6.2 PARPi monotherapy
The first data about PARPi in patients with PCa came from a phase I study of 60 BRCAm patients treated with olaparib, among which 5% had CRPC, and one patient achieved > 50% PSA and radiological bone response [
74].
The aim of the TOPARP studies was to evaluate PARPi effectiveness, identify the molecular pattern of PCa cells and look for predictive biomarkers. The first clinical data came from the open-label, single-arm TOPARP-A phase II study (Trial of Olaparib in Patients with Advanced Castrate Resistant Prostate Cancer). In the first part of the study, the activity of olaparib 400 mg twice daily was evaluated in genetically unselected patients with mCRPC. Initially, 50 patients were enrolled onto the study, but only 49 could be evaluated. All of the evaluated patients received docetaxel, 98% enzalutamide or abiraterone, and 58% cabazitaxel. The enrolled patients did not receive platinum-based regimens. The primary end-points were radiological response rate, a greater than 50% reduction in PSA, and a reduction in circulating tumour cells (CTC) from > 5 to < 5 cells per 7.5 mL of blood. Whole-exome sequencing and transcriptome studies were performed on fresh-frozen cores in tumour-biopsy samples obtained before treatment during screening. Germline targeted sequencing was performed on DNA from saliva samples. The copy number of the genes was validated with droplet digital polymerase-chain-reaction testing. In addition, tumour samples from biopsies performed before and during treatment were analysed. Biomarker-positive patients had a homozygous deletion or deleterious mutation in a gene involved in DNA repair or in sensitivity to PARP inhibition. Sixteen of the 49 patients (33%) had a response. In the second part of the study, a pre-planned biomarker analysis was performed in the sensitive group. Seven patients had
BRCA2 loss (four with biallelic somatic loss and three with germline mutations), and five patients had an alteration in the
ATM gene. Every patient with the
BRCA2 mutation responded. Moreover, responses were observed in patients with somatic homozygous deletions of
BRCA1 and
FANCA, somatic frameshift mutations in
PALB2, heterozygous
PALB2 deletions, biallelic aberrations in
HDAC2, and homozygous somatic deletions of
BRCA1 or
CHEK2 with
FANCA deletion. The group of patients with
BRCA1/2 and
ATM mutations had an 88% response rate but there was no radiological response among
ATM patients. Interestingly, patients with biallelic
PALB2 mutation achieved a durable response and only two patients without DNA-repair gene alterations had a response (6%). Radiological progression-free survival (rPFS) and OS were longer in the biomarker-positive group than in those who were negative (rPFS: 9.8 vs. 2.7 months,
P < 0.001; OS: 13.8 vs. 7.5 months,
P = 0.05) [
12].
The second open-label randomised TOPARP-B phase II trial was designed to confirm the previous results from the TOPARP-A study. Patients with metastatic PCa, pretreated with one to two lines of chemotherapy, were randomised to 400 mg or 300 mg olaparib twice daily. The patients were stratified according to DDR gene aberrations. The primary end-points were the same as in part A. Among patients who were assigned to 400 mg twice daily of olaparib, the composite response was achieved in 54.3% of patients (95% CI 39.0–69.1), the radiological response was achieved in 24.2% (95% CI 11.1–42.3), the PSA response in 37% (95% CI 23.2–52.5), and CTC conversion in 53.6% (95% CI 33.9–72.5). Patients who had
BRCA1/2 mutations achieved the greatest composite overall response (83.3%; 95% CI 65.3–94.4) in comparison to
PALB2 (57.1%; 95% CI 18.4–90.1),
ATM (36.8%; 95% CI 16.3–61.6),
CDK12 (25%, 95 CI 8.7–49.1), and other mutations (20%; 95% CI 5.7–43.7). The study confirmed the activity of PARPi in both germline and somatic mutations [
75].
