Being the largest private practice urology center in Kentucky has its advantages, said Ganesh Rao, MD, president of First Urology, PSC, in Louisville. The practice was created from a merger between Metropolitan Urology and Allied Urology. First and foremost, it means the practice can provide better and easier access to care for its patients. Rao says with its 24 physicians and offices located in greater Louisville and southern Indiana, patients can expect to receive a multidisciplinary approach to urology-related cancer treatments. Patients with genitourinary cancer can look forward to consulting with an in-house radiation oncologist, medical oncologist, and urologic oncologist.

“All 3 physicians can sit together with the patient and family to discuss the varied treatment options,” said Rao. “The patient doesn’t need to make 3 different appointments, and if the patient has a complex disease, it helps to have all the physicians sitting under the same roof working together to come up with a strategy.”

That integration is evident in the practice’s pathology department located in Jeffersonville, Indiana, which is staffed with 2 board certified pathologists licensed to practice in Indiana and Kentucky. The pathology department started providing service in 2009. The department offers expertise in urological specimens, and includes a chemistry department that specializes in prostate-specific antigen (PSA), free PSA and testosterone testing. The laboratory also offers fluorescence in situ hybridization (FISH) testing—a technique used to identify particular DNA sequences in cells, tissues, and also in tumors that may be cancerous.

On more than one occasion, the practice was the first to bring cutting edge technologies to the Bluegrass State. “We were the first to bring robotic surgery to town,” said Rao. “We were the first to use intensity-modulated radiation therapy (IMRT) to treat prostate cancer here. And about 2 months ago, we were the first private urologic center in the United States to begin using high-intensity focused ultrasound (HIFU) to treat prostate cancer.”

HIFU uses ultrasound energy that is focused at a specific location in the prostate gland called the focal point. At the focal point, prostate tissue is heated to nearly 195 degrees Fahrenheit (90 degrees Celsius). The tissue at the focal point is destroyed, but the surrounding tissue remains unharmed. Because the technology uses ultrasound energy, not radiation, to destroy targeted tissue, the procedure can be repeated, if necessary. The minimally invasive procedure can be used to perform prostate ablations up to 40 cm3 without previously performing a TURP (transurethral resection of the prostate) procedure. HIFU has been widely available for 15 years in more than 40 countries in Europe, Asia, and Latin America.

“One of my partners, John Jurige, MD, has performed more than 400 HIFU procedures and he’s a national preceptor for HIFU,” said Rao. “Specialists from all over the country come here to learn how to perform the procedure from him, and patients from all over the country come here to receive treatment.” The benefit of the procedure is its minimally invasive methodology with few patients experiencing bladder control problems or erectile dysfunction, which can be common with traditional treatments. In addition, the procedure only takes about 3 hours and the patient gets to go home the same day. “There are a lot of treatments that can cure prostate cancer, but many leave the patient with erectile dysfunction and urinary incontinence,” added Rao. “With HIFU, the patient can get back to work in 3 days. With a radical prostatectomy, a full recovery can take 6 weeks.”

Rao also emphasized that patients can also undergo partial treatment, a hemi-ablation. This procedure avoids contact with the nerve bundle, said Rao. In addition, HIFU allows for further treatment, such as surgery or radiation, if it is necessary. Bringing cutting-edge technology to the state is only part of the picture, however. First Urology also performs clinical research, which gives patients access to the latest treatments. This is especially important when patients have exhausted all traditional treatment options.

The center’s research department is led by its medical director, James L. Bailen, MD, and Debbie Johnson, CCRC, director of research. The facility has been involved in multiple phase II and phase III trials for the treatment of genitourinary cancers, erectile dysfunction, initial cystitis, osteoporosis secondary to androgen deprivation therapy, overactive bladder, prostate intraepithelial neoplasia, stress incontinence, and urinary tract infections. Traditionally, academic centers were the bastions of clinical research, but with cuts in funding, research needs to take place in other settings. “We now offer more clinical trials for genitourinary cancers than our local cancer center,” said Rao. “Our access to a large, diverse patient population also makes us attractive to pharmaceutical companies who need to test their medications as they progress through the drug development cycle.”

He noted that First Urology has many of the safeguards that traditional academic centers also employ—internal review board reviews and frequent site visits by the trial sponsor&mdash;but not the bureaucracy that can accompany working with a large academic institution in drug development.

