PARP Investigations Continue on Path Toward Precision Medicine in Prostate Cancer

William Oh, MD

The use of PARP inhibitors against DNA damage repair (DDR) alterations in prostate cancer is the first display of the potential for widespread precision medicine in the field, according to William K. Oh, MD, in a presentation during the 13th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies.

DDR alterations are present in 23% of all metastatic castration-resistant prostate cancer (mCRPC) cases.¹ Moreover, approximately 1 in 10 men will have a germline mutation in DDR,² said Oh, who is the chief of the Division of Hematology and Medical Oncology, a professor of medicine and urology, and the Ezra M. Greenspan, MD Professor in Clinical Cancer Therapeutics at the Mount Sinai Health System.

“About half of those germline mutations are in BRCA2, which is probably the most important mutation because of the nature of response to subsequent therapy [to PARP inhibitors],” said Oh, who is also deputy director of the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.

In explaining the rationale for PARP inhibitors in this space, Oh said that BRCA1/2 is a protein that repairs double-strand DNA breaks. When the gene is mutated, it can cause single-strand breaks, leading to cancer growth. When the PARP1 protein, which is responsible for repairing single-strand breaks, is inhibited in a BRCA1/2-mutant cell that has lost the ability to repair double-strand breaks, it leads to synthetic lethality.

One of the first demonstrations of efficacy of PARP inhibition in patients with DDR alterations was shown in the phase II TOPARP-A trial. In the trial, olaparib (Lynparza) led to a 14-fold increase in overall response rates (ORR) and a significant improvement in radiographic progression-free survival (rPFS) and overall survival (OS) in patients with mCRPC who harbored a DDR alteration versus those who did not.³ Subsequently, the phase II TOPARP-B trial was published, showing significant benefit with olaparib in patients with mCRPC who harbored BRCA1/2 mutations.⁴

At the 2019 ESMO Congress, data from the phase III PROfound trial were presented. To be eligible for enrollment, patients had to have mCRPC, ≥1 DDR alteration, and have progressed on a next-generation antiandrogen and a taxane. Patients with BRCA1/2 or ATM mutations (cohort A) or other alterations (cohort B) were randomized 2:1 to receive 300 mg of olaparib twice daily or physician’s choice of therapy. The results showed a significant improvement in rPFS with olaparib versus placebo in cohort A. The median PFS was 7.39 months with olaparib versus 3.55 months with placebo in this cohort (HR, 0.34; 95% CI, 0.25-0.47; P <.0001).⁵

According to an exploratory analysis, the benefit of olaparib was seen in patients with other DDR alterations, such as RAD51B, and RAD54L, CHEK2, and CDK12, albeit to a lesser extent.

“These were really small numbers, but they suggest there may be other types of mutations for which PARP inhibitors may be of benefit,” said Oh.

While the interim OS analysis from the PROfound trial favored the use of olaparib in cohort A (HR, 0.64) and cohort B (HR, 0.67), it is too early to comment on, said Oh.

Clinical trials up to this point had focused on the effects of PARP inhibition in patients with DDR alterations, leaving the potential synergistic activity of PARP inhibitors and androgen receptor (AR)-targeted therapy in all comers undefined. Therefore, investigators launched the phase II Study 08 trial, in which patients with mCRPC were randomized to the combination of olaparib and abiraterone acetate (Zytiga; n = 71) versus placebo/abiraterone (n = 71).

The results indicated a significant improvement in rPFS with the combination (HR, 0.65; 95% CI, 0.44-0.97; P =.034)⁶ with some surprise, said Oh. The combination is now being evaluated in the ongoing phase III PROpel trial (NCT03732820) in all comers with mCRPC.

Rucaparib (Rubraca) is another PARP inhibitor under investigation. In the phase II TRITON2 trial, patients who progressed on prior AR-directed therapy and a taxane were screened for a deleterious somatic or germline alteration in homologous recombination repair and received 600 mg of rucaparib twice daily. As in the TOPARP-B trial, patients with BRCA1/2 mutations had the highest ORR at 43.9%.⁷

A third PARP inhibitor in clinical development in this space is niraparib (Zejula). Data from the phase II GALAHAD trial showed that patients with previously treated, biallelic BRCA1/2-mutant mCRPC experienced superior ORRs, composite responses rates, and prostate-specific antigen (PSA) responses versus those with other DDR mutations.⁸ The phase III MAGNITUDE trial is currently ongoing and is examining niraparib plus abiraterone and prednisone in treatment-naïve patients with mCRPC.

Furthermore, talazoparib (Talzenna) is being explored in the 2-part phase III TALAPRO-2 trial, in which patients with mCRPC will receive the combination of the agent plus enzalutamide (Xtandi). To date, the drug has shown promising efficacy in PSA reduction, according to Oh.⁹

Although the use of PARP inhibitors in prostate cancer remains investigational, it’s clear that the detection of a pathogenic germline mutation in a gene, such as BRCA2 or other DDR alterations, can gear individuals and their relatives toward tailored screening and risk-reducing strategies, said Oh.

“In my practice, I’m referring my patients with metastatic disease for germline, and often somatic, testing at the same time—particularly to look for BRCA mutations, but also to look for other potentially actionable mutations,” concluded Oh.

References

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8. Smith MR, Sandhu SK, Kelly WK, et al. Pre-specified interim analysis of GALAHAD: a phase 2 study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD). Ann Oncol. 2019;30(suppl 5; abstr LBA50). doi: 10.1093/annonc/mdz394.043
9. Agarwal N, Shore ND, Dunshee C, et al. Clinical and safety outcomes of TALAPRO-2: a two-part phase III study of talazoparib (TALA) in combination with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(suppl 15; abstr 5076):5076. doi: 10.1200/JCO.2019.37.15_suppl.5076