Learning Objective

At the conclusion of the activity, participants will be able to describe the various disease states comprising advanced prostate cancer and advancement in management.

Advanced prostate cancer (APC) is a diverse disease state encompassing biochemical recurrence, metastatic hormone sensitive prostate cancer (mHSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC), and metastatic castration-resistant prostate cancer (mCRPC). Over the past several decades many advances have yielded improvements in patient quality of life and survival, but still prostate cancer accounts for 11% of all cancer-related death in men in the United States.¹ This AUA2022 course highlighted the current and rapidly evolving diagnostic and treatment landscape for men with APC.

It is well established that prostate cancer is an androgen-driven disease, and in patients with APC, androgen deprivation therapy (ADT) remains the mainstay of treatment. However, the course reviewed updated Guidelines which note that men with biochemical recurrence alone should not routinely initiate ADT. When considering factors such as total PSA, PSA doubling time, and patient comfort, ADT may be initiated in select, truly high-risk patients. In the absence of metastatic disease, intermittent ADT may be considered, given noninferior overall survival (OS) and improved patient quality of life, and in fact this is the one place the Guidelines consider intermittent ADT.²

The course reviewed exciting and rapidly advancing management options for patients with mHSPC. Discussion centered on important treatment-related considerations like baseline PSA, PSA velocity, patient symptomatology, prior therapy, disease volume, and genetic test results. Regarding disease extent, the CHAARTED definition of high-volume (visceral metastasis and/or 4+ bone metastases with at least 1 beyond pelvis and vertebral column) and low-volume disease were reviewed, noting the impact of disease burden on response to therapy.³ Additionally, for mHSPC and throughout the continuum of APC, we discussed the recommendation for germline testing and genetic counseling. This is particularly important given that newly diagnosed metastatic patients have an ˜12% chance of harboring an inherited DNA repair gene mutation—a scenario where cascade counseling may be beneficial.⁴

The course stressed that, while androgen deprivation with medical or surgical castration is essential, no longer is “ADT alone” the standard of care in men with mHSPC. We reviewed robust, high-level evidence demonstrating that either docetaxel chemotherapy or an androgen pathway directed therapy like abiraterone, apalutamide, or enzalutamide in combination with ADT improves survival. CHAARTED stratified men according to several factors including extent of metastatic disease and performance status prior to randomization. Results indicated improved OS with the addition of docetaxel and a more robust advantage in high-volume patients.³ Similarly, in STAMPEDE, patients who received docetaxel with ADT experienced a highly significant OS benefit although there was no survival difference by volume status, likely reflecting differences in the study populations.⁵ Abiraterone, a potent androgen synthesis inhibitor, is also approved for treatment of mHSPC based on LATITUDE, which demonstrated OS and progression-free survival benefits, and STAMPEDE, with an OS benefit favoring combination therapy over ADT alone.^6,7 And finally, we reviewed the androgen receptor-targeted treatments that have established superiority over ADT alone with apalutamide in the TITAN trial, and enzalutamide in ARCHES and ENZAMET.^8-10 We noted that local therapy may benefit select patients with low-volume mHSPC based on STAMPEDE, but additional data are needed prior to offering surgery to men with metastatic disease.¹¹

The course also highlighted new data not yet included in the Guidelines but likely to be reflected in upcoming revisions regarding “treatment intensification” in mHSPC. A recent multicentered 4-arm, phase III trial, PEACE-1, evaluated the potential benefit of adding abiraterone to ADT and docetaxel, with or without radiation.¹² Results were highly significant with improvements in radiographic progression-free survival and OS. Subgroup analysis showed a benefit in both high- and low-volume patients, although intensification yielded more adverse events including hypertension and liver toxicity. ARASENS also examined treatment intensification with the addition of darolutamide to ADT and docetaxel.¹³ This international, randomized, double-blind, placebo-controlled trial again demonstrated a highly significant survival benefit without any increase in adverse events. The benefit of treatment intensification for mHSPC is intriguing, but there remain unanswered questions regarding the potential for overtreatment and increased side effects. Ultimately, an adaptive treatment approach may be required with consideration of fitness for chemotherapy, symptom burden, cost, patient preference, disease volume, and histological or molecular features. One consideration may be its use for this triple therapy in select patients who present with de novo high-volume metastatic disease for example.

