New treatment option for patients with mCRPC

Metastatic castration-resistant prostate cancer (mCRPC) patients with PTEN loss or BRCA1, BRCA2, or ATM mutations all benefit from targeted therapy. In addition, HLE BiTE® immune therapy is a promising option for all patients with mCRPC.

About 40%-50% of mCRPC tumours show loss of the AKT phosphatase PTEN, which leads to hyperactivation of the oncogenic PI3K/AKT signalling pathway. In addition, it has been demonstrated that, due to reciprocal cross talk, blockade of the androgen receptor (AR)-activated pathway activates the PI3K/AKT signalling pathway, enabling prostate cancer cell survival [1]. Therefore, PTEN loss in mCRPC is associated with worse prognosis and reduced benefit of AR blockade.

In the randomised phase 3 IPATential 150 trial; 1,101 treatment-naïve patients with asymptomatic or mildly symptomatic mCRPC were 1:1 randomised to receive ipatasertib (400 mg daily) plus abiraterone (1,000 mg daily) and prednisone (5 mg twice daily) or placebo plus abiraterone and prednisone [2]. Patients were stratified to PTEN loss as determined by immunohistochemistry (≥50% of the tumour cells having no detectable PTEN staining). Median radiographic progression-free survival (PFS) in the intention-to-treat (ITT) population did not meet the prespecified significance level (19.2 months vs 16.6 months; HR 0.77; P=0.043). In the prespecified subgroup analysis of patients with PTEN loss (n=521), median radiographic PFS was 18.5 months in the ipatasertib arm versus 16.5 months in the placebo arm (HR 0.77; P=0.033). Secondary endpoints favoured the combination arm: objective response rate increased from 39% to 61%, PSA response rate increased from 72% to 84%, and time to PSA progression increased from 7.6 months to 12.6 months in the PTEN-loss population. Treatment with ipatasertib plus abiraterone/placebo was associated with more toxicity. Most prominent adverse events were diarrhoea, hyperglycaemia, and skin rash.

The phase 3 PROfound trial evaluated PARP inhibition in mCRPC patients with alterations in BRCA1, BRCA2, or ATM [3,4]. A total of 245 patients were 2:1 randomised to receive olaparib (300 mg twice daily) or control (enzalutamide or abiraterone plus prednisolone). Median PFS was significantly improved in the olaparib arm (7.4 vs 3.6 months; HR 0.34; P<0.001). Median final OS was significantly longer with olaparib compared with controls (19.1 vs 14.7 months; HR 0.69; P=0.0175), despite 56% cross-over from control to olaparib.

Bispecific T-cell engager (BiTE) antibody constructs represent a novel immunotherapy that bridges cytotoxic T cells to tumour cells, thereby inducing target-cell-dependent polyclonal T-cell activation and proliferation, and leading to apoptosis of bound tumour cells [5]. AMG 160 is a PSMA-targeted BiTE that engages patients’ own T cells to kill prostate cancer cells via binding of CD3 on T cells and PSMA on cancer cells. In an ongoing phase 1 study, AMG 160 was administered to 43 patients with mCRPC refractory to prior novel hormonal therapy and 1-2 taxane regimens and evidence of progressive disease, at doses of 0.003–0.9 mg [6].

A total of 41 patients experienced treatment-related adverse events, not resulting in treatment discontinuation. Most common treatment-related adverse event was cytokine-releasing syndrome, which occurred in 39 patients. Preliminary efficacy data showed 68% of patients had any PSA decline across all dose cohorts; 34% of patients showed more than 50% PSA decline. Of 15 patients with available RECIST response evaluation, 2 had confirmed partial response, 1 had unconfirmed partial response, and 8 had stable disease.

1. Carver BS, et al. Cancer Cell 2011;19:575-586.
2. de Bono JS, et al. IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). ESMO 2020 Virtual Meeting, abstract LBA4.
3. de Bono JS, et al N Engl J Med 2020;382:2091-2102.
4. de Bono JS, et al. Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations. ESMO 2020 Virtual Meeting, abstract 610O.
5. Klinger M, et al. Immun Rev 2016;270:193-208.
6. Tran B, et al. Results from a phase I study of AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE®) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). ESMO 2020 Virtual Meeting, abstract 609O.