Patients with HRD prostate tumours have more aggressive disease than wild-type patients , and the prognosis is worse in patients with identified HRD such as germline BRCA1 or 2 mutations [2, 3].
Several PARP inhibitors are under investigation for prostate cancer; these include use of olaparib, rucaparib, talazoparib, niraparib and pamiparib as monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC) and both olaparib and rucaparib in hormone-sensitive prostate cancer.
In the phase II TOPARP-A trial investigating olaparib in mCRPC patients, olaparib showed an ORR of 33% (16/49 patients) in patients who no longer responded to standard treatments, with 12 patients receiving olaparib for more than 6 months (NCT01682772) . An analysis of tumour samples from TOPARP-A patients using next generation sequencing to analyse DNA repair genes found 16 patients with somatic homozygous deletions of both BRCA1 and FANCA, somatic frameshift mutations in PALB2, heterozygous PALB2 deletions, and biallelic aberrations in HDAC2; of these 16 patients, 14 responded to olaparib .
The phase II TOPARP-B trial confirmed olaparib activity in mCRPC patients with DDR alterations (germline or somatic; mono- or bi-allelic), showing an ORR of 54% in the 400 mg cohort and 37% in the 300 mg cohort. At a median follow up of 17.6 months, median progression-free survival was 5.4 months (NCT01682772) .
The ongoing phase III randomized, open-label, PROfound trial is evaluating olaparib versus enzalutamide or abiraterone in patients with mCRPC (NCT02987543). Included patients must have failed prior treatment with a novel hormonal agent and have a mutation in one of 15 genes involved the HRR pathway.
A phase II open-label, single-arm trial evaluating olaparib in men with biochemically-recurrent prostate cancer reported interim efficacy results; three patients (15%) had PSA50 responses (all with BRCA2 mutations, 2 had complete PSA responses) and 20% had minor PSA responses (NCT03047135) . Median PSA progression-free survival was greater in men with BRCA/ATM mutations versus those without these mutations (9 versus 4 months, respectively; p=0.02).
Combination therapy with PARP inhibitors is also explored. The ongoing placebo-controlled phase III study PROpel evaluates the combination of olaparib and abiraterone as first-line treatment for patients with mCRPC (NCT03732820).
A phase I/II study (NCT02484404) investigates olaparib in combination with the immune checkpoint PD-L1 inhibitor durvalumab in previously treated patients with mCRPC . Mutation status was not an eligibility criterion for this trial . The trial reported that 53% of the patients had a radiologic or PSA response .
Several studies are assessing rucaparib in patients with mCRPC and HRD:
The phase II TRITON-2 study reported an ORR of 44% for rucaparib in patients with a BRCA mutation, a confirmed objective response was also seen in 2/8 patients (25%) with other mutations (a BRIP1 alteration in one patient and an FANCA alteration in one patient) (NCT02952534) .
The phase III TRITON-3 study is evaluating rucaparib versus physician's choice of abiraterone acetate, enzalutamide, or docetaxel in patients with HRD (NCT02975934).
The phase II ROAR study is assessing rucaparib in non-metastatic, hormone-sensitive prostate cancer with HRD (NCT03533946).
The phase II TRIUMPH trial is assessing rucaparib in patients with metastatic hormone-sensitive prostate cancer with HRD (NCT03413995).
The TALAPRO-1 phase II open-label study will assess response rate to talazoparib in men with DNA repair defects and mCRPC who have progressed after taxane-based chemotherapy and ≥1 novel hormonal agent (NCT03148795).
Talazoparib is being investigated in combination with the hormone therapy enzalutamide versus enzalutamide monotherapy in a phase III trial (TALAPRO-2; NCT03395197) in men with mCRPC; HRD mutation status will be assessed for each patient in Part 2 where talazoparib plus hormone therapy will be evaluated versus hormone therapy alone . Results from part 1 of this study have determined that this combination has a manageable safety profile.
The QUEST trial (NCT03431350) is assessing combining the PARP inhibitor niraparib with immunotherapy in prostate cancer . Niraparib is being administered in combination with either the anti-PD-1 monoclonal antibody JNJ-63723283, or the hormone therapy drug abiraterone. Results are expected in 2021.
Pamiparib is being investigated in a phase II study in men with mCRPC with circulating tumour cells with an HRD phenotype or BRCA defects (NCT03712930) .
- Christenson ES, Antonarakis ES. PARP inhibitors for homologous recombination-deficient prostate cancer. Expert Opin Emerg Drugs 2018; 23: 123-133.
- Castro E, Romero-Laorden N, del Pozo A et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. Journal of Clinical Oncology 2019; 37: 490-503.
- Castro E, Goh C, Olmos D et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2013; 31: 1748-1757.
- Mateo J, Carreira S, Sandhu S et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373: 1697-1708.
- Antonarakis ES, Wang H, Teply BA et al. Interim results from a phase 2 study of olaparib (without ADT) in men with biochemically-recurrent prostate cancer after prostatectomy, with integrated biomarker analysis. J Clin Oncol 37, 2019 (suppl; abstr 5045).
- Karzai F, VanderWeele D, Madan RA et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer 2018; 6: 141.
- Abida W, Bryce AH, Vogelzang NJ et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. In European Society of Medical Oncology (ESMO). Munich, Germany: 2018.
- 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 37, 2019 (suppl; abstr 5076).
- Subudhi SK, Aparicio A, Zurita AJ et al. A phase Ib/II study of niraparib combination therapies for the treatment of metastatic castration-resistant prostate cancer (NCT03431350). J Clin Oncol 37, 2019 (suppl; abstr TPS5087).
- Chowdhury S, Mateo J, Gross M et al. Pamiparib, an investigational PARP inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) and a circulating tumor cell (CTC) homologous recombination deficiency (HRD) phenotype or BRCA defects: A trial in progress. J Clin Oncol 37, 2019 (suppl; abstr TPS5086).