Are we reaching a turning point in metastatic prostate cancer?

At yesterday’s Presidential Symposium, a Late-Breaking Abstract presentation of the PROfound study reported a clinically meaningful benefit in radiological progression-free survival (PFS) with olaparib in men with BRCA1, BRCA2 or ATM mutations in metastatic castration-resistant prostate cancer (mCRPC) (Abstract LBA12_PR).

PROfound is a prospective, multicentre, randomised, open-label, phase III study evaluating the efficacy and safety of olaparib versus enzalutamide or abiraterone in 387 patients with mCRPC who have failed prior treatment with a new hormonal agent and have a tumour mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. This trial could be considered the first positive phase III biomarker-selected study in mCRPC and it is the largest to have central prospective HRR mutation tissue testing.

The targeted agent also demonstrated an improved objective response rate (ORR). There was also a trend towards improvements in overall survival in those with BRCA1, BRCA2 or ATM mutations and those with any qualifying HRR gene mutation (hazard ratios [HRs] 0.64 [p=0.017] and 0.67 [p=0.006, nominal], respectively), despite the opportunity for treatment crossover (Abstract 847PD). Olaparib reduced the risk of progression by 66% (p<0.0001) in patients with alterations in BRCA1, BRCA2 or ATM and by 51% (p<0.0001) in patients with alterations in any qualifying HRR gene.

"The results certainly look impressive but there are a number of issues we should not overlook,” says Prof. Silke Gillessen Sommer from the University of Manchester, UK. "Firstly, the use of the alternative new hormonal agent may not be considered to be a strong comparator in these patients, who have already failed on abiraterone or enzalutamide. We know that response rates, especially with abiraterone after enzalutamide, but also vice versa, are low. In fact, in countries such as the UK, this poor efficacy precludes treatment with the second agent.” Another issue is the fact that from 4,047 samples tested only about two-thirds (69%) yielded interpretable results, which means that some patients will miss the opportunity to receive a potentially helpful drug. Also, toxicity has to be considered, with twice as many patients discontinuing treatment due to adverse events with olaparib compared with hormonal therapy—16.4% versus 8.5%.

Despite these concerns, Gillessen thinks it is likely that results from PROfound will be practice changing for patients with BRCA mutations while the situation remains less clear-cut for patients without BRCA mutations. At ESMO Congress 2019, new hope for a more effective treatment of men with advanced prostate cancer stem from the results of the phase II CheckMate 9KD trial, presented on Sunday (Abstract LBA52). This trial evaluates the combination of nivolumab with docetaxel, rucaparib or enzalutamide. Data on 41 chemotherapy-naïve patients with mCRPC from the nivolumab plus docetaxel arm were presented. Clinical activity, with an ORR of 36.1% in 19 evaluable patients, a confirmed prostate-specific antigen (PSA)-response rate of 46.3% and a median radiographic PFS of 8.3 months were observed. Any-grade and grade 3–4 treatment-related adverse events occurred in 92.7% and 48.8% of patients, respectively. Commenting on the results, Gillessen recommends cautious optimism. "Up to now, no agent added to docetaxel has shown a benefit over docetaxel alone in phase III trials, despite exhibiting promising activity in phase II trials,” she says. "The response rate for measurable disease of around 40% in this study looks encouraging compared with historic data, but we do not know if these measurable lesions were mostly lymph nodes. In addition, the study involves only a small number of patients. Added to that is the challenge of not having a single-agent comparator arm, so it is difficult to determine if the activity is due to the combination partner—chemotherapy—rather than the trial agent. And we know that patients can respond well to docetaxel, particularly when they are chemotherapy naïve. We also know that phase II trial response rates are often higher than those in phase III trials. Finally, if we look at the PSA response rate, this is similar to what can be expected with docetaxel monotherapy. So, while we should remain positive about the efficacy of immunotherapy–chemotherapy combinations in general, we need more data before we can draw conclusions.”

Gillessen suggests what she considers to be the most important research priorities going forward. "We need to find out why some patients have profound, durable responses to PARP inhibitors and immunotherapy, and explore how this can be extended to other patients. There also needs to be more research on the optimal evaluation of HRR alterations and investigation of potential functional assays that could improve patient selection.”