Clinical Trials: From the Editor

08 February 2019

We have known for decades that androgen deprivation offers remarkable efficacy and palliation for men with advanced prostate cancer.  Yet, soon after Charles Huggins Nobel Prize-winning discovery, many case series started emerging, describing paradoxical benefits of testosterone supplementation for patients with prostate cancer.^1,2  These clinical observations seem so counterintuitive given that androgen deprivation therapy is the hallmark of treatment for advanced prostate cancer.  Yet, there may be supportive biological rationale to this surprising observation.

07 January 2019

When this monthly Clinical Trials Portal first started at the beginning of 2017, I focused on what I thought to be one of the newest, hottest areas of clinical investigation in prostate cancer. This was capitalizing on the discovery that 23% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor alterations in DNA repair genes that result in homologous recombination deficiency (HRD) e.g. BRCA1/2, etc.¹ 

12 December 2018

We now know better than to treat everyone with low-risk prostate cancer with definitive local therapy.  But, we also know there is a clear benefit to radical prostatectomy over watchful waiting for those with high-risk disease who are healthy enough to benefit from such an intervention.¹  Additionally, there is data from multiple randomized trials to show that adding androgen deprivation therapy (ADT) to definitive external beam radiation (EBRT) leads to a survival benefit.^{2, 3} 

05 November 2018

It has now been 8 years since sipuleucel-T demonstrated an overall survival benefit in the randomized phase 3 IMPACT trial.¹  This was a welcome new option for patients with metastatic castration-resistant prostate cancer and the health care providers that treated them.  However, there were some findings that were not considered standard in the field at the time.  First off, there was no improvement in time to progression, and sipuleucel-T also did not offer a significant PSA decline rate.  Additionally, sipuleucel-T was limited in regulatory approval to those patients with asymptomatic or minimally symptomatic disease, creating a smaller window of opportunity to identify patients appropriate for treatment with sipuleucel-T.

01 October 2018

Prostate-specific membrane antigen (PSMA) is a 750 amino acid type II transmembrane glycoprotein expressed in normal human prostate epithelium.  However, PSMA is overexpressed on virtually all prostate cancer cells.  Poorly differentiated, metastatic and castration-resistant prostate cancers harbor even higher expression.  Hence, not only is PSMA a potentially good target for diagnostic imaging but also for targeted therapy.  The field of PSMA PET imaging offers significant promise and is currently being utilized for detection and may off potential to direct oligometastatic disease ablation. 

06 September 2018

Just recently, we discussed neoadjuvant systemic therapy for cisplatin-ineligible patients with muscle-invasive urothelial carcinoma of the bladder.¹  For those patients “unfit” for cisplatin with at least one of the following criteria: creatinine clearance <60 ml/min, grade ≥2 hearing loss, grade ≥2 neuropathy, ECOG performance status 2, and/or New York Heart Association Class III heart failure,² there are no good options other than cystectomy alone.  Yet, we know the outcomes are not ideal for these patients with cystectomy alone.  Finding systemic therapies that may improve outcomes for these patients is clearly an unmet need in the field.

03 August 2018

Three randomized phase 3 trials of adjuvant therapy for high-risk renal cell carcinoma have led to conflicting results.  S-TRAC was the one trial with a positive outcome, as sunitinib prolonged disease-free survival (DFS) by a median of 1.2 years compared with placebo (6.8 versus 5.6 years; HR 0.76, 95% CI 0.59-0.98, p=0.03).¹  Based on these results, the US FDA approved sunitinib for the adjuvant treatment of patients with high-risk renal cell carcinoma.  However, the ASSURE trial revealed negative results as median DFS was 5.8 years for sunitinib, 6.2 years for sorafenib and 6.6 years for placebo.²  The PROTECT trial also had negative results as pazopanib compared to placebo had a HR 0.86; 95% CI

09 July 2018

Although urothelial carcinoma of the bladder represents the fourth most common malignancy in men, 70% of these cases are non-muscle invasive (NMIBC).  Most of these patients will have outstanding outcomes, however, up to 70% will recur after initial treatment and 10-20% will progress to muscle-invasive bladder cancer (MIBC).¹  Once a patient has MIBC, then treatment options become more intense, with discussions of definitive cystectomy, chemotherapy, and radiation, all of which carry greater morbidity and cost. 

18 June 2018

We are now using PARP inhibitors for DNA repair-deficient patients with breast, ovarian, fallopian tube or primary peritoneal cancer.  In the realm of genitourinary oncology, we are meticulously exploring PARP inhibition, particularly for enriched patient populations with prostate cancer.  This is due to the fact that DNA repair deficiency occurs in approximately 23% of men with metastatic castration-resistant prostate cancer,¹ and approximately 12% of men with metastatic prostate cancer harbor germline alterations.²

04 June 2018

The title of this article is admittedly ironic and amusing. It goes back to the term “watchful waiting” of low and very low-risk prostate cancer. Although we were waiting for either something bad to happen or more often nothing exciting to happen due to indolent prostate cancer, the term “watchful” may have been a misnomer, as it is unclear if or how patients were being watched. The modern term of “active surveillance” is probably a more accurate term. It implies that patients are indeed, being surveyed by some accepted “active” script, usually with PSA testing and intermittent prostate needle biopsies. What that script looks like differs based on national

