PARP Inhibitors in Prostate Cancer

PARP Inhibitors

Poly-ADP-ribose polymerases (PARPs) are a family of enzymes that catalyze the transfer of ADP-ribose to target proteins (9). PARPs play a crucial role in various cellular processes including transcription, replication, recombination, cell proliferation, and most notably, DNA repair (10, 11). Evidence for the importance of PARP in DNA repair comes from the finding that both DNA damaging agents and radiation-induced DNA damage caused increased PARP activity (11).

PARP1, the best-known enzyme in this family, plays a pivotal role in the detection and repair of DNA breaks (12, 13). Upon detecting and subsequently binding to sites of single strand DNA damage, PARP1 synthesizes poly-ADP-ribose (PAR) and transfers it to acceptor proteins (9). It then recruits other important repair enzymes to the damaged DNA site (14). PARP1 has also been shown to be a rate limiting step in both base-excision repair (BER) and nucleotide-excision repair (NER) (15, 16). Since studies have shown that BER and NER are key pathways that enable the repair of DNA damage caused by certain alkylating and chemotherapeutic agents, the upregulation of PARP is one of several mechanisms by which tumor cells can gain resistance to cancer therapy (10). Counter studies have also shown that the treatment of PARP^−/− mice by either alkylating agents or γ-irradiation result in high genomic instability and an extreme sensitivity to both agents (17). Thus, because PARPs are integral to DNA repair, the down-regulation or blocking of PARP has the potential to increase the susceptibility of tumor cells to various forms of anti-cancer therapy.

Since PARP has an important role in DNA repair, the inhibition of PARP results in increased genomic instability as well as the accumulation of damaged cells in cell cycle arrest (18). This has been demonstrated by experiments that show how ADP-ribosylation reactions are used to repair damaged DNA as well as to progress through the G2 and M phases of the cell cycle (18). Thus, PARP inhibition leads to cells that are more vulnerable to DNA damage.

Studies have shown that DNA damaging agents lead to rapid apoptosis in PARP^−/− cells (17). Although, as noted earlier, PARP^−/− mice were shown to be extremely sensitive to DNA damaging agents, the same PARP deficient mice remained healthy under control conditions (17). The viability of the PARP^−/− mice suggests that PARP is relatively dispensable for normal activity but is an essential survival factor for DNA damage (17). These are some of the characteristics that make PARP inhibition an attractive approach to use for the treatment of cancer in general, and specifically in PCa.

PARP Inhibitors and Prostate Cancer

Multiple studies have reported a strong association of frequent deleterious germline mutations in DNA Damage Repair (DDR) genes with advanced PCa, which defines the basis for the use of PARP inhibitors to treat this disease (9). DDR alterations are present in nearly 23% of all metastatic castration-resistant prostate cancer (mCRPC) (19). These mutations often involve the BRCA1/BRCA2 genes, as well as the PTEN gene (20, 21). These genes are involved in DNA damage repair as well as in tumor suppression (22). They are also crucial to the homologous recombination repair (HRR) pathway (23). Due to a reduced ability to repair DNA and regulate cell growth, patients with inherited BRCA2 mutations are five times more likely to be diagnosed with prostate cancer than the general population (24). BRCA mutations are also more frequently associated with prostate cancer of a high grade, high stage, with increased nodal involvement, and metastasis (20). Additionally, 20% of all prostate cancers involve deficient PTEN expression (21). Since BRCA plays a vital role in homologous recombination, researchers believe that BRCA mutant cells depend more heavily on the PARP-associated repair pathway (9). Various experiments have even shown evidence for the upregulation of PARP activity in certain types of cancer cells (10). This has been the rationale behind many recent clinical trials (9).

Since tumor cells with DDR gene mutations rely more heavily on PARP to correct DNA breaks and mismatches, the inhibition of PARP should make these cancerous cells more susceptible to chemotherapy and other treatment options (14). Further, PARP inhibition might even be potent as a single anti-cancer agent. Studies have shown that HRR defective cells are hypersensitive to PARP inhibition alone (25). Recent results have also shown that PARP inhibition in BRCA deficient patients with ovarian cancer led to significantly less cancer progression and mortality (26). These results have encouraged further research into PARP inhibition for PCa therapy.