Surveying the current landscape, Rao warns other group practices to be wary of merging with local hospitals. That warning applies to other specialist practices as well. He said the “money upfront might be enticing” but hospital administration can become too controlling, micromanaging the number of patients seen or cutting salaries.

For practices to remain viable, he recommends exploring ancillary services that provide other sources of revenue, which can improve patient care and supplement the bottom line. “We started an imaging department where we conduct our own computed tomography scans. Our patients don’t have to travel to different locations to obtain scans, we have easy access to the results, and we’re not tracking down scans from other offices,” said Rao. “In a similar way, the clinical research that we conduct provides patients with cutting edge care, but the practice also benefits from the revenue generated from the trial sponsor. The process to get trials up and running can be difficult, but once it is implemented, it’s a steady stream of revenue.”

Articles

Being the largest private practice urology center in
Kentucky has its advantages, said Ganesh Rao, MD,
president of First Urology, PSC, in Louisville.

First Urology of Louisville Enjoys Many Firsts in Technology and Research

Change is inevitable. It can move at a glacial pace or with the speed of an idea. The outcome of change can be a detriment or a benefit, depending on whom it affects. Healthcare, in general, is a conservative business, so the uptake of anything new can take time. The development and approval of high-intensity focused ultrasound (HIFU)—featured this month&mdash; doesn’t qualify as moving at a glacial pace; if anything, it seems quite measured. In a crowded field of treatments, the technology is trying to gain a toehold.

HIFU has been around for about 15 years in Europe, Asia, and elsewhere in the world, but until now, not in the United States. In fact, a cottage industry of medical tourism developed around this technology’s availability in Europe and Asia, where US physicians have performed the procedure at international clinics in London or Tokyo.

But in November 2015, the FDA voted to approve this technology for prostate tissue ablation. This is not quite an indication for prostate cancer but, as we all know, once a treatment or technology is cleared for approval, a physician can prescribe or use it as he or she deems medically appropriate. Some urologists view HIFU as a viable treatment for the patient who prefers not to partake in active surveillance but who thinks surgery is too aggressive; others voice concern that every Tom, Dick, and Harry is going to open standalone clinics without the proper training and overtreat patients who could be managed conservatively over time. Whichever is the case, urologists are going to do what’s best for their patients, and what’s best for their practice.

What seems to have moved fast, compared with the approval of HIFU technology, is the role of immunotherapy in genitourinary cancers. In medical meetings covered in this issue, urologists were energized by the possibility of checkpoint blockade inhibitors in renal and bladder cancer. Specifically, at the 16th Annual Meeting of the Society of Urologic Oncology (SUO), data from CheckMate-025 with the clinical development of PD-1 and PD-L1 inhibitors in renal cell carcinoma demonstrated the extended durability associated with nivolumab over everolimus.

A similar buzz was generated by ongoing research on the potential role of PARP inhibitors in prostate cancer. The FDA recently granted olaparib (Lynparza) breakthrough therapy designation as a treatment for patients with 

-mutated metastatic castration-resistant prostate cancer (mCRPC) in those who have received a prior taxanebased chemotherapy.

Perhaps the most compelling research involving PD-1 and PD-L1 inhibitors has to do with their potential role in combination therapy. If one immune checkpoint inhibitor works well, what about combining two different ones?

At the 2016 Genitourinary Cancers Symposium in San Francisco, data involving the antitumor activity and low toxicity in bladder cancer of anti-PD-L1 antibody avelumab continues to accumulate, as noted by clinical investigator Andrea B. Apolo, MD. Immunotherapy for the treatment of bladder cancer has been available for years, but now researchers are learning a lot more about how active it is in the metastatic setting.

Similarly, updated data from IMvigor 210 that involved atezolizumab in bladder cancer showed a median overall survival of 11.4 months in patients with locally advanced or metastatic urothelial carcinoma who had high PD-L1 levels. The agent’s second-line potential seems firmly in place.

To close out this month’s issue, we highlight a local practice—First Urology of Louisville, Kentucky. Created by a merger between two large private practices, First Urology, now encompasses greater Louisville and parts of Indiana. As a dominant player in the genitourinary space, it boasts its own laboratory and, according to its president, Ganesh Rao, MD, “conducts more genitourinary clinical trials than the local cancer center.” Rao explained that in order for his practice to remain viable, ancillary services needed to be identified. Most notable was his practice’s adoption of HIFU technology, making it the first private practice center in the United States to do so. Yes, change is inevitable.

