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Androgen receptor (AR) signaling is the most important driver of prostate cancer initiation, development, and progression, even into the castration-resistant state.  Androgen deprivation therapy (ADT) is the original “targeted therapy” in oncology.  The next generation androgen- and AR-targeted agents, such as abiraterone acetate, enzalutamide, apalutamide and darolutamide further prove the concept that AR signaling remains critical in even later disease states.  There are various mechanisms of resistance that continue to be inclusive of AR; this ranges from AR amplification, AR mutation, and potentially AR spliced variants.

It’s hard to believe that it’s been nearly a decade since the ALSYMPCA trial with radium-223 was published, showing an overall survival benefit for men with bone metastatic castration-resistant prostate cancer and symptoms.1  Radium-223 is an alpha-particle emitting radiopharmaceutical that incorporates into areas of osteoblastic activity, with subsequent induction of double-strand DNA breaks in neighboring tumor cells.  Although radium-223 has clear efficacy, one of the practical challenges of use is that prostate-specific antigen (PSA) level does not always decline in response to treatment and the association with clinical outcomes is poor.  As a result, it is sometimes difficult for patients and health care providers to determine if radium-223 is working well or not.

Darolutamide first received regulatory approval for patients with non-metastatic (M0) castration-resistant prostate cancer based on the results of the ARAMIS trial.1  Although apalutamide and enzalutamide were regulatory approved prior to darolutamide, all three agents were successful in demonstrating both metastasis-free and overall survival benefit in their respective randomized phase 3 trials over placebo.1-3

Patients with urothelial bladder cancer now have many efficacious treatment options, spanning many unique mechanisms of action.  The immune-oncology agents in urothelial carcinoma have had significant success with current regulatory approvals in various disease states for pembrolizumab, nivolumab, atezolizumab, and avelumab.  Likewise, antibody drug conjugates are monoclonal antibodies specific for a tumor antigen, connected by a linker molecule to a cytotoxic drug payload, offering selective intensification of therapy.  Direction of increased drug concentration to the target cancer cell with minimal collateral damage to healthy tissue is a purported advantage of these antibody drug conjugates.  Yet, there is now some discussion surrounding whether increased specificity of targeting is ideal or whether it may be advantageous to have a more cleavable linker that could allow for greater bystander effect against cancer cells that may lack target antigen expression.1

Fortunately, most people are cured, however, 15-20% of patients with metastatic testicular germ cell tumors will relapse following initial chemotherapy.  Approximately half will still be cured with salvage treatments, including either conventional cisplatin-based combination chemotherapy or high-dose chemotherapy followed by autologous stem cell rescue.1-3  Over the years, I’ve written a couple of different Urotoday Clinical Trials Portal articles summarizing the very few clinical trials, at the time, for those who have refractory/resistant germ cell tumors.4, 5  Unfortunately, to date, none of those previously highlighted clinical trials have changed the standard of care for this unmet need population.  In these situations, palliative chemotherapy, with regimens containing oxaliplatin, is commonly used, yet it has limited efficacy.6

Five years ago, I wrote an article focused on neoadjuvant treatment options in clinical trials for patients with cisplatinum-ineligible, muscle-invasive urothelial carcinoma.1  The trials highlighted at that time were all focused on exploring immune-oncology agents.  Since that time, we have learned that neoadjuvant pembrolizumab or atezolizumab may contribute significant complete response rates when administered prior to radical cystectomy.2, 3  Yet, the standard of care for patients who are ineligible to receive cisplatinum chemotherapy is the same today as it was 5 years ago and that is to proceed to radical cystectomy without any systemic therapy.

The idea of oral androgen deprivation therapy (ADT) sounds great!  Why take a big needle when you can take a pill?  That certainly makes a lot of sense, but there are some major disadvantages to oral medications in the United States.  Most importantly is that oral prescription coverage for high-cost oncologic medications is less than ideal, and our patients can be left with large copays.  Even with copay assistance from sponsors and foundations, the overall cost to the health care system may be significant.  Also, the risk of non-compliance is real, and patients may forget to take their medications.  Yet, these are pragmatic considerations.  In the field of oncology, the most important drivers tend to still be efficacy and tolerability.

