The Potential Role for PARP Inhibitors in Prostate Cancer

Few cancers have had more drugs approved or indications expanded within the last 10 years than prostate cancer (PCa). This has created much hope for the future, yet the failure of androgen deprivation therapy (ADT) still signals the change to lethal, castration-resistant PCa (CRPC), and more than 25,000 men still die each year from PCa in the United States.¹ 

Precision oncology involves matching molecular aspects of a tumor to drugs targeting those pathways and is a routine consideration for patients with lung, ovarian, breast, colon, and hematologic cancers. PCa may be next with the use of Poly (ADP-ribose) Polymerase (PARP) inhibitors (e.g., olaparib, rucaparib, veliparib, talozaparib) for patients with genetic defects in pathways regulating DNA repair, dominated by BRCA2 (Breast Cancer Gene 2), BRCA1 (Breast Cancer Gene 1), and ATM (Mutated in Ataxis Telangieectasia) alterations.  Precision oncology requires an intensive genetic analysis of the tumor to identify these genetic changes. For patients with metastatic disease, this requires multiple core needle biopsies of a single metastatic site, with subsequent pathologic review, tumor enrichment (commonly through micro-dissection), and isolation of DNA. These are analyzed by high-throughput sequencing platforms and compared with population databases to define sequence-based alterations such as mutations, insertions, deletions, and translocations, as well as architectural changes such as whole gene/chromosome duplications. This intricate analysis requires high-quality tumor tissue, which is not a trivial process for metastatic CRPC (mCRPC).

Tissue-based challenges in metastatic PCa

Obtaining sequencing data from PCa metastases can be challenging for several reasons. A biopsy may not be technically safe to perform because of disease location, or the risks involved in the procedure may not be acceptable to the patient. The major limitation, though, is related to the difficulties with obtaining usable tissue from bone, as 42.9% of men with metastatic PCa have bone-only disease.² Bone biopsies obtain tumor only 69% of the time.³ Performing genetic sequencing on bone biopsies requires removal of the bone matrix, a process that can damage tumor cell integrity, resulting in a sequencing success rate of 67% (compared with 80% for non-bone sites).⁴

An attractive alternative would be to analyze the prostate itself (for de novo metastatic patients) or to use archived samples from a prior prostate biopsy or prostatectomy. In a study by Mateo et al, formalin-fixed paraffin embedded prostate biopsies were collected from 91 patients who also underwent mCRPC biopsies,⁵ with sequencing performed on both specimens. Only 4% of patients had 5 or more new mutations in the metastatic specimen and, in 26% of the cases, mutational profiles were identical. Focusing on DNA repair genes, all aberrations in primary tumors were present in mCRPC biopsies; however, in 6.8% of cases, a DNA repair aberration was found only in the mCRPC biopsy. In another study by Mateo et al, 49 paired biopsies were sequenced, and all mutations in BRCA2 and ATM were shared between the primary and metastatic biopsies.⁶

Circulating cell-free DNA (cfDNA) may be another avenue for identifying DNA repair mutations, offering a relatively non-invasive approach to capture this same information.⁷  The best biopsy site (primary vs new metastatic site) and utility of cfDNA are still being explored, but as chances of finding a new actionable mutation remain, a new metastatic biopsy is currently the preferred approach in the clinic.

Prevalence of DNA repair defects

One of the central focuses of precision oncology in PCa is on identifying patients with defects in DNA repair genes as some phase II trials have shown they are uniquely sensitive to PARP inhibitors. These DNA repair genes maintain genomic integrity by participating in the repair of DNA damaging events (such as oxidation or depurination) and involve processes such as base-excision repair, homologous recombination, or non-homologous end-joining. Defects in homologous recombination are the most prominent in this context and include germline or somatic alterations in BRCA2, BRCA1, and ATM. Other candidate genes may be identified in the future. Mutations in any of these genes increases the risk of PCa development, and some—particularly BRCA2—are associated with increased tumor aggressiveness.^8-11 Focusing on the metastatic phase of disease, based on an analysis of 150 metastatic site biopsies, these defects were found in 19.3% of cases (12.7% BRCA2, 5.6% ATM, 0.7% BRCA1).¹² Ultimately, if DNA repair directed therapy is truly beneficial, 1 in 5 patients would have a precision oncology therapy option.

