Precision therapy for prostate cancer – at last

Precision therapy for prostate cancer (PC) is becoming reality, with recent studies demonstrating efficacy of this approach in patients with metastatic castration-resistant PC (mCRPC) with certain DNA damage repair (DDR) alterations or PTEN loss.

PC is a hormone-dependent tumour, driven by recurrent alterations in the androgen receptor and its pathway. [N Engl J Med 1995;332:1393-1398] In the early stages, it tends to respond well to androgen ablation, which was pioneered by Charles Huggins in the 1940s, and remains the primary form of PC treatment to this day. [Arch Surg 1941;43:209]

Nevertheless, the majority of advanced or metastatic PC patients develop castration-resistant disease unresponsive to androgen deprivation therapy (ADT), highlighting the need for alternative treatment approaches, especially upon disease progression. [Curr Opin Urol 2016;26:231-239]

While multiple studies have failed to identify highly recurrent clinically actionable genetic alterations in the primary setting, the extensive mutational landscape of mCRPC has exposed the possibility of targeted therapies and precision medicine for these patients. [Cell 2015;163:1011-1025; Nat Genet 2015;47:736-745; Cell 2015;161:1215-1228]

Genomic profiling

Comprehensive genomic profiling (CGP) is increasingly used in routine clinical management of PC, with evidence accumulating that certain genomic alterations drive responses to specific therapies. [JCO Precis Oncol 2017, doi: 10.1200/PO.17.00029]

For example, genomic biomarkers, such as BRCA1/BRCA2/ATM, PTEN/AKT, and PIK3CB, are shown to predict response to poly(ADP-ribose) polymerase (PARP) inhibitors, AKT inhibitors, and phosphatidylinositol 3-kinase (PI3K)-β inhibitors, respectively. [N Engl J Med 2015;373:1697-1708; Ann Oncol 2016;27:7180; J Clin Oncol 2017;35:2251-2259; Clin Cancer Res 2017;23:5981-5992] Furthermore, while immunotherapy has thus far been only moderately successful in PC, recent research suggests that responses to immunotherapy may be more prominent in tumours with CDK12 and POLE genomic alterations and those with tumour mutational burden-high (TMB-H) or microsatellite instability-high (MSI-H) genomic signatures. [Cell 2018;173:1770-1782.e14; JCO Precis Oncol 2018;2:1-8; Science 2017;357:409-413]

A recent real-world CGP study of 1,660 primary-site and 1,816 metastatic-site unique PC tumours identified investigational biomarker genomic alterations for targeted therapies in 57 percent of cases. [JCO Precis Oncol 2019, doi: 10.1200/PO.18.00283] The European Society for Medical Oncology (ESMO) Virtual Congress 2020 reported some of the developments in the emerging field of precision PC medicine.

PROfound improvements for BRCAmut patients

Germline deleterious mutations in DDR genes are present in 8–16 percent of metastatic PC patients, while inherited BRCA1 and BRCA2 mutations that impair gene function occur in 0.9 percent and 3–5 percent of patients with advanced PC. [Cell 2015;161:1215-1228; N Engl J Med 2016;375:443-453; J Clin Oncol 2019;37:490-503] BRCA2 mutations, in particular, are significantly associated with worse overall and cancer-specific survival in PC. [Prostate 2019;79:880-895] Of note, overall DDR genes’ (12 percent) and BRCA1 (0.63 percent) and BRCA2 (6.3 percent) mutation frequencies are similar between Caucasian and Asian metastatic PC patients. [Eur Urol 2019;76:280-283]

In May 2020, the PARP inhibitor olaparib became the first US FDA-approved agent for mCRPC with deleterious germline or somatic homologous recombination repair genetic mutations. The approval was based on results of the phase III PROfound trial presented at ESMO 2019, which demonstrated significantly longer radiographic progression-free survival (rPFS) in patients with ≥1 alteration in BRCA1/2 or ATM genes who had failed previous therapy with abiraterone and/or enzalutamide (median PFS, 7.4 months with olaparib vs 3.6 months with physician’s choice of enzlutamide or abiraterone plus prednisone; hazard ratio [HR], 0.34; 95 percent confidence interval [CI], 0.25 to 0.47; p<0.001). The rPFS HRs were 0.41 and 0.21 for patients with BRCA1 or BRCA2 alterations, respectively.