I’ve recently focused on metastatic castration-sensitive prostate cancer (mCSPC) as a disease state undergoing significant novel therapeutic investigation.  With the PEACE-11 and ARASENS2 publications, the concept of triple combination therapy with androgen deprivation therapy (ADT), novel androgen pathway inhibitor, and docetaxel chemotherapy for front line treatment of patients with metastatic castration-sensitive prostate cancer is now ripe for digestion.  Beyond the triple combination therapy approach, there are yet many ongoing clinical trials for patients with this disease state.  I have recently concentrated on novel chemohormonal therapy, PD-1/PD-L1 antibody, and PARP inhibitor trials.3-5
I’ve now written many articles about PARP inhibitor use in prostate cancer.  We currently have United States Food and Drug Administration (FDA) approval, on an accelerated pathway, for rucaparib for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who harbor a deleterious BRCA1 or BRCA2 germline or somatic alteration and who have been treated with androgen receptor (AR)-directed therapy and taxane-based chemotherapy.1  We also have full FDA approval for olaparib for the treatment of patients with pathogenic germline or somatic homologous recombination repair gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone.2  Recognizing that response rates still approximate the 40-50% range, even with DNA repair gene alteration biomarker selection, there have been many proposals for rationale combination therapies with PARP inhibitors.

The most commonly recognized prostate cancer aggressive variant is a high-grade neuroendocrine carcinoma.  De novo neuroendocrine prostate cancer (NEPC) is very rare, and it is much more common to see treatment-emergent NEPC arise after treatment with androgen deprivation therapy.1, 2  Some of these tumors may exhibit small cell morphology, although that is not a uniform characteristic.  By immunohistochemistry, NEPC typically has low expression of prostate lineage markers (e.g. androgen receptor [AR], NKX3.1, and HOXB13), yet high expression of neuroendocrine markers ( e.g. synaptophysin, chromogranin, and INSM1).  For this disease, it is well accepted that platinum chemotherapy is the standard of care.  Beyond that, our therapeutic options are limited, without any clear standard in patients who have previously been treated with platinum chemotherapy.

Non-muscle invasive bladder cancer is a topic that I tackled in previous UroToday Clinical Trials Portal articles, including last month’s discussion.  Although transurethral resection is standard of care, recurrence rates are high.  Prognostic factors for recurrence include the number of tumors, tumor size, prior recurrence, stage, grade, and concurrent carcinoma in situ (CIS).1  Patients with high risk features have approximately a 60-70% chance of recurrence and a 10-45% chance of progression to muscle invasive bladder cancer over a 5 year period.  Intravesical Bacillus Calmette-Guerin (BCG) is the standard for intermediate and high-risk disease, but BCG is not adequate to prevent relapses or frank resistance in approximately 50% of treated patients.2

It has now been over a year since pembrolizumab received FDA approval on January 8, 2020, for treatment for Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or who have elected to not undergo radical cystectomy.  This approval was a nice step towards expanding treatment options for a patient population that harbors a clear unmet medical need. Intravesical BCG is the standard for intermediate and high-risk disease, but BCG is not adequate to prevent relapses or frank resistance in approximately 50% of patients.1  BCG-unresponsive disease includes both BCG-refractory and BCG-relapse populations.  BCG-refractory refers to the presence of persistent high-grade cancer 6 months after the start of induction therapy or cancers that have progressed by either stage or grade 3 months after the initiation of induction therapy.2

I recently wrote about “triple combination therapy” with androgen deprivation therapy (ADT), docetaxel, and a novel hormonal agent a few months ago.1  In that article, I described a list of enrolling trials utilizing either novel hormonal, chemotherapy and/or chemohormonal strategies for patients with metastatic castration-sensitive prostate cancer.  Yet, we are fortunate, as a field, that the landscape is rapidly changing as new advances continue to be reported.

I’m continuing this series focused on metastatic castration-sensitive prostate cancer (mCSPC), as it is a disease state with many upcoming potential changes to standard of care.  A couple of months ago, I briefly summarized what is known about the PEACE-1 trial, and I highlighted ongoing chemohormonal therapy trials.1  Since then, there has been a press release that the ARASENS trial with androgen deprivation therapy (ADT) plus docetaxel and darolutamide is superior in overall survival compared to ADT plus docetaxel.  We eagerly await the data to be presented at the upcoming 2022 ASCO Genitourinary Cancers Symposium.  Additionally, just last month, I summarized the trials that are ongoing using PD-1/PD-L1 antibody inhibition for patients with mCSPC.2  Although single agent PD-1/PD-L1 inhibitors have not shown definitive promise yet in metastatic castration-resistant prostate cancer (mCRPC) for unselected populations, hope remains that earlier use may offer benefit to our patients.

