New interventions offer prostate cancer hope

Abstract

Prostate cancer is one of the most common cancers worldwide, with about 1·1 million cases diagnosed annually. Depending on the stage of disease at diagnosis, prostate cancer can be managed with combinations of active surveillance, surgery, radiotherapy, and androgen-deprivation therapy (ADT). However, some men have aggressive disease, in which rising concentrations of prostate-specific antigen (PSA) herald biochemical relapse and metastatic disease, even after treatment. Currently, no standard treatment is available for these men; however, promising new data from two trials presented at the 2018 ASCO Genitourinary Cancers Symposium (Feb 8–10, 2018, San Francisco, CA, USA) suggest that this situation might be about to change. The two trials PROSPER and SPARTAN both treated men with early-stage, castration-resistant M0 disease who were unsuitable for curative treatment, and who were being treated with ADT, but continued to have rapidly increasing PSA concentrations. Patients whose PSA doubling time is between 6 and 10 months are very likely to develop metastatic disease, making any interventions at this point extremely beneficial. SPARTAN is the first phase 3 trial to test a new antiandrogen, apalutamide, whereas PROSPER tested enzalutamide. For both trials, the primary endpoint was metastasis-free survival (MFS). Both trials reported exceptional outcomes. In SPARTAN, men receiving apalutamide had a median MFS of 40·5 months compared with 16·2 months for those receiving placebo (hazard ratio [HR] 0·28; 95% CI 0·23–0·35; p<0·001). Similarly, in PROSPER, men receiving enzalutamide had a median MFS of 36·6 months compared with 14·7 months with placebo (HR 0·29; 95% CI 0·24–0·35). Apalutamide was subsequently approved by the US Food and Drug Administration on Feb 14, 2018, under Priority Review for non-metastatic, castration-resistant prostate cancer on the basis of SPARTAN's findings—the first drug to be approved for this patient population. The nature of this intervention is contingent upon actively monitoring PSA changes. Prostate cancer provides one of the best examples in oncology for which active surveillance has been proven to be as effective an intervention as treatment. For example, in 20-year follow-up data from the PIVOT trial for men diagnosed with early localised prostate cancer, no significant difference was found in either all-cause or prostate-cancer specific mortality when comparing men treated with either surgery or observation alone, but men in the surgery group had worse functional outcomes from surgery (eg, incontinence, erectile dysfunction) for up to 5 years after treatment. Given these outcomes, the impetus for early detection and thus early management of prostate cancer is important, making recent news of faster prostate cancer diagnosis in the UK welcome. Diagnosis in the UK typically requires multiple hospital visits to obtain scans and biopsies; however, three London hospitals are trialling whether or not patients can be diagnosed within a day. This faster approach hinges on the use of multiparametric MRI scans instead of transrectal ultrasound-guided biopsy, allowing all diagnoses to be done through imaging, which is both faster and non-invasive. About 5000 men will be tested for prostate cancer at these hospitals over the next 2 years, before a decision can be made as to whether the new system should be rolled out nationally. If successful, this one-stop-shop approach might stimulate the development of other short and intense assessments for diagnosis of other cancer types. Caution is still needed though. First, although PSA can be useful for prostate cancer diagnosis or growth, its utility is in providing an early warning through measuring change over time. Use of an arbitrary cut-off for PSA concentration can lead to over diagnosis and over treatment, and measures—eg, those regarding doubling times—should be standardised. Second, it is important to be aware that despite such advances as increased time to distant metastases, the endpoint used in the latest trials do not necessarily also indicate increased survival. For example, in SPARTAN the median time to overall survival—a prespecified, albeit unpowered endpoint—did not differ significantly between the groups; comparable data are still awaited for PROSPER. Moreover, although no development of distant metastases does lead to a better prognosis, local recurrence and progression cannot be disregarded. This factor, and treatment-related adverse events, must be considered when deciding therapy options. Nonetheless, it cannot be denied that progress is being made in prostate cancer treatment and management, and such advances must be applauded.