Systemic treatment for prostate cancer progressing while receiving initial ADT (castration-resistant prostate cancer)

For most males, ADT should be continued as additional systemic therapy options are utilized sequentially. Where cost is an issue, another option is to hold the GnRH agonist and monitor serum testosterone at two- to three -month intervals; treatment can be resumed when testosterone levels begin to rise. All males with advanced prostate cancer should undergo germline and somatic genomic testing to identify potentially actionable genetic variants. Individuals with bone metastases should receive therapy with an osteoclast inhibitor, and those with painful bone metastases should be referred for external beam RT.

PSA: prostate-specific antigen; ADT: androgen deprivation therapy; ARPI: androgen receptor pathway inhibitor; PSMA: prostate-specific membrane antigen; PARP: poly(ADP-ribose) polymerase; GnRH: gonadotropin-releasing hormone; RT: radiation therapy; CRPC: castration-resistant prostate cancer.

* Examples of aggressive features include: morphologic or histologic evidence of small cell neuroendocrine differentiation, exclusively visceral metastases, predominant lytic bone disease, bulky lymphadenopathy, low PSA at initial presentation or at symptomatic progression, short interval to androgen-independent progression following initiation of hormone therapy. Refer to UpToDate topics on castration-resistant prostate cancer for more information.

¶ All three trials demonstrating a survival benefit for apalutamide, enzalutamide, or darolutamide in nonmetastatic CRPC enrolled patients with a PSA doubling time of 10 months or less.

Δ ARPIs include abiraterone, enzalutamide, darolutamide, and apalutamide.

◊ Sipuleucel-T use should be restricted to asymptomatic or minimally symptomatic males with CRPC who have slowly progressing disease not requiring a rapid response. It is contraindicated in those receiving glucocorticoids or opioids for cancer related pain, and should only be used cautiously in those with liver metastases. Radium-223 is only for patients with symptomatic bone metastases, no visceral metastases.

§ PARP inhibitor for those with homologous recombination repair deficiency; pembrolizumab or dostarlimab are options for patients with deficient mismatch repair/high levels of microsatellite instability, or pembrolizumab if a high tumor mutational burden.

¥ Chemotherapy is a more toxic approach than an ARPI but may be chosen over an ARPI in the setting of rapidly progressive, symptomatic advanced disease.

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Systemic treatment for prostate cancer progressing while receiving initial ADT (castration-resistant prostate cancer)