mCRPC: challenges and treatments

Metastatic prostate cancer epidemiology

Prostate cancer is one of the most prevalent malignant cancers in the world¹.

Many newly diagnosed patients with prostate cancer have localised disease, and receive prostatectomy or radiation therapy, followed by androgen-deprivation therapy (ADT). Prostate cancer cells can become resistant to ADT within 2–3 years, although there is variation in this figure in the published literature^2-10. Cell malignancy can progress, even when serum testosterone is below castrate level^2-10.

Due to this loss of hormone sensitivity, some patients develop castration-resistant prostate cancer (CRPC)^2-10. CRPC can advance to metastatic CRPC (mCRPC), which is associated with high mortality¹¹. mCRPC can also develop de novo, or from metastatic castration-sensitive prostate cancer (mCSPC)^2-10.

Approximately 700,000 men diagnosed with prostate cancer have metastatic disease, accounting for more than 400,000 deaths globally per year¹². This mortality is expected to more than double by 2040¹³. Despite the available treatments for mCRPC, the disease remains incurable.

Unmet needs in metastatic castration-resistant prostate cancer include no curative treatment, treatment selection, sequencing, and intensification

Unmet patient needs for a given disease or condition reflect several common factors³⁸:

Precision medicine in metastatic castration-resistant prostate cancer

Genomic alterations tend to be heterogeneous in mCRPC, and show specific effects in mCRPC progression, and resistance to treatments^19,50. Through understanding how specific genes or pathways are altered in an individual with mCRPC (Figure 5), precision medicine could advise on suitable diagnostic tests, and treatment approaches, for patients^19,50.

To help meet unmet treatment needs for mCRPC, novel first-line pharmaceutical strategies, including new therapeutic combinations, are under investigation

A new standard-of-care for metastatic castration-resistant prostate cancer?

In advanced prostate cancer, there is an unmet need for new, alternative treatments that could overcome treatment resistance. In the mCRPC setting, several investigational treatments have emerged as candidate first-line treatments, and could become the next-generation standard-of-care (SOC) (Table 3)^21,48.

Treatment sequencing and intensification for metastatic castration-resistant prostate cancer

Current clinical practice guidelines for mCRPC advise first-line androgen-receptor signaling inhibitor followed by chemotherapy, as the preferred treatment sequence^3,6-10,47. However, how can individual treatments for mCRPC be best used? Is there an optimal treatment sequence, or intensification? There is a lack of evidence comparing the different treatment options for mCRPC (Figure 3), especially head-to-head clinical trial evidence. This deficit can increase clinical uncertainty^108,109.

In clinical practice, ideal treatment decision-making for mCRPC relies on evaluation of patient health, comorbidities, degree of frailty, previous treatments (efficacy, toxicity), patient preferences, or the availability of clinical trials¹⁰⁸.

Based on the data in Table 3, and on the preceding analysis in this section, a speculative mCRPC treatment algorithm (sequencing and intensification), encompassing four possible scenarios, has been proposed (Figure 11)¹⁰⁹.