In May 2020, the Food and Drug Administration (FDA) officially approved the first two PARP inhibitors, Rucaparib and Olaparib, for the treatment of prostate cancer (8). Table I highlights the key developments of the different PARP Inhibitors in the treatment of PCa.

Rucaparib

On May 15, 2020, the FDA granted accelerated approval to Rucaparib (RUBRACA, Clovis Oncology) for patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration resistant prostate cancer (mCRPC) who have already been treated with both androgen receptor-directed therapy and taxane-based chemotherapy (27). Two of the recent clinical trials that have paved the way for Rucaparib’s FDA approval include TRITON2 and TRITON3 trials (27, 28).

TRITON2 is an ongoing phase II trial evaluating 600 mg doses of Rucaparib in patients with mCRPC and an alteration in BRCA1/BRCA2, ATM, CKD12, or another prespecified DDR gene (27). Eligible patients have already progressed on prior androgen receptor directed therapy and taxane-based chemotherapy. Preliminary results show that among patients with a BRCA mutation, 43.9% had a confirmed objective response rate (ORR). Among these patients with a BRCA mutation, 52% had a confirmed decrease in PSA levels. The ORR and PSA response to treatment were less substantial for patients with other genetic mutations (27).

TRITON3 is a phase III trial that aims to evaluate the effectiveness of Rucaparib as compared to second-line androgen receptor directed therapy and docetaxel in patients with mCRPC (28). All patients in this study have a BRCA1/BRCA2 or ATM mutation and have previously progressed on a first-line androgen receptor directed therapy. The patients included in this trial have not received chemotherapy. The aim of this study is to confirm the benefit seen in TRITON2.

Olaparib

On May 19, 2020, the FDA approved Olaparib (LYNPARZA, AstraZeneca) for the treatment of adult patients with germline or somatic HRR gene mutated metastatic castration resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone (Zytiga) (8). This was largely due to the success of the PROfound clinical trial series (29).

PROfound is a recently completed phase III trial that showed the efficacy of Olaparib as a single therapy for PCa (30). All participants in this trial had mCRPC and previously progressed following treatment with enzalutamide or abiraterone. Patients were divided into two separate cohorts. Cohort A (n=245) consisted of patients with at least one alteration in BRCA1, BRCA2, or ATM. Cohort B (n=142) consisted of patients with alterations in other HRR genes. Patients were randomly assigned to receive either Olaparib or to continue hormonal treatment with enzalutamide or abiraterone. Patients in Cohort A who received Olaparib had a greater median overall survival rate than those who continued to receive hormone therapy. Within Cohort A, the imaging-based cancer progression was also significantly lower in those who received Olaparib as compared to those who received a hormonal agent (30).

The ongoing phase III PROpel trial aims to take this approach further. This study will evaluate the efficacy and safety of Olaparib in combination with abiraterone in treating patients with mCRPC (30). This approach is being studied as a potential first-line therapy in mCRPC patients. This is similar to the ongoing KEYLYNK trial, which aims to assess the effectiveness of using Olaparib alongside pembrolizumab in the treatment of mCRPC patients who have failed to respond to abiraterone acetate, enzalutamide, and chemotherapy (30).

TOPARP is a recently completed phase II trial that aimed at evaluating the anti-tumor effect of Olaparib in mCRPC, determining the molecular signatures of tumor cells in responsive patients, and identifying the predictive biomarkers of positive response to Olaparib (18). This trial found that Olaparib has antitumor activity against mCRPC with DDR gene aberrations including BRCA1, BRCA2, ATM, CDK12, and PALB2 (31).

Niraparib

Niraparib, although not yet FDA approved, is the other notable PARP inhibitor that has recently shown tremendous potential in treating PCa. The GALAHAD trial, in progress since 2016, aims to assess the efficacy, safety, and pharmacokinetics of Niraparib in men with mCRPC and DNA repair anomalies (32). The interim results of this study showed that Niraparib achieved an objective response rate of 38% and composite response rate of 65% in patients with a BRCA mutation (33, 34). These preliminary results suggest that PARP inhibition through Niraparib may soon play an important role in the treatment of mCRPC patients with DNA repair mutations (33).