The clinical data surrounding inhibition of PD-1/PD-L1 in prostate cancer is evolving.  In the past, I have written a couple of articles about both single-agent and combination approaches for metastatic castration-resistant prostate cancer (mCRPC).1, 2  The field has evolved to the point where we recognize that single-agent PD-1/PD-L1 inhibition is unlikely to yield a major benefit for an unselected population.  In the KEYNOTE-199 trial, pembrolizumab yielded 5% and 3% objective response rates in patients with PD-L1 positive and negative tumors, respectively.3  

The topic of metastatic castration-sensitive prostate cancer has been on the forefront of clinical research in prostate cancer for many years now.  In 2017, and again in 2019, I wrote Clinical Trials Portal articles on the topic of metastatic castration-sensitive prostate cancer, summarizing the key ongoing trials during those times.1, 2  We now know that early treatment intensification with the addition of either docetaxel, abiraterone acetate, enzalutamide or apalutamide to androgen deprivation therapy (ADT) offers a significant overall survival benefit.  Docetaxel is the only agent that may have questionable benefit for low volume metastatic prostate cancer, with benefit perhaps being restricted to high-volume metastatic disease only, defined as ≥4 bone metastases with at least one in the appendicular skeleton and/or a visceral metastasis.3

The majority of urothelial carcinomas occur in the lower urinary tract, yet 5-10% originate in the upper urinary tract, including the renal calyces, renal pelvis, and ureters.1  Although upper and lower urinary tract urothelial carcinoma may share similar histology, the natural history differs, and upper tract disease often has a higher incidence of local invasion at diagnosis.2  Risk factors for upper tract urothelial carcinoma are similar to those of the lower tract, but there are some unique risk factors are associated with environmental exposures.  For example, Taiwan has an extremely high incidence of upper tract urothelial carcinoma, with a counterintuitive 1:2 male-to-female ratio due to arsenic-contaminated water, termed Blackfoot disease.  Additionally, in both Taiwan and the Balkan countries, exposure to the Aristolochic herbs (fangchi and clematis) is carcinogenic, leading to progressive renal fibrosis and upper tract urothelial carcinoma.4, 5

Avelumab initially received regulatory approval for patients with metastatic urothelial carcinoma in the post-platinum chemotherapy setting based on an objective response rate of 16.5%.1  In the post-platinum chemotherapy setting, both nivolumab and pembrolizumab also currently retain their regulatory approval status.  However, the situation where avelumab has the strongest data is in the maintenance-switch setting.  I initially discussed that topic in a Urotoday Clinical Trials Portal article almost 4 years ago.2  Of course, everything discussed in that article has been completed, and all highlighted trials were positive.

PSMA PET imaging has now achieved regulatory approval in the United States.  On December 1, 2020, the United States (US) Food and Drug Administration (FDA) granted a limited approval to the University of California, Los Angeles and the University of California, San Francisco, for 68Ga-PSMA-11 PET imaging for patients “with suspected prostate cancer metastasis who are potentially curable by surgery or radiation therapy” and for patients with “suspected prostate cancer recurrence based on elevated serum PSA levels.”1  More recently, on May 27, 2021, a second PSMA imaging agent, PYLARIFY® (piflufolastat F 18) injection (also known as 18F-DCFPyL or PyL), received FDA approval for the exact same indication.2  Although neither 68Ga-PSMA-11 and PYLARIFY® (piflufolastat F 18) injection (also known as 18F-DCFPyL or PyL) are widely available yet, both likely soon will be, and they will change how we think about and treat patients with prostate cancer and both high-risk localized disease and biochemical recurrence.

The “abscopal effect” in cancer is frequently discussed, although very rarely seen.  While the term is used quite loosely, it technically is a situation where an untreated metastatic tumor will shrink concurrently while another site is undergoing a localized treatment.  Most commonly, radiation therapy is referenced as that local treatment.  Although the exact mechanism is unknown, it is postulated that the immune system is responsible for such an effect.1

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