Emerging treatment options for the management of metastatic castration-resistant prostate cancer


Prostate cancer is the most common solid organ malignancy diagnosed in men in the United States, accounting for 13% of new cancer cases annually.1,2 Although localized disease is associated with high survival rates, advanced or metastatic disease has proven more challenging to treat, with 5-year survival rates found to be approximately 30%.2

Metastatic castration-resistant prostate cancer (mCRPC) is responsible for the majority of prostate cancer–related deaths. In recent years, newer imaging technologies have yielded additional insights about mortality risks, including the number and location of metastatic sites, whereas novel therapeutic agents have provided more options for patients.1,3

Androgen deprivation therapy (ADT) with androgen receptor (AR)–pathway blockers are the commonly used treatments for patients with metastatic or recurrent disease and are usually associated with good initial response.3,4 However, many patients develop resistance and relapse even with castrate testosterone levels. For these patients, more aggressive treatment is needed, said Leonard Gomella, MD, the Bernard W Godwin Jr Professor of Prostate Cancer, chairman of the Department of Urology, clinical director of the Jefferson Kimmel Cancer Center Network, and senior director for clinical affairs at the Jefferson Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, in an interview with Urology Times®. “When a man initially presents with metastatic disease or fails initial systemic therapy, our approach has to be different. We are more concerned that their disease is more aggressive,” he said.

Newer imaging technologies may impact some men with nonmetastatic CRPC (M0) based on standard imaging, according to Gomella. “A big unknown right now is in the setting of stage M0 CRPC disease and the impact of the PSMA [prostate-specific membrane antigen] scan,” Gomella observed. “Will the PSMA scan’s widespread use suddenly reduce the number of men considered to be M0 and reclassify them as stage M1? That remains to be seen and is something we’ll be watching.”

Another exciting technology that is having an immediate impact in prostate cancer management is liquid biopsy, which has become a more widely available testing option and allows identification of specific genetic alterations in tumors and evaluation of a patient’s germline, according to Gomella. “You don’t need to have a tissue biopsy of a metastatic lesion. Liquid biopsy is becoming more common [for evaluating] treatment options for metastatic disease,” he said. Liquid biopsies are not yet in broad use across the urologic specialty, but Gomella believes their convenience and reliability will increase their adoption. “Simply doing a blood draw vs biopsying a lymph node or a metastatic lesion is a much more appealing approach,” he observed. Additionally, he noted, “Having been involved with the first report using molecular techniques to detect prostate cancer cells in the blood in 1992, I am a big believer in the future of this technology in daily patient care.”5

Current Treatment Approaches

For patients with newly diagnosed hormone-sensitive, metastatic prostate cancer, ADT (luteinizing hormone-releasing hormone [LHRH] agonists or antagonists or surgical castration) combined with apalutamide, abiraterone acetate plus prednisone, enzalutamide, or docetaxel are recommended options in the 2021 treatment guidelines set forth by the American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology. After a patient has progressed on any of these initial ADT combination approaches and has developed CRPC (as defined by castrate level of testosterone and rising prostate-specific antigen [PSA] levels), next-generation agents that target the AR are the next option to consider.3,4 For patients with negative standard imaging (CT or bone scan) and staging as M0 nonmetastatic CRPC, Gomella noted that currently approved drugs are apalutamide, darolutamide, and enzalutamide. These medications should be considered in this group of men at high risk for developing metastatic disease—for example, in those with a PSA doubling time of at least 10 months. If the patient has evidence of mCRPC, however, “continuing ADT is the mainstay, but many agents are now available as additional first line therapy, such as abiraterone, enzalutamide, chemotherapy, radionuclide therapy with radium-223, or immunotherapy using sipuleucel-T,” explained Gomella.

According to Gomella, taxane-based chemotherapy such as docetaxel, despite being beneficial in certain patients, may be underused because of the feared impact of toxicities by the patient. “When you say ‘chemotherapy’ to any patient [diagnosed with] with cancer, it creates a negative impression [and is associated with things like] hair loss, nausea, and vomiting. That’s sad, because chemotherapy is administered much more safely than in the past,” said Gomella. “Today, we better understand which patients are good candidates for chemotherapy. When you have widespread, castrate-resistant metastatic disease, chemotherapy is often the best way to go based on clinical trial data,” noted Gomella. “However, you need to consider many parameters, such as patient history and laboratory values; [there are] many more considerations with chemotherapy than with some of the other agents.”

