challenges when combining therapies. First, it is important to demonstrate efficacy and not combine therapies based on anecdotal experience. Combining therapies always raises a concern about increased toxicity and lower tolerability. Any increase in efficacy must be reviewed within the context of those safety concerns. New toxicities that may arise may also require additional monitoring.
With respect to PARPi and targeted therapy in general, other important questions center on optimal approaches to molecular testing and patient selection. Are we looking at the right biomarkers? What gene panels should we use? Should testing be tissue based, archival, metastasis directed, or liquid based? Do we need to test at each subsequent line of therapy? These are all important questions.
An indication that combining PARP inhibition with AR-targeted therapy could be a promising line of inquiry comes in part from this study, comparing abiraterone vs abiraterone plus veliparib, where they found that patients with DNA repair mutations had better outcomes on either therapy than those without mutations.17 There is also preclinical evidence for crosstalk between the DNA repair pathways and hormone receptor signaling.18,19 If one is able to target the AR effectively, a period of what we might call “BRCAness” can be induced, meaning a setting similar to that conferred by BRCA1/2 mutations.
In addition to potentially enhancing the efficacy of AR-directed therapy, there is some evidence for synthetic lethality when combining AR-directed therapy and PARPi.20 Targeting the AR weakens DNA repair that, in turn, may stimulate PARP activation, so inhibiting PARP at the same time may lead to synthetic lethality.
A large randomized, double-blind phase II study compared olaparib plus abiraterone vs placebo plus abiraterone in 142 patients with mCRPC who were pretreated with docetaxel.21,22 A maximum of 2 previous lines of chemotherapy were allowed but no previous second-generation antihormonal agents. Patients in the combination group received olaparib 300 mg twice daily and abiraterone 1000 mg once daily plus prednisone. Patients continued treatment until disease progression and the primary endpoint was rPFS. HRR mutation testing was done using tumor, germline, or plasma samples. Biomarker data were available for 96% of patients and revealed that 15% of them had HRR mutations including mutations in BRCA2, ATM, and CHEK1.
There was a benefit for combining olaparib and abiraterone in the intent-to-treat population with a median rPFS of 13.8 months for combination therapy compared with 8.2 months for abiraterone alone (HR: 0.65; P = .034). There also appeared to be an early benefit for olaparib plus abiraterone in patients with HRR mutations that resulted in a median rPFS of 17.8 months vs 6.5 months for abiraterone alone, but this was not statistically significant.
When combining drugs, it is important that the combination is both well tolerated and efficacious. Nausea, anemia, and constipation were all more common in patients receiving the combination therapy compared with abiraterone alone. Of the 22 patients (30.9%) who developed anemia while receiving olaparib plus abiraterone, grade ≥3 anemia occurred in 15 (68%). By contrast, only 1 patient developed anemia while receiving abiraterone alone and it was grade ≤2. Overall grade ≥3 adverse events were more common in the combination arm. Of note, serious cardiovascular adverse events occurred in 7 patients receiving the combination therapy including myocardial infarction, chronic cardiac failure, and cardiac failure or ischemic stroke leading to death. This is something to be mindful of as investigation of this combination continues.
Further analysis of this combination is ongoing in the phase III PROpel trial that is a randomized, double‑blind phase III trial that has enrolled 796 treatment-naive patients with progressive mCRPC.23 Patients are stratified by location of metastatic disease and previous docetaxel for metastatic hormone-sensitive prostate cancer. Patients are randomized 1:1 to receive olaparib 300 mg twice daily plus abiraterone 1000 mg once daily with prednisone 5 mg twice daily or placebo plus abiraterone/prednisone. Crossover between the arms is not permitted. This is important because significant crossover can affect OS and may have affected the OS result observed in PROfound. The primary endpoint is rPFS and key secondary endpoints are OS, time to subsequent therapy or death, and time to pain progression. We anticipate the first results later this year.
Talazoparib plus enzalutamide is also being examined in an ongoing, 2-part phase III trial, TALAPRO‑2, in the first‑line setting.24,25 Part 1 is nonrandomized and open-label to confirm the starting dose of talazoparib with a planned enrollment of 19 patients. Part 2 is the randomized, placebo-controlled portion of the trial (planned N = 1018). It is important to note that this is an all-comers trial, but DDR mutation status will be prospectively assessed and will be a stratification factor, unlike the PROpel trial. Patients will also be stratified based on their previous exposure to novel hormonal therapy or taxane. The primary endpoints are rPFS in DDR-unselected and DDR-mutant populations. Select secondary endpoints include OS, ORR, health-related quality of life, and safety.
Another trial comparing PARPi plus AR inhibition is the randomized, open-label phase III CASPAR trial comparing rucaparib plus enzalutamide with enzalutamide alone (estimated N = 1002) that is currently enrolling.26 Rucaparib will be given at a dose of 600 mg twice daily with enzalutamide 160 mg once daily and androgen deprivation therapy. Treatment will continue until progressive disease and then long-term follow-up. The primary endpoints of this study are rPFS and OS; secondary endpoints include rPFS and OS by HRR mutation status, ORR, safety, and quality of life. Correlative endpoints will also help delineate the prevalence of germline and somatic HRR mutations and AR aberrations.
Data from the phase Ib RAMP trial of rucaparib plus enzalutamide in 8 patients support this combination.27,28 In this early-phase trial, PSA decreased in 6 patients (75%), and 1 patient had a confirmed radiographic complete response from baseline. In terms of safety, no dose-limiting toxicities were noted and the most common adverse events were nausea, decreased appetite, and fatigue.
The phase Ib BEDIVERE trial determined optimal dosing of niraparib and abiraterone acetate plus prednisone and ultimately led to another trial for mCRPC. MAGNITUDE is a double-blind, international phase III trial (planned N = 1000) consisting of 2 cohorts. One cohort will include patients with DNA repair gene alterations, and patients in the other cohort will not have DNA repair gene alterations. Within each cohort, patients will be randomized to receive niraparib 200 mg once daily with abiraterone acetate and prednisone or placebo with abiraterone acetate and prednisone.29,30 Therapy will continue until disease progression, unacceptable toxicity, death, or the end of the study (approximately 66 months). The primary endpoint is rPFS with key secondary endpoints of OS, time to symptomatic progression, and time to cytotoxic chemotherapy.
It is clear that this is a very active avenue of research in prostate cancer. In addition to the trials discussed, selected additional ongoing trials are shown here. It is interesting to note that PARPi/AR inhibitor combinations are also being explored in earlier disease, specifically metastatic castration-sensitive prostate cancer (mCSPC). These trials include the phase III AMPLITUDE study comparing niraparib plus abiraterone/prednisone vs placebo plus abiraterone/prednisone in mCSPC patients with HRR mutations. There is also a randomized phase II study, ZZ-First, comparing talazoparib plus enzalutamide with enzalutamide in mCSPC.