We then reviewed management of patients with nmCRPC, focusing on 3 trials evaluating androgen-­targeted therapies in men with a rapid PSA doubling time (≤10 months) at high risk for metastasis. In SPARTAN, apalutamide was compared to placebo, and initial publication demonstrated a significant delay in metastasis-free survival (MFS) while mature data indicated a survival benefit.^14,15 With a similar trial design and outcome, PROSPER results showed improved MFS with enzalutamide and ultimately a risk of death 27% lower than with placebo.^16,17 Darolutamide with ADT was compared to placebo for M0 castration-resistant prostate cancer patients in ARAMIS, again yielding impressive MFS and OS benefits.¹⁸

Over the past several years, numerous therapies have emerged offering a survival benefit for men with mCRPC, a disease generally associated with poor outcomes. Many of these agents were first approved in this advanced state and have since “moved up” earlier in the disease continuum as discussed above, including docetaxel, abiraterone, and enzalutamide.^19-21 We reviewed the mechanism of action and data in support of the novel immunotherapeutic sipuleucel-T and the radiopharmaceutical radium-223, both of which have demonstrated an OS advantage for specific mCRPC patient subsets.^22,23

One of the most exciting recent advancements in mCRPC highlighted at this year’s course was the approval of poly(adenosine diphosphate-ribose) polymerase inhibitors. These novel drugs target defects in DNA repair genes in mCRPC patients, resulting in antitumor activity and more favorable outcomes. In the phase III PROfound trial, patients with prespecified gene alterations experienced improved clinical outcomes (radiographic progression-free survival, OS) with olaparib following progression through at least 1 novel androgen directed therapy.²⁴ In the TRITON2 study, rucaparib benefited patients with germline or somatic BRCA1/2 alterations who had progressed through both a second-generation antiandrogen- and taxane-based chemotherapy.²⁵ Here again we reviewed the importance of somatic and genetic testing in conjunction with genetic counseling.

Throughout the course, faculty discussed the development and implications of and indications for next-generation imaging in APC. Specifically, prostate-specific membrane antigen (PSMA) positron emission tomography (PET) was noted to be an absolute gamechanger, altering the way we evaluate patients and, soon, how we treat the disease (theranostics). In December 2020, the U.S. Food and Drug Administration approved the first PSMA-targeted PET imaging drug (Ga 68 PSMA-11) for men with prostate cancer and a rising PSA after failed local therapy. This approval was based on data indicating that PSMA PET offers a high positive predictive value and provides important information that impacts therapeutic approach, even at very low PSA values.²⁶ In May 2021, the U.S. Food and Drug Administration approved a second PSMA-targeted PET imaging drug for men with prostate cancer (piflufolastat F18) based on 2 studies. In the CONDOR study, men with a rising PSA after failed local therapy underwent ¹⁸F-DCFPyL-PET, which resulted in a change in management.²⁷ In OSPREY, 2 populations were examined—those with high-risk prostate cancer undergoing prostatectomy with lymphadenectomy and those with rising PSA after prior local therapy.²⁸ Again, results indicated a high positive predictive value. Likely, many patients with APC previously considered nonmetastatic will now be reclassified as metastatic. We must also consider that the use of PSMA PET may not change the way patients respond to therapy. We expect updated guidelines and future courses to address advanced imaging in further detail.

So, the landscape for men with APC continues to evolve. Key themes that will be further explored as we go forward include moving effective agents up earlier in the disease state, treatment intensification and combinations that have different mechanisms of action, and a greater role for precision medicine. We are also beginning to get a much clearer picture on treatment sequencing, particularly in the mCRPC disease state. We look forward to crafting many of these updates and new trial information into a revised AUA Guidelines for APC this year, so stay tuned.