The initial results from the first phase of the PROFOUND III study were presented during the European Society for Medical Oncology (ESMO) conference in 2019 [
15]. The efficacy and safety of olaparib was compared with enzalutamide or abiraterone (as per the choice of the clinician) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed onto new hormonal agents. Previous taxane therapy was allowed. Patients were eligible if they had any of the qualifying gene alterations. Patients were randomised 2:1 between cohort A (
BRCA1,
BRCA2,
ATM) and B (
BRIP1,
BARD1,
CDK12,
CHEK1,
CHEK2,
FANCL,
PALB2,
PPP2R2A,
RAD51B,
RAD51C,
RAD51D,
RAD54L). The somatic mutation status was revealed in primary or metastatic sites with the FoundationOne CDx NGS test, and the tissue was either from the archive or newly obtained. The primary end-point was rPFS in cohort A. The secondary end-points were rPFS in cohort B and ORR, time to pain progression, and OS in cohort A. Patients were assigned in a 2:1 ratio to receive olaparib or a drug chosen by the clinician (enzalutamide or abiraterone). Analysis revealed that olaparib significantly improved rPFS in cohort A (olaparib 7.4 months vs. 3.6 months (HR 0.34; 95% CI 0.25–0.47,
P < 0.0001)) and B (olaparib 5.8 vs. 3.5 months (HR 0.49; 95% CI 0.38–0.63,
P < 0.0001)). In addition, olaparib improved the objective response rate (ORR) (Cohort A: 33.3% for olaparib, B: 2.3% for enzalutamide/abiraterone). rPFS in the overall population (cohorts A and B) was prolonged (5.82 vs. 3.52 months (HR 0.49; 95% CI 0.38–0.63;
P < 0.0001)). The median OS in cohort A was significantly longer (18.5 vs. 15.1 months) than in the hormonal therapy arm (HR 0.64; 95% CI 0.43–0.97,
P = 0.02). Eighty-one percent of the patients who had progression in the control group received PARPi. The PROFOUND subgroup analysis and a retrospective review of 23 studies revealed that the benefit among patients with
ATM alterations is weaker than in
BRCA mutated patients [
76]. ATR inhibitors and PARPis may be effective treatment strategies in ATM deficient PCa cell lines because in such cells olaparib acts cytostatically, not cytotoxically [
77]. ATM loss sensitised cells to ATR kinase, which prevents genome instability in tumours and promotes tumour progression by enhancing Warburg effects [
78].
In the TRITON2 study, mCRPC patients with a deleterious germline or somatic deleterious mutations in DDR genes (
BRCA2,
BRCA1,
CDK12,
CHEK2,
FANCA,
NBN,
PALB2,
RAD51,
RAD51B,
RAD51C,
RAD51D,
RAD54L) with disease progression on AR-directed therapy and one taxane-based chemotherapy, were treated with rucaparib 600 mg twice daily. The population included 115 patients with
BRCA alterations (
BRCA1 = 13;
BRCA2 = 102; germline = 44, somatic = 71, measurable disease = 62). The confirmed ORR per modified RECTIST/Prostate Cancer Working Group 3 for patients with measurable disease and PSA response rate (≥ 50% decrease) for patients without measurable disease were the primary end-points. The ORR per independent radiology review was 43.5% (95% CI 31.0–56.7). A PSA response was seen in 54.8% (95% CI 45.2–64.1) of patients. ORRs in patients with germline/somatic BRCA1/2 alterations were similar, but higher PSA response rates were observed in patients with
BRCA2 than
BRCA1 alterations (59.8%; 95% CI 49.6–69.4 vs. 15.4%; 95% CI 1.9–45.4). Non-BRCA gene alterations were seen in 78 patients (
ATM = 49,
CDK12 = 15,
CHEK2 = 12, other DDR = 14). ORR and PSA responses were reported in patients with non-BRCA gene alterations, as follows:
ATM (10.5% vs. 4.1%),
CDK12 (0% vs. 6.7%),
CHEK2 (11.1% vs. 16.7%). Importantly, patients with
PALB2,
FANCA,
BRIP1 and