Current use of PARP inhibitors

As of this writing, no PARP inhibitors have FDA approval for PCa treatment. In January 2016, olaparib received FDA breakthrough therapy designation as a treatment for patients with BRCA2, BRCA1, or ATM mutated mCRPC who had received a prior taxane and either enzalutamide or abiraterone. FDA breakthrough designation accelerates clinical development to support approval of olaparib, but is not full approval. For now, olaparib is only available in clinical trials or compassionate use programs. Other PARP inhibitors such as rucaparib, talozparaib, and veliparib have not been as extensively studied, but are in clinical trials.

The FDA breakthrough therapy designation was given as a result of findings from the TOPARP-A trial.¹³ In this phase II trial of 50 heavily-treated patients, all men had received docetaxel, 98% had received abiraterone or enzalutamide, and 58% had received cabazitaxel. Patients were treated with olaparib 400mg BID until progression or unacceptable adverse events (AEs). The primary endpoint of the trial was response rate, defined as either an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, a reduction in PSA of at least 50%, or a reduction in the circulating tumor-cell (CTC) count from 5 or more cells per 7.5 mL of blood to less than 5 cells per 7.5 mL of blood (CTC conversion). The overall response rate was 33%. The response was divided among the 3 endpoints that made up the composite response criteria. Results showed that 22% of patients had reductions in PSA of 50% or more, 29% had a confirmed reduction in CTC count to less than 5 cells per 7.5 mL, and 19% of evaluable patients had a partial radiologic response. Having a defect in a DNA repair gene appeared to predict response to olaparib, with an 88% response rate in biomarker positive patients and a 6% response rate in biomarker negative patients. Overall survival (OS) was also prolonged in the biomarker positive group (median OS 13.8 vs 7.5 monhs, p=0.05). The drug was well tolerated, with the most common grade 3 or 4 drug-related AEs being anemia (20%), fatigue (12%), leukopenia (6%), thrombocytopenia (4%), and neutropenia (4%).

While PSA response and radiographic response by RECIST criteria are commonly used primary endpoints in PCa trials, the CTC conversion endpoint used in the TOPARP-A trial is only recently being employed. In a disease such as PCa where the natural progression from diagnosis to death can be quite long, there is a need for identification of earlier surrogate endpoints to accelerate development of new therapies. CTC conversion has been evaluated as a surrogate endpoint via an analysis of individual patient data from more than 6000 patients enrolled in 5 prospective phase III trials.¹⁴ This analysis compared 8 surrogate endpoints: CTC nonzero at baseline and 0 at 13 weeks (CTC0), CTC conversion (≥5 CTCs at baseline, ≤4 at 13 weeks), a 30%, 50%, and 70% decrease in CTC count, and a 30%, 50%, and 70% decrease in PSA level. CTC0 and CTC conversion provided greater discrimination for patient survival than the percent change in CTC or PSA endpoints. While not yet recognized by the FDA as a surrogate endpoint for drug approval, CTC0 and CTC conversion are becoming more commonly used for non-registration trials.

