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Metastatic castration-sensitive prostate cancer (mCSPC) is a disease state where the benefits of treatment intensification are clear. Androgen receptor pathway inhibitors (ARPIs) offer overall survival benefit when added to conventional androgen deprivation therapy (ADT). The specific ARPIs include abiraterone acetate,1,2 enzalutamide,3,4 and apalutamide.5 Docetaxel chemotherapy offers survival benefit for patients with high volume disease,6 and either abiraterone7 or darolutamide8 offer survival benefit when added to ADT and docetaxel for patients, especially for those with de novo and high-volume mCSPC.
Immunotherapy for prostate cancer is a loaded topic. This is one of the first solid tumors to instill immunotherapy as a standard of care, with sipuleucel-T offering a survival benefit for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer.1 To rewind even further back, our field of genitourinary oncology has been using immunotherapy, with Bacillus Calmette-Guerin (BCG), for non-invasive muscle invasive bladder cancer. Yet, the rest of the field of oncology has seen dramatic gains with immunotherapy, especially in the form of checkpoint inhibitors; its use has become common practice for most cancers. Unfortunately, prostate cancer has not seen major immunotherapy advances, with accumulation of many negative randomized phase 3 trial attempts, spanning vaccines, like Prostvac,2 and checkpoint inhibitors, like anti-PD-(L)13,4 or anti-CTLA-45,6 antibodies.
Metastatic castration-sensitive prostate cancer (mCSPC) is a disease state that has grown in complexity, with arguably some of the greatest gains in our field of genitourinary oncology. That’s because the benefits of treatment intensification are indisputable with outstanding clinical trial hazard ratios and large median overall survival benefits. To briefly summarize, androgen receptor pathway inhibitors (ARPI) offer overall survival benefits when added to conventional androgen deprivation therapy (ADT). These benefits extend to abiraterone acetate,1,2 enzalutamide,3,4 and apalutamide.5 Docetaxel chemotherapy offers survival benefit for patients with high volume disease,6 and either abiraterone7 or darolutamide8 offer survival benefits when added to ADT and docetaxel for patients with de novo and high-volume mCSPC. There is also supportive data for low volume prostate cancer to apply prostate directed radiation for survival benefit from a subgroup analysis of the STAMPEDE trial.9
Von Hippel-Lindau (VHL) loss is a near critical event for clear cell renal cell carcinoma, the most predominant histologic subtype of kidney cancers. The actual VHL genetic syndrome is an autosomal dominant inherited disorder resulting from a deletion or mutation in the VHL gene, which is located on the short arm of chromosome 3. The clinical phenotype manifests with the development of clear cell renal cell carcinomas, pheochromocytomas, pancreatic neuroendocrine tumors, and hemangioblastomas.1 However, the inherited syndrome is not mandatory for clear cell renal cell carcinoma development, as the 3p chromosomal region is lost in 91% of these tumors.2 Subsequent loss of heterozygosity generally occurs through mutation or hypermethylation, resulting in biallelic inactivation of the VHL tumor suppressor gene.3
It has been almost 6 years, since I’ve talked about the fibroblast growth factor receptor (FGFR) family in the Urotoday Clinical Trials Portal.1 Since then, the United States Food and Drug Administration granted accelerated approval to erdafitinib for patients with locally advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alteration, that has progressed during or following platinum-containing chemotherapy, including within 12 months of perioperative platinum-containing chemotherapy.2 This accelerated approval was based on tumor response rate from the phase 2 trial,3 and required confirmation of clinical benefit from additional clinical trials.
Like HER2, HER3 is a receptor tyrosine kinase that plays a key role in cell growth and survival signaling pathways. Together, along with epidermal growth factor receptor, EGFR (HER1), and HER4, they make up the EGFR family. These are all well-known targets for diseases like lung and colon cancer with EGFR, and breast and gastric cancer with HER2. In earlier articles, I’ve mentioned how important HER2 might be for urothelial bladder cancer.1,2 Similarly, HER3 has a significant role in disease progression and treatment resistance of multiple genitourinary cancers, particularly prostate cancer.3 As a result, targeting HER3 may be a fruitful therapeutic strategy.
PSMA is all the craze in the field of prostate cancer. We now sensitively image PSMA on prostate cancer with using various PET imaging radiotracers. We also are therapeutically targeting PSMA using radioligand therapy, with the regulatory approval of 177Lutetium-PSMA-617 as the first example of this class of agents.1 This is likely the first of many other PSMA-targeted radioligand therapies. Yet, many other viable mechanisms of therapeutic targeting of PSMA are currently being explored with antibody-drug conjugates, bispecific antibodies, and even CAR-T cell therapeutics.
Antibody drug conjugates (ADCs) have now worked their way into the standard treatment of many malignancies, including urothelial carcinoma. We already have FDA approvals for both Enfortumab vedotin1 and Sacituzumab govitecan2 for patients with advanced urothelial carcinoma. Some of the advantages of this class of agents include high objective response rates, reasonable durability, and acceptable adverse event profiles, as the chemotherapeutic payload is delivered directly to the target to decrease systemic toxicity.
Checkpoint inhibitor immunotherapy is regularly used for patients with urothelial carcinoma for many disease states now. Although the research started in the advanced disease scenarios, these immune-oncology agents have been imported earlier and earlier in the treatment paradigm. Monoclonal antibodies targeted PD-(L)1 now hold regulatory approvals in the United States for patients with metastatic disease who are 2nd-line and beyond,1 for maintenance therapy using avelumab for patients with stable disease or response after platinum chemotherapy,2 for first-line platinum-ineligible patients,3 most recently for first-line cisplatin-ineligible patients with metastatic disease using pembrolizumab in combination with enfortumab vedotin,4 for adjuvant therapy with nivolumab,5 and for BCG unresponsive non-muscle invasive bladder cancer with pembrolizumab.6

Although anti-PD-1 or -PD-L1 (B7-H1) therapy is efficacious as an immunotherapy target for multiple malignancies, including bladder and renal cancers, we have not seen significant efficacy in prostate cancer, either as a single agent or in combination therapy regimens.1, 2  There are, of course, exceptions, as a patient with mismatch repair deficiency, microsatellite instability, and/or hypermutation, may have an outstanding response to immune checkpoint blockade.3, 4  However, estimates of the presence of these predisposing tumor alterations as a predictive marker for response to immune checkpoint blockade for patients with metastatic castration-resistant prostate cancer is low, approximately 3-5% of cases.5

We now have FDA approval for the PARP inhibitor, olaparib, in prostate cancer, for men who harbor any one of many potential homologous recombination repair (HRR) gene mutations.1 However, we have not seen extreme efficacy beyond the BRCA2 population of patients. In the PROFOUND randomized phase 3 trial that showed the survival benefit of olaparib over standard novel hormonal therapy for men with HRR-deficient metastatic castration-resistant prostate cancer, patients with ATM alterations had notably less profound outcomes with olaparib.2

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.

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