Emerging and Later-Line Options

Given the possibility of progressive disease in patients with mCRPC treated with initial first-line therapy, selection of therapeutic agents and the best sequence of agents remain unclear. Baseline resistance, acquired resistance, and cross-resistance have all been observed with the second line use of second-generation antiandrogens such as abiraterone and enzalutamide in this setting.6,7 Along with continuing ADT and reviewing the role of chemotherapy, clinicians should consider other treatment options, according to Gomella. “We tend to focus a lot on the AR-targeting agents or chemotherapy. We have immunotherapy; radionuclide radium-223 infusions; and, over the last year, a new class of drugs, the poly (ADP-ribose) polymerase (PARP) inhibitors. This is in addition to an impressive number of investigational agents in the US and abroad,” Gomella explained. “This is an area of tremendous interest, because the concept of curing prostate cancer when it’s metastatic is still not with us. Many other cancers can be definitively ‘cured’ in advanced stages, but we are not there yet with prostate cancer, and that’s why we are seeing a continual interest in developing new agents.”

As noted, a major challenge with these new and emerging options in later lines of therapy is knowing which agent/regimen would be most beneficial for a particular patient. “One study may say that agent A may be better to use than agent B, as second line,” Gomella explained, “but these are often relatively small studies, and there are few absolutes. Most of the agents used in the first-line setting could be used again in the salvage second-line or third-line settings.”

PARP inhibitors.

In 2020, olaparib (Lynparza) was approved for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene–mutated mCRPC. Around the same time, rucaparib was granted accelerated approval for adult patients with a deleterious BRCA mutation (germline and/ or somatic)–associated mCRPC who have been treated with AR-directed therapy and a taxane-based chemotherapy.8,9 To gauge optimal response to PARP inhibitors, genetic testing is recommended. According to Gomella, some clinicians are using these agents as a salvage therapy without appropriate genetic information. “The more we can define the specific patient who will have the best response, the more likely an agent will have widespread use,” he said.


Immunotherapy has demonstrated great efficacy for a variety of oncologic diseases, but, when considering its use for patients diagnosed with mCRPC, oncologists should evaluate specific histological and molecular biomarkers to predict potential response before treatment decision making.10 The first immunotherapy approved by the FDA for use in prostate cancer was sipuleucel-T (Provenge) in 2010; it is indicated for the treatment of asymptomatic or minimally symptomatic mCRPC.10,11 “Sipuleucel-T is a good option for mCRPC patients with minimal disease and relatively low levels of [PSA],” stated Gomella. However, for patients diagnosed with disease that is more symptomatic—for instance weight loss and narcotic-dependent bone pain—other treatments are more suitable. Pembrolizumab is another relatively new immunotherapy option for most solid tumors. It has efficacy in heavily pretreated patients who have metastatic disease harboring microsatellite instability–high (MSH-high) or mismatch repair–deficient (MMRd) solid tumors, including prostate cancer. Notably, however, few patients who have prostate cancer were included in the initial studies leading to FDA approval.12

There is strong interest in using immunotherapy in combination with other active agents. Given the study of pembrolizumab as a component of combination therapy in the KEYNOTE-365 trial, Gomella noted that researchers have interest in identifying whether pembrolizumab may be effective in combination with abiraterone acetate (Zytiga) and enzalutamide (Xtandi).

Another immunotherapy regimen that may hold promise for patients with mCRPC is nivolumab (Opdivo) plus ipilimumab (Yervoy). The phase 2 CheckMate 650 trial evaluating nivolumab plus ipilimumab combination therapy vs ipilimumab or cabazitaxel (Jevtana) monotherapy showed positive findings, with objective response rates (ORRs) of 25% and 10% in prechemotherapy and postchemotherapy cohorts, respectively.13 These results suggest that larger trials would be useful and that use of this regimen in mCRPC could be expanded.

Cytoskeleton disruption.