The development and approval of high-intensity
focused ultrasound
doesnâ€™t qualify as moving at a glacial pace; if anything, it
seems quite measured. In a crowded field of treatments, the
technology is trying to gain a toehold.

Advancing Immunotherapies and Focused Ultrasound Signal a Change

The landscape for the patient with localized prostate cancer is filled with both new and exciting treatments. With better methods to screen, improved imaging scans to determine physical location and extent of cancer, and even active surveillance (AS), there are many options to consider.

Despite these advances, however, no consensus has emerged regarding the optimal treatment for the most common patient with prostate cancer: the man with clinically localized stage T1 to T2 disease with no regional lymph node or distant metastasis (T1 to T2N0-NxM0). Of the 234,460 men in the United States diagnosed with prostate cancer annually, 91% have localized disease, according to the American Urological Association (AUA).

“A substantial proportion of men who are diagnosed with prostate cancer can very safely and effectively just be monitored and don’t require any treatment,” said Scott Eggener, MD, associate professor of surgery and co-director, Prostate Cancer Program at the University of Chicago. Traditional treatments like radical prostatectomy or radiation are still the standards of care with the best known, long-term outcomes for cure, but there are adverse effects associated with each. He noted that whole gland treatment of prostate cancer carries a risk of incontinence and sexual dysfunction.

Appropriately selected patients who choose AS, monitoring of their cancer without immediate treatment, can expect excel-lent long-term results but may experience anxiety that stems from not treating a diagnosed cancer. The AUA notes that patients with lower-risk tumors (low Gleason score, PSA level, and clinical stage) could be candidates for this management strategy. Several studies have shown that patients with lower- grade, localized prostate cancer have an extremely low risk for metastatic progression within the first 10—15 years after the diagnosis, although approximately 30% to 50% of men will re-quire surgery or radiation at some point after initiating AS.

Parameters for surveillance is a discussion that needs to occur between the patient and his physician before this course of action is undertaken. Currently, providing evidence-based recommendations for when to intervene in patients with a long life expectancy are not possible since markers of disease progression are poorly validated. Most reports describe a clinical strategy that includes regular prostate-specific antigen (PSA) level measurement and digital rectal examination with a periodic repeat prostate biopsy along with an option of more active therapy if biochemical (increasing PSA) or histopathologic (in-creased tumor grade or volume) progression occur.

Focal therapy has been proposed in recent years as a means of filling the gap in the treatment spectrum between whole gland treatment and AS. Many believe that for patients with intermediate-risk disease, focal therapy is an attractive option for maximizing quality of life by avoiding the effects of whole gland radiation or surgery while alleviating the anxiety and uncertainty of AS by targeting and ablating the tissue that contains disease which may pose a real threat to the patient. Ablation of the entire prostate or targeted ablation of only the malignant parts of the prostate are possible by a variety of technologies, including cryoablation, radiofrequency, microwave, laser, vascular targeted, and electroporation devices. One new option in the United States is the use of focal therapy using high-intensity focused ultrasound (HIFU).

“There’s been a movement to consider more minimally invasive approaches, such as treating part of the prostate, rather than the entire prostate, which may lead to quicker recovery and fewer side effects but has not been established with long-term cancer-related outcomes,” said Eggener.

Ultrasound energy is focused at a specific location in the prostate gland called the focal point. At the focal point, prostate tissue is heated to nearly 195°F (90°C). The tissue at the focal point is destroyed, but the surrounding tissue remains un-harmed. Because the technology uses ultrasound energy, not radiation, to destroy targeted tissue, the procedure can be repeated if necessary. The minimally invasive procedure can be used to ablate prostates up to 40 cm3 in volume without previously performing a transurethral resection of the prostate procedure.

Tissue analysis is conducted via radio frequency (RF). An RF signal is sent to a targeted ablation site prior to delivery of HI-FU and then another signal is sent after delivery of HIFU to the same site. The device calculates the change that took place and displays it on the screen. Tissue changes are quantified based on a comparison of RF ultrasound pulse-echo signals at each ablation site.

In addition, with the use of magnetic resonance (MR)-guided HIFU, the urologist can obtain an accurate anatomic depiction of the prostate gland and the tumor itself. This method also allows for a good depiction of thermoregulation in which the temperature of the tissue is monitored in real time. MR-guided HIFU has recently demonstrated promising results in the treatment of both benign and malignant tumors, said Alexander Copelan, MD, a radiologist at Beaumont Health and Oakland University William Beaumont School of Medicine.