Combination therapy: Abiraterone + PARP inhibition

As shown in the TOPARP-A trial, PARP inhibitor monotherapy can lead to response in a subset of patients deficient in DNA repair as a result of genetic mutations. Pre-clinical data have shown that a similar homologous repair deficient phenotype can be induced by ADT. In work done in PCa cell lines, loss of the androgen receptor led to downregulation of homologous repair gene expression. In addition, PARP-mediated repair pathways were upregulated in PCa cells following ADT.¹⁵ This rationale led to a phase II trial of abiraterone and olaparib in patients with mCRPC.¹⁶ In this trial, men who had recevied docetaxel were randomized to abiraterone with placebo or abiraterone with olaparib. The primary endpoint was radiographic progression-free survival (rPFS). The median rPFS in the olaparib + abiraterone group was 13.8 months compared with 8.2 months in the placebo + abiraterone group (HR 0.65, CI 0.44-0.97, p=0.034). The grade 3 or 4 event rates were 54% in the olarpaib arm vs 28% in the abiraterone alone arm. The most common AEs of any grade in the olaparib arm were nausea (37% grade 1 or 2), constipation (25% grade 1 or 2), and anemia (20% grade 3 or 4, 10% grade 1 or 2, 1% grade 4). DNA repair status was not known in all patients, but 15% of trial patients were confirmed to have a DNA repair mutation. In these patients the median rPFS in the olaparib group was 17.8 months  compared with 6.5 months in the placebo group. The study was not powered to detect a statistical difference based on DNA repair status.

A similar phase II trial conducted with the PARP inhibitor veliparib used a different primary endpoint of PSA response rate. In this trial, men with mCRPC were randomized to treatment with abiraterone alone or abiraterone plus veliparib. The study was powered to detect an improvement of 20% in PSA response rate between the study arms. The study failed to detect a significant difference in outcomes between the 2 arms, with a PSA response rate of 63.9% in the abiraterone alone arm and 72.4% in the abiraterone plus veliparib arm (p=0.27).¹⁷ Some have hypothesized that this discordant result with the prior trial is due to weaker PARP trapping activity of veliparib compared to olaparib.¹⁸

Combination therapy: Trials in progress

Given the encouraging results from the TOPARP-A and combination abiraterone + olaparib trials, there are many trials currently underway to evaluate PARP inhibitors in various combinations and phases of treatment (Table 1).  One exciting subset is the combination of PARP and checkpoint inhibition (NCT03572478, NCT03330405, NCT02484404). The rationale for this combination comes from pre-clinical data demonstrating that DNA breaks can activate type I interferons and other immunomodulatory molecules¹⁹ and could lead to neoantigen formation with subsequent immune recognition. In addition, the combination has been shown to upregulate PD-L1 and lead to tumor reduction in animal models.²⁰ While still preliminary, the durvalumab + olaparib trial (NCT02484404) reported a PSA response rate of 47% at the main ASCO meeting this year.²¹

Summary

This review illustrates how a precision oncology approach may yield benefit through the identification of DNA repair defects within PCa. Hopefully, additional trials exploring other targeted agents and mutations (e.g., CDK12, PTEN) will expand the targetable genomic landscape (or offer guidance in sequencing of standard therapies) in PCa, resulting in a truly personalized approach to every man’s PCa.

 

¹Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan

²Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan

 

Table 1: Examples of Trials in Progress with PARP Inhibition in Prostate Cancer

Trial Name	Drug	Phase	NCT #	Study Population
Talazoparib + Enzalutamide vs. Enzalutamide Monotherapy in mCRPC With Deoxyribonucleic Acid (DNA) Damage Repair Deficiencies (DDR) (TALAPRO-2)	Talazoparib +/- Enzalutamide	3	NCT03395197	Metastatic Castrate Resistant
Javelin PARP Medley: Avelumab Plus Talazoparib In Locally Advanced Or Metastatic Solid Tumors	Talazoparib + Avelumab	2	NCT03330405	Metastatic Castrate Resistant
Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers	Durvalumab + Olaparib and/or Cediranib	1/2	NCT02484404	Metastatic Castrate Resistant
Trial of Rucaparib in Patients With Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations (TRIUMPH)	Rucaparib	2	NCT03413995	Metastatic Castrate Sensitive
Olaparib Before Surgery in Treating Participants With Localized Prostate Cancer	Olaparib	2	NCT03570476	Localized Disease Pre-Surgery
Studying the Effects of Olaparib (± Degarelix) Given to Men With Intermediate/High Risk Prostate Cancer Before Radical Prostatectomy	Olaparib +/- Degarelix	1	NCT02324998	Localized Disease Pre-Surgery
Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis	Olaparib	2	NCT03047135	Biochemically Recurrent

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