Another emerging modality of mCRPC treatment is cytoskeletal disruptors. The oral agent sabizabulin has shown enhanced antitumor activity by acting on microtubules; it inhibits division of cancer cells by disrupting AR transport to the nuclei.14,15 In combined efficacy data from phase 1b/2 trials, men with measurable disease at baseline in the intent-to-treat population (n = 29) who received sabizabulin at 63 mg per day had an ORR of 20.7% (5 partial responses, 1 complete response). In the phase 2 portion of the study, median radiographic progression-free survival (rPFS) had not been reached as of February 2021, when 10 men were still on study. No significant neutropenia or neurotoxicity was reported, and the overall safety profile appeared similar to that of AR-targeting agents.15

A phase 3 trial is under way to evaluate sabizabulin 32 mg vs an AR-targeting agent (enzalutamide or abiraterone) in 245 patients diagnosed with mCRPC who have failed at least 1 AR-targeting agent.16 The primary efficacy end point is rPFS; secondary end points include ORR, duration of objective response, overall survival (OS) at interim analysis, time to intravenous chemotherapy, and pain progression. Investigators have the option of reducing the dose to 26 mg per day based on tolerability of the 32-mg dose until radiographic progression.16

PSMA-based radioligand therapy.

Prostate cancer is resistant to most forms of chemotherapy, apart from taxanes such as docetaxel and cabazitaxel. However, the fact that external-beam radiotherapy can be effective for localized disease has provided a rationale for systemic treatment using radiopharmaceuticals. In the setting of metastatic castration–resistant disease, lutetium Lu 177 (177Lu)-PSMA-617 has been studied; it combines a targeting compound, or ligand, with a therapeutic cytotoxic radioisotope that binds with prostate cancer cells that express PSMA.17

The ongoing, open label, phase 3 VISION trial is comparing 177Lu-PSMA-617 therapy with best supportive care alone in approximately 750 patients with progressive PSMA-positive mCRPC.18,19 Patients have received at least 1 novel androgen axis–targeted drug (eg, enzalutamide, abiraterone) and were previously treated with 1 or 2 taxane regimens. Patients have been been randomized 2:1 to 177Lu-PSMA-617 therapy or best supportive care alone, respectively. Patients were monitored for survival, disease progression, and adverse events over a treatment period of 6 to 10 months. In the first half of 2021, researchers reported that 177Lu-PSMA-617 therapy met the primary end points of OS and rPFS.18,19

Future Directions In Care

Coupled with advances in imaging and genomic testing, the emergence of new therapeutic options for mCRPC suggests the potential for optimizing outcomes and survival. However, increasing patient access to these therapies remains a challenge, Gomella observed. Cost is one potential barrier, “Men are living longer, and many of these newer regimens can run $8000 to $10,000 or more a month, a financial burden for most. We are going to have to deal with these practical challenges.” Also, it can be difficult to provide patients with appropriate treatment when also navigating challenges associated with insurance coverage and prior authorization. “Insurance coverage is one of those unforeseen problems [that occurs] with these advances made over the last 10 years,” Gomella said. The costs of developing novel agents are very significant, as well.

Beyond the cost of these therapies, coordination of care is critical for patients with advanced prostate cancer who require the continuing care of a primary care provider. These patients can now receive many of these therapies in the large urology group practice setting in the community, often with individual providers who specialize in areas such as prostate cancer therapeutics. Increasingly, large, late-phase clinical trials are being conducted in these settings. Larger academic medical centers, particularly those that are National Cancer Institute–designated cancer centers, are where most of these new therapeutics are being developed and investigated in very early clinical trials. Many patients with a diagnosis of complex, advanced disease may benefit using a multidisciplinary approach commonly found at academic centers, where medical oncologists, radiation oncologists, urologic surgical oncologists, genetic counselors, interventional radiologists, oncology social workers, and others play a role in first studying these new agents and integrating all aspects of prostate cancer patient care.

“It is critical for providers to look at each patient as a unique individual and decide which agent or which site of service might be best for them at a particular point in time of their prostate cancer diagnosis and treatment,” observed Gomella. From the growing variety of standard and new options, the best treatment approach must be selected, he said: “It’s not a one-size-fits-all situation with advanced disease, and it remains a challenge today for prostate cancer–care providers.” With the wealth of standard and experimental treatment options available, it is important to optimize sequencing and combination strategies and consider how biomarkers and precision medicine may also help individualize treatment to optimize outcomes.

