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PARPi Beyond mCRPC
PARP Inhibitors in Settings Beyond Metastatic Castration-Resistant Prostate Cancer

Released: April 02, 2021

Expiration: April 01, 2022

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Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated efficacy in the setting of metastatic castration-resistant prostate cancer (mCRPC). The role of PARP inhibitors in other prostate cancer disease settings is also being explored including in metastatic castration-sensitive prostate cancer (mCSPC), biochemically recurrent disease, and as neoadjuvant therapy. In this commentary, we will discuss ongoing trials using PARP inhibitors in settings other than mCRPC including in the neoadjuvant setting and in combination with androgen inhibition and checkpoint inhibitors in patients with mCSPC.

PARP Inhibitors in mCSPC
Current approvals for PARP inhibitors in prostate cancer are in the mCRPC setting, and there are little data on the efficacy and long-term safety of PARP inhibitors in patients with mCSPC. Given that, we would not recommend a PARP inhibitor for a patient with mCSPC and a BRCA2 mutation. Overall, patient outcomes in the mCSPC setting are good, but patients with basal subtypes and complex genetic alterations may have poor outcomes. However, clearly this is an area of interest and there are clinical trials ongoing.  

Several ongoing clinical trials are simultaneously targeting the PARP and androgen receptor pathways in patients with mCSPC, building on early data in mCRPC. These pathways are interconnected, and testosterone suppression with androgen receptor therapy can enhance the effects of PARP inhibition. The phase III AMPLITUDE trial (NCT04497844) is currently recruiting patients (planned N = 788 patients) with mCSPC and a homologous recombination repair (HRR) mutation who have not previously received a PARP inhibitor. The trial will compare the efficacy of niraparib plus abiraterone acetate and prednisone (AAP) to placebo plus AAP with a primary endpoint of radiographic progression-free survival. The randomized phase II ZZ-First trial (NCT04332744) is comparing talazoparib plus enzalutamide with enzalutamide monotherapy. The study population for ZZ-First (planned N = 54) is men with high volume metastatic hormone-naive prostate cancer with no previous systemic therapies for metastatic disease. The primary endpoint is prostate-specific antigen (PSA) complete response. Unlike AMPLITUDE, the ZZ-First trial has no inclusion criteria based on HRR mutation status. Another phase II trial (NCT04734730), which is not yet recruiting (planned N = 70), will compare standard therapy of AAP plus androgen deprivation therapy with and without talazoparib in patients with mCSPC. This study is also biomarker unselected. The primary endpoint of this trial will be PSA nadir <0.2.

PARP Inhibitors in Biochemically Recurrent Disease
In the nonmetastatic setting, PARP inhibitors are being investigated as single agents or in combination with immune checkpoint inhibitors for the treatment of men with biochemically recurrent, castration-sensitive disease. Two phase II trials are using a combination of olaparib plus durvalumab in this setting. One trial is enrolling patients with DNA damage repair mutations (NCT03810105) while eligibility for the other trial includes patients with high microsatellite instability or a homologous recombination deficiency (NCT04336943). The primary endpoint for both these studies is undetectable PSA. Another phase II trial (NCT03047135) is currently recruiting men with biochemically recurrent disease after radical prostatectomy (planned N = 50) and ≥6 months without androgen deprivation therapy or antiandrogen therapy. This trial is evaluating the efficacy of olaparib as a single-agent, and the primary endpoint is PSA response rate. The first stage of this trial included 20 patients that were not biomarker selected and who received olaparib 30 mg twice daily. In an interim report, olaparib was well tolerated, and 35% of patients had a PSA response with 15% of patients having a ≥50% PSA decline. Olaparib showed more activity in patients with BRCA2/ATM mutations with a median PSA progression-free survival of 9 months vs 4 months for men without the noted mutations (P = .02). This trial is ongoing with a biomarker-unselected population.

PARP Inhibitors as Neoadjuvant Therapy
One intriguing possibility is the use of neoadjuvant/adjuvant PARP inhibitor therapy for patients with higher risk disease and BRCA2 or HRR mutations. This situation, where the tumor burden is low and there is a short duration of therapy and resulting synthetic lethality, could lead to interesting outcomes prior to prostatectomy. So far, targeted therapy development has led to improvements in survival in later-stage disease, but could targeted therapy used earlier in the course of disease result in an increase in the number of patients who have a reduced risk of relapse after surgery or after radiation? An interesting phase II trial (NCT04030559) is investigating the use of niraparib before radical prostatectomy in patients (planned N = 30) with high-risk localized prostate cancer, and DNA damage response defects, including BRCA1 or BRCA2 mutations. This trial is currently recruiting and has a primary outcome of pathologic response rate.

There are many great questions being answered in upcoming and ongoing clinical trials, and it will be interesting to see how the field evolves as trial results come out and how patient outcomes will improve with further research.

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