02 April 2018

Antibody drug conjugates (ADCs) are a promising method of selective intensification of therapy, offering increased drug concentration to the target with minimal collateral damage to healthy tissue.¹   Structurally, ADCs are monoclonal antibodies specific for a tumor antigen connected by a linker molecule to a cytotoxic drug payload.  After endocytotic internalization of the complex, the linker is degraded in a lysosome, releasing the cytotoxic payload.  There are now many FDA approved ADCs, including brentuximab vedotin for anaplastic² and refractory Hodgkin lymphomas,³ trastuzumab emtansine

01 March 2018

One year ago, in this column, I highlighted the non-metastatic (M0) castration-resistant prostate cancer (CRPC) disease state as a fruitful area for clinical trial exploration.¹  As part of that article, I emphasized the concept of testing low toxicity, high efficacy agents from metastatic CRPC in earlier disease states.  Two of the randomized, phase 3 trials have just came out and the results are quite impressive.

01 February 2018

Immune checkpoint inhibitors (e.g. anti-PD1/PDL1, anti-CTLA4) have revolutionized the treatment of multiple tumor types, including urothelial and renal cell carcinomas.^{1, 2} Unfortunately, response rates to anti-PD1/PDL1 therapy are still generally low, although those who do respond or who have stable disease may have long-term durable clinical benefit.  It is likely that combination immunotherapy strategies targeting multiple negative regulators of tumor immune responses will be more effective than anti-PD1/PDL1 monotherapy.

01 January 2018

PD-1/PD-L1 antibodies are being studied in every disease state imaginable for patients with urothelial carcinoma.  Atezolizumab, nivolumab, durvalumab and avelumab are all regulatory approved for patients with metastatic disease in the post-platinum chemotherapy setting.^1-4  Pembrolizumab is also approved and is the only agent to have demonstrated an overall survival benefit to date when compared to taxane chemotherapy in the post-platinum setting.⁵  Additionally, atezolizumab and pembrolizumab are approved for patients who are ineligible for cisplatin chemotherapy in the 1^st-line. ^6,7 

06 December 2017

The fibroblast growth factor receptor (FGFR) family has functional roles in regulation of cell proliferation, differentiation, migration, angiogenesis and tumorigenesis.  Activating point mutations of FGFR3 are common (~86%) in low grade and stage bladder tumors.¹  However, The Cancer Genome Atlas Research Network identified only 12% of muscle invasive bladder cancers with FGFR3 mutations.²  FGFR3 mutations are also very common in upper tract urothelial tumors, especially of the ureter.³  FGFR1 has been less intensively studied, but increased expression at both the mRNA and protein level is present in a large proportion of bladder tumors.⁴ 

10 November 2017

Radium-223 is actually quite capable of dancing on its own without a partner.  It offers an overall survival, symptomatic skeletal events and multiple pain and quality of life benefits for patients with bone metastatic castration-resistant prostate cancer and symptoms.¹  Yet, the ALSYMPCA trial, which established the beneficial effects of radium-223, did not mandate regular imaging, so image surveillance expectations are uncertain.  Additionally, prostate-specific antigen (PSA) level does not always associate with clinical outcomes with Radium-223.  Given the mechanism of action of Radium-223, as an alpha-particle emitting radiopharmaceutical that incorporates into areas of osteoblastic activity, it is not surprising that alkaline phosphatase serves as not only a good baseline prognostic marker² but also a good treatment response biomarker.³

28 October 2017

Neoadjuvant chemotherapy use has been on the rise in the last 15 years for patients with high-risk localized urothelial carcinoma.  This is obviously due to randomized control data supporting an overall survival benefit.^1,2  However, it has taken significant time for the field to embrace and adopt widespread use of cisplatin-based combination chemotherapy regimens in this setting.  Early reports showed neoadjuvant chemotherapy utilization rates to be 7.6% in 2006, 3 years after the original randomized control trial was published supporting the use of methotrexate, vinblastine, adriamcyin and cisplatin.³ 

08 September 2017

It is fortunate that we cure the vast majority of men with testicular germ cell tumors.  Estimates show that only approximately 10% of men with metastatic Stage III germ cell tumors are not cured.¹  The bad news if that for those who aren’t cured with standard dose combination cisplatin-based chemotherapy with or without eventual high dose chemotherapy with autologous stem cell rescue (stem cell transplant), there are few options.  Palliative chemotherapy is often limited in efficacy, and regimens such as gemcitabine with oxaliplatin have been used.²  

14 August 2017

Early attempts at checkpoint inhibition in prostate cancer seemed to offer little promise.  The initial trial with CTLA-4 inhibition with ipilumumab was performed in patients with metastatic castration-resistant prostate cancer (mCRPC) in the post-docetaxel setting and resulted in a HR 0.85, 95% CI 0.72-1.00; p=0.053.¹ 

14 July 2017

For the longest time metastatic hormone-sensitive prostate cancer has been treated with androgen deprivation therapy (ADT).  Recently, the CHAARTED¹ trial and STAMPEDE,² both showed a dramatic survival benefit when 6 cycles of docetaxel was added to ADT.  For the CHAARTED trial, subgroup analyses confirmed survival benefit for those patients with high volume disease, defined as ≥4 bone metastases with at least one in the appendicular skeleton and/or a visceral metastasis.