As urologists face these challenges, Gomella believes that the many new developments in testing, imaging, and treatment of mCRPC signal a brighter future for patients. “We are in an amazing place and time,” he concluded. “While sometimes challenging, having many different therapeutic options available is helping to extend the quantity and quality of [the lives of] many men with advanced prostate cancer.”


1. Lowrance WT, Breau RH, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline part I. J Urol. 2021;205(1):14- 21. doi:10.1097/JU.0000000000001375

2. Cancer stat facts: prostate cancer. National Cancer Institute/ Surveillance, Epidemiology, and End Results Program. Accessed June 22, 2021. https://seer.cancer.gov/statfacts/html/prost.html

3. Rice MA, Malhotra SV, Stoyanova T. Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer. Front Oncol. 2019;9:801. doi:10.3389/fonc.2019.00801

4. Teo MY, Rathkopf DE, Kantoff P. Treatment of advanced prostate cancer. Annu Rev Med. 2019;70:479-499. doi:10.1146/annurev-med-051517-011947

5. Gomella LG. The liquid biopsy for prostate cancer 25 years later. Can J Urol. 2017;24(2):8693-8694. https://canjurol.com/article.php?ID=3105

6. Pal SK, Patel J, He M, et al. Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration-resistant prostate cancer (CRPC). Cancer. 2018;124(6):1216-1224. doi:10.1002/cncr.31161

7. Zhao J, Ning S, Lou W, et al. Cross-resistance among next-generation antiandrogen drugs through the AKR1C3/ AR-V7 axis in advanced prostate cancer. Mol Cancer Ther. 2020;19(8):1708-1718. doi:10.1158/1535-7163.MCT-20-0015

8. Lynparza. Prescribing information. AstraZeneca; 2021. Accessed June 22, 2021. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/00997c3f-5912-486f-a7db-930b4639cd51/00997c3f-5912-486f-a7db-930b4639cd51_viewable_rendition__v.pdf

9. Rubraca. Prescribing information. Clovis Oncology; 2020. Accessed June 22, 2021. https://clovisoncology.com/pdfs/RubracaUSPI.pdf

10.Rizzo A, Mollica V, Cimadamore A, et al. Is there a role for immunotherapy in prostate cancer? Cells. 2020;9(9):2051. doi:10.3390/cells9092051

11. Provenge. Prescribing information. Dendreon; 2017. Accessed June 22, 2021. https://provenge.com/resources/files/Provenge_Prescribing_Information.pdf

12.Tucker MD, Zhu J, Marin D, et al. Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. Cancer Med. 2019;8(10):4644-4655. doi:10.1016/j.ccell.2020.08.007

13. Sharma P, Pachynski RK, Narayan V, et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell. 2020;38(4):489-499.e3. doi:10.1016/j.ccell.2020.08.007

14.Lu Y, Chen J, Wang J, et al. Design, synthesis, and biological evaluation of stable colchicine binding site tubulin inhibitors as potential anticancer agents. J Med Chem. 2014;57(17):7355-7366. doi:10.1021/jm500764v

15. Markowski MC, Tutrone RF, Eisenberger MA, et al. VERU-111, an oral cytoskeleton disruptor, to treat men with metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. J Clin Oncol. 2021;39(15 suppl):abstr 5056. doi:10.1200/JCO.2021.39.15_suppl.5056

16.Efficacy evaluation of VERU-111 for mCRPC in patients who have failed at least one androgen receptor targeting agent (VERACITY). ClinicalTrials.gov. Updated August 16, 2021. Accessed August 24, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04844749

17. Kratochwil C, Haberkorn U, Giesel FL. Radionuclide therapy of metastatic prostate cancer. Semin Nucl Med. 2019;49(4):313- 325. doi:10.1053/j.semnuclmed.2019.02.003

18. Study of 177Lu-PSMA-617 in metastatic castrate-resistant prostate cancer (VISION). ClinicalTrials.gov. Updated July 27, 2021. Accessed August 2, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03511664?term=NCT03511664&draw=2&rank=1

19. Sternberg A. Phase 3 trial of 177Lu-PSMA-617 meets survival end points. Cancer Network. March 23, 2021. Accessed August 2, 2021. https://www.cancernetwork.com/view/phase-3-trial-of-177lu-psma-617-meets-survival-end-points

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