RAD51B mutations presented a response contrary to patients with germline or biallelic loss of
ATM. In contrast to
BRCA mutated tumours, the ORR and PSA responses in patients with
ATM,
CHEK2 and
CDK12 mutations were low. The TRITON2 study, on the one hand, confirmed safety and efficacy in
BRCA-mutated tumours, but on the other hand showed that there are no accurate biomarkers in non-BRCA-mutated tumours, which needs further investigation [
65]. The results of the study led to FDA approval for rucaparib. The efficacy of rucaparib is currently being evaluated in the TRITON 3 (NCT02975934) phase III trial. Eligible mCRPC patients who experienced disease progression after one prior line of next generation AR-targeted therapy with
BRCA1,2 or
ATM deleterious mutations will be randomised to rucaparib or one of the standard therapies (abiraterone acetate, enzalutamide or docetaxel). Rucaparib is also being evaluated in non-metastatic hormone-naïve PCa with BRCAness (ROAR trial, NCT03533946) after prostatectomy and/or radiation therapy, with or without systemic therapy. The primary outcome measure is 50% reduction in PSA levels. BRCAness is defined as an alteration in any of the following genes:
ATM,
ATR,
BARD1,
BRCA1,
BRCA2,
BRIP1,
CDK12,
CHEK1,
CHEK2,
ERCC3,
FAM175A,
FANCA,
FANCL,
GEN1,
HDAC2,
MLH1,
MRE11,
NBN,
PALB2,
PPP2R2A,
RAD51 or
RAD54L. Mutations are tested by soft-tissue based genomic testing or liquid biopsy-based genomic or genetic testing.
In contrast to the previously described studies, the DDR status among patients for the ongoing phase II, single-arm GALAHAD study is being evaluated with a plasma or tissue gene panel (
BRCA1/2,
ATM,
FANCA,
PALB2,
CHEK2,
BRIP1,
HDAC2). The study was designed to determine the safety and efficacy of niraparib among mCRPC patients who progressed on taxane-based chemotherapy and AR-targeted therapy. The primary end-point was ORR by RECIST 1.1/PCWG3 criteria and composite response rate (CRR) conversion of circulating tumour cells to < 5/7.5 mL blood, or ≥ 50% decline in PSA. The preliminary results of the study presented during ESMO 2019 showed that biallelic DDR defects in
BRCA (46 patients) were associated with a higher ORR 41% (95% CI 23.5–61.1) than non-BRCA (35 patients) 9% (95% CI 1.1–29.2). In addition, patients with
BRCA1/2 biallelic DRD in comparison to non-BRCA gene alterations achieved a greater PSA response (50%; 95% CI 34.9–65.1 vs. 3%; 95% CI 0.1–14.9), CTC conversion (47; 95% CI 31.0–64.2 vs. 21; 95% CI 7.1–42.2), CRR (63%; 95% CI 47.6–76.8 vs. 17%; 95% CI 6.6–33.7), median rPFS (8.2; 95% CI 5.2–11.1 vs. 5.3 months; 95% CI 1.9–5.7) and median OS (12.6; 95% CI 9.2–15.7 vs. 14.0 months; 95% CI 5.3–20.1) [
79]. The results will be confirmed in the MAGNITUDE (NCT03748641) phase III randomised, placebo-controlled study. The comparator for niraparib is abiraterone with prednisone.
TALAPRO-1 is a phase II study in men with mCRPC and DDR mutation (
ATM,
ATR,
BRCA1/2,
CHEK2,
FANCA,
MLH1,
MRE11A,
NBN,
PALB2 or
RAD51C). Enrolled patients received one to two chemotherapy regimens (one or more taxane based) and novel hormone therapy (enzalutamide or abiraterone). The primary end-point is ORR. The secondary end-points are time to response and its duration, PSA decrease ≥ 50%, time to PSA progression, CTC count conversion, rPFS, OS, and safety. The initial results of the interim analysis were presented during the American Society of Clinical Oncology (ASCO) meeting in 2020. The results of the study show that talazoparib presented the strongest activity measured as a composite response (OR and/or PSA response ≥ 50% and/or CTC conversion) in
BRCA1/2 tumours (76.1%); however, the response in
ATM (50%) and
PALB2 (27.8%) patients was also promising [
80].
In preclinical tumour models, veliparib potentiated the activity of DNA-damaging agents like temozolomide, cisplatin, carboplatin and also radiation [
81]. It was suggested that veliparib can overcome temozolomide resistance in PCa cell lines and that this combination increased the survival of mice in comparison to temozolomide monotherapy [
82]. Veliparib maintenance after carboplatin-based chemotherapy regimens in metastatic
BRCA2 mutated ERG positive CRPC led to a durable complete response with a good toxicity profile [
83]. The clinical utility of veliparib was evaluated in a phase II study. Patients were stratified according to ETS status and randomised to the following arms: abiraterone, with or without veliparib. ETS fusion failed to be a predictive factor [
84]. The results of this study were negative; however, a subgroup of patients with DDR achieved a higher PSA rate, PSA decline ≥ 90% and a median PFS that was 6.4 months longer. There have been no phase III clinical trials with veliparib to date.
PARPi in monotherapy is currently being evaluated in the neoadiuvant setting and in non-metastatic CSPC. Patients with high-risk, localised PCa with DNA alterations in the repair pathway will receive three cycles of niraparib (NCT04030559) or olaparib (BrUOG 337B, NCT 03,432,897) before prostatectomy. In the NCT03047135 trial, olaparib is being tested in high-risk, non-metastatic, biochemically recurrent PCa after prostatectomy. An analysis of biomarkers will be performed. In addition to the known drugs, newly designed PARPis are being investigated as a treatment option in phase I trials in advanced and metastatic solid tumours (NCT04182516, NMS-03305293; NCT03508011, IMP 4297-Senaparib). Pamiparib is a selective PARP1/2 inhibitor with a capability to penetrate the brain. Presently, it is being tested in a phase II trial in mCRPC positive for CTC with HRD (NCT03712930).
6.3 PARPis in Combination Therapy
After the promising results of PARPis in monotherapy, they are now being tested with drugs which, in recent years, have significantly broadened the treatment options for PCa patients, like novel antiandrogens, chemotherapy, radiopharmaceuticals and immunotherapy. The aim of combination therapy is to extend the population of patients who will benefit, especially in the group without DDR alteration.
Abiraterone and enzalutamide are second-generation AR axis-targeted therapies that decrease AR signalling, and increase OS in hormone-sensitive and -resistant PCa. The reciprocal relationship between AR signalling and PARP supports the development of combinational strategies. PARPi may enhance the potency of AR-targeted therapies, because PARP1 modulates interactions between chromatin and AR [
28,
85]. The efficacy of both drugs was evaluated in combination with PARPi in a phase II, randomised, placebo-controlled trial that compared abiraterone with or without olaparib. Abiraterone was seen to inhibit androgen synthesis by inhibition of CYP17 steroidogenesis enzymes. Irrespective of HRR status, combination therapy increased the median rPFS by 5.6 months, and may be considered as a new type of synthetic lethality [
86]. Enzalutamide is a second-generation antiandrogen that inhibits key stages of AR signalling. Preclinical research shows that PARPi and enzalutamide change the expression of apoptosis-related signalling pathways, and the most promising therapeutic strategy is enzalutamide following enzalutamide and olaparib therapy [
87]. In 2018, Clarke et al. published the results of a randomised, double-blind, placebo-controlled, phase II trial that provided clinical efficacy of combining therapy for patients with mCRPC who received docetaxel and were candidates for abiraterone treatment. Patients (
n = 142) were randomly assigned to olaparib + abiraterone or placebo + abiraterone arms. Median rPFS was significantly longer in the abiraterone plus olaparib group than in the abiraterone plus placebo group (13.8 vs. 8.2 months; HR 0.65; 95% CI 0.44–0.97,
P = 0.034), and this was independent of genetic status. The study BRCAAway is an ongoing randomised phase II trial in mCRPC with DNA repair defects (loss of
ATM,
BRCA1,
BRCA2). Patients who want to take part in the study will have to provide new material for biopsy. Enrolled patients are randomised to abiraterone + prednisone (arm I), olaparib (arm II), or abiraterone + prednisone and olaparib (arm III). If patients have non-canonical DNA-repair gene alterations, they will receive olaparib in monotherapy. Patients in olaparib or abiraterone arms may cross over to the combination therapy arm at progression. The primary end-point is radiographical and clinical PFS. The secondary end-points are objective disease and PSA response rates. PROpel is the first phase III trial (NCT03732820) designed to compare abiraterone + placebo to abiraterone + olaparib in patients with
BRCA1,2 or
ATM mutations with progressive mCRPC in the first-line setting of mCRPC. The aim of the TALAPRO-2 phase III trial (NCT03395197) is to compare rPFS in patients with asymptomatic or minimally asymptomatic patients with mCRPC treated with talazoparib or talazoparib with enzalutamide. Part I of the study determined the starting dose for talazoparib. Part II of the study will evaluate the efficacy, safety and pharmacokinetics of combination therapy. Patients are stratified by prior treatment and DDR mutation status.
An interesting proposal is combining PARPi with immunotherapy (anti PD-1 and PD-L1 inhibitors). PARP increases the tumoral immunogenicity by accumulation of neoantigens, epigenetic changes, and affecting the immune response and tumour microenvironment, which explains the possibility of increasing the efficacy of anti-PD-1/L1 inhibitors. The Keynote-365 phase Ib/II trial showed that median radiographic rPFS for pembrolizumab and olaparib was 4.3 months, and median overall survival (OS) was 14 months [
88]. The Keylink-010 study (NCT03834519) with olaparib and pembrolizumab is designed to test if combinations of these drugs increase OS and rPFS. Unselected patients enrolled into the study were pre-treated with enzalutamide/abiraterone and chemotherapy. The comparator will be a next-generation hormonal agent. Another phase II study is underway with durvalumab and olaparib for patients with biochemically recurrent (PSA double time < 9 months), non-metastatic CSPC with DDR mutations (NCT03810105). In addition, a phase Ib/II trial of anti PD-L1 avelumab and talazoparib will be tested to assess dose-limiting toxicity and overall response in patients with locally advanced, metastatic solid tumours, including CRPC (NCT03330405).
Docetaxel is an old chemotherapeutic agent that is currently used in castration-sensitive and CRPC patients. Patients with mCRPC with homologous HRR DNA deficiency (BRCA2, BRCA1, ATM, PALB2) will be enrolled in the PLATI-PARP study to receive four cycles of docetaxel and a carboplatin chemotherapy regimen, with rucaparib as a maintenance therapy (NCT03442556, PLATI-PARP).
In addition, there are clinical data that show that patients with BRCAmut are better responders to radiation therapy and, surprisingly, Radium-223 therapy [
89]. The ASCLEPlus trial (NCT04194554) is a phase I/II trial that will be evaluating dose-limiting toxicities and the proportion of patients experiencing biochemical failure. The inclusion criteria include node-positive PCa and/or high-risk PCa. Patients will receive niraparib, leuprolide, abiraterone, and stereotactic body radiotherapy at a total dose of 37.5–40 Gy. The ongoing clinical trials with radioligands include the combination of olaparib or niraparib with radium-223 in mCRPC (COMRADE, NCT03317392; NiraRAD, NCT03076203). 177 Lu-PSMA is a new innovative radioligand that demonstrates activity in heavily pretreated PCa. The LuPARP study is a phase I dose-escalation and dose-expansion study that will evaluate the safety and tolerability of olaparib in combination with 177Lu-PSMA (NCT03874884). A new concept in therapy includes combining PARPi with ATR inhibitor (AZD 6738, NCT03787680) or antiangiogenic drugs like cediranib (NCT02893917). ATR is a kinase of DNA damage response and modulates the ATR checkpoint kinase 1 signalling pathway [
90]. Cediranib is an orally active, small molecule inhibitor of VEGFR (vascular endothelial growth factor receptor).