Adverse events (AEs) occurred more frequently with olaparib than with physician’s choice of hormonal therapy, which is possibly in part due to the longer duration of therapy in the olaparib arm (7.4 months vs 3.9 month). The most common adverse events (AEs) were anaemia (46.1 percent vs 15.4 percent), nausea (41.4 percent vs 19.2 percent), fatigue and asthenia (41.0 percent vs 32.3 percent), and decreased appetite (30.1 percent vs 17.7 percent). [N Engl J Med 2020;382:2091-2102]

Final PROfound data reported at ESMO 2020 showed a median overall survival (OS) of 19.1 months with olaparib in patients with BRCA1/2 or ATM mutations, vs 14.7 months with abiraterone or enzalutamide (HR, 0.69; 95 percent CI, 0.50 to 0.97; p=0.0175). Longer follow-up yielded no new safety signals. [Ann Oncol 2020;31(Suppl 4):S507-S549]

IPATential treatment for tumours with PTEN loss

mCRPC is characterized by the activation of the PI3K–Akt–mTOR and androgen receptor signalling pathways. The PI3K–Akt–mTOR is frequently hyperactivated in cases of PTEN loss, an important tumour suppressor phosphatase that is inactivated in 40–60 percent of mCRPCs. [Cancer Cell 2011;19:792-804; Cell 2015;161:1215-1228] Loss of PTEN expression is associated with worse survival and shorter time on abiraterone treatment. [Eur Urol 2015;67:795-802] At the same time, the combined pharmacologic inhibition of PI3K and androgen receptor signaling causes near-complete prostate cancer regressions in a PTEN-deficient murine prostate cancer model and in human prostate cancer xenografts. [Cancer Cell 2011;19:575-586]

Ipatasertib is a potent, selective ATP-competitive small-molecule inhibitor of all three isoforms of Akt. A study in tumour biopsies demonstrated PI3K–Akt–mTOR pathway inhibition by ipatasertib at clinically achievable doses, while a phase I study of single-agent ipatasertib in 52 pretreated patients with various tumour types demonstrated an acceptable tolerability profile. [Clin Cancer Res 2013;19:6976-6986; Cancer Discov 2017;7:102-113]

Results of the phase III IPATential150 study reported at ESMO 2020 showed that ipatasertib improved rPFS in asymptomatic or mildly symptomatic patients previously untreated for mCRPC. At a median follow-up of 19 months, rPFS in patients with PTEN loss (confirmed by immunohistochemistry [IHC] in ≥50 percent of tumour cells) was 18.5 months in the ipatasertib plus abiraterone and prednisone group vs 16.5 months in the abiraterone and prednisone plus placebo group (HR, 0.77; 95 percent CI, 0.61 to 0.98; p=0.0335). [Ann Oncol 2020;31(Suppl 4):S1153-S1154]

Serious AEs occurred in 40 percent vs 23 percent of patients in the ipatasertib vs placebo group, with AEs leading to treatment discontinuation reported in 21 percent vs 5 percent of patients. In an earlier phase II trial, the most common serious AE with ipatasertib was pneumonia. The most commonly reported AEs with ipatasertib combination regimen included diarrhoea (76.2 percent vs 44.8 percent), nausea (52.4 percent vs 34.5 percent), vomiting (31 percent vs 27.6 percent), and asthenia (27.4 percent vs 19.5 percent). [Clin Cancer Res 2019;25:928-936]

Future directions

Positive phase III data mark a significant advance for PC treatment, which has lagged behind other common tumours, such as breast, ovarian and lung cancers, where precision therapy has become the standard of care.

Other potentially actionable PC biomarkers of interest highlighted at ESMO 2020 included the HSD3B1 gene and HER2 expression in circulating tumour cells (CTCs).

The 1245C allele of the HSD3B1 gene encodes for a missense and hyperactive enzyme that increases extragonadal androgen synthesis and is associated with poorer outcomes after ADT in PC. Homozygous mutant CRPC patients on ADT had significantly shorter median PFS than wild-type patients (18.0 months vs 54.0 months; p=0.01), while the presence of only one mutant allele did not significantly impact PFS (54.0 months vs 44.0 months; p=0.376). The researchers suggested that HSD3B1 gene screening could therefore be used to identify patients with rapid progression on ADT for closer follow-up. [Martín-Abreu CM, et al, ESMO 2020, poster 658P]

Several studies showed that IHC-detected HER2 expression in primary or metastatic PC is associated with poor outcomes. While studies of HER2-targeted agents trastuzumab and lapatinib failed to show significant antitumour activity in PC to date, they did not select patients according to HER2 status. [Cancer Res 2017;77:74-85; Prostate 2004;60:332-337; Urol Oncol 2013;31:82-86]

In a study in 41 mCRPC patients (31 treated with abiraterone or enzalutamide), HER2 mRNA expression was detected in CTCs of 63 percent of patients and was associated with significantly shorter PFS as measured by prostate-specific antigen levels (6.2 months in patients with HER2-positive CTCs vs 13.0 months in patients with HER2-negative CTCs; p=0.034) and with shorter rPFS (6.8 months vs 25.6 months; p=0.022). Median OS was 22.7 months vs not reached (HR, 2.85; 95 percent CI, 0.95 to 8.5; p=0.05). [Maillet D, et al, ESMO 2020, poster 675P]

Although none of the patients with HER2-positive CTCs had HER2 expression detected on available biopsies of soft tissue metastases, the researchers concluded that HER2 mRNA expression in CTCs could be a novel prognostic and targetable marker for mCRPC.