“In prostate cancer, HIFU shows promise in very early prostate cancer and I think it’s an attractive option for patients who don’t want to undergo radical prostatectomy,” said Copelan.

HIFU has been used for treating malignancy in the kidney, liver, pancreas, and breast. In Europe, it has been widely used for whole gland therapy for prostate cancer. There are two major systems in use, the Ablatherm (EDAP TMS SA) and the Son-ablate (Focus Surgery Inc). The FDA granted regulatory approval to both the Sonablate and the Ablatherm devices via the 510 K pathway, approving the devices for prostate tissue ablation.

“HIFU offers a middle ground approach whereas the traditional therapies have been all-or-nothing: radical or passive,” says John C. Rewcastle, PhD, medical director at EDAP TMS. “With HIFU you have an accurate, minimally invasive ablation option that can be applied to the whole gland or focally.”

For the urology practice that is interested in investing in this technology, there is the cost of the equipment, the warranty, and the maintenance contract to consider, said Marc Oczachowski, chief executive officer of EDAP TMS. “Acquisition of a HIFU device does require a capital investment, but it is at significantly less than other robotic technologies.”

Rewcastle added that the technology is mobile—the bench that the patient rests upon can be wheeled around&mdash;as is the desk that houses the computer. Ambulatory centers that perform other scans could also incorporate HIFU technology. “Service providers are getting on board,” said Rewcastle, “Getting access to HIFU does not necessarily require purchase of the device.”

Urologists see a lot of men who are appropriate candidates for AS and who are going to stay on AS. But they also see pa-tients with intermediate disease which is on the lower end of the spectrum. For those men, HIFU is a viable option. The other benefit of undergoing HIFU treatment is that further treatment options like surgery or radiation are not ruled out because the surrounding tissue receives minimal damage.

As with any new technology, a rigorous and comprehensive training program should be undertaken by the urologist. “We’ve seen this in other settings, where low-volume, early adopters of technologies are not adequately trained and bad things can happen,” cautioned Eggener.

EDAP TMS has been operating in Europe for more than 20 years using the HIFU procedure, said Oczachowski. With active HIFU programs in over 50 countries, “we have perfected the training process to ensure reproducible outcomes in all these countries. We are very well versed in physician training,” he added.

The urology surgeon receives a HIFU training manual prior to visiting one of the qualified HIFU reference sites to observe a complete treatment process performed by a certified proctor treating his own patients. HIFU training materials include a training program, a training manual, a complete HIFU literature review, and a device user manual. In addition, nurses and operating room staff are provided with a dedicated HIFU training program supported by a specific documentation.

Over time, HIFU technology will likely become more prevalent in the United States, and “its attractiveness as a treatment option to patients who do not want to undergo surgery is evident,” said Copelan.

Eggener concurs but also emphasizes that vast majority of patients who are going to be good candidates for active surveillance do not require expensive interventions that have potential side effects. “But for the patient who might benefit from treatment, HIFU is going to be the new kid on the block on a long list of potential prostate cancer treatments,” he said.

The landscape for the patient with localized prostate cancer is filled with both new and exciting treatments. With better methods to screen, improved imaging scans to determine physical location and extent of cancer, and even active surveillance, there are many options to consider. 

In a Crowded Field, High-Intensity Focused Ultrasound Stakes a Claim

PD-1 and PD-L1 inhibitors, including nivolumab, atezolizumab, and avelumab, will likely play a major role as the backbone of combination therapy for patients with renal cell carcinoma (RCC). The agents "are going to disrupt the current treatment paradigm and will likely be the backbone of combination therapy,” said Hans J. Hammers, MD, PhD, during his presentation at the 16th Annual Society of Urologic Oncology, December 2-4, in Washington, DC.

“There’s a plethora of PD-1 and PD-L1 inhibitors undergoing clinical development in renal cell carcinoma (RCC), with nivolumab the most advanced, followed by atezolizumab and avelumab,” he explained. Hammers, an assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins Medicine, in Baltimore, Maryland, provided an overview of some of the current research and posed some provocative questions to consider as the role of these agents in combination therapy is delineated.

He first highlighted data by Sharma et al, presented during the 2015 European Cancer Congress, which involved nivolumab versus everolimus in patients with advanced RCC. In that trial, CheckMate-025, the PD-1 inhibitor reduced the risk of death by 27% and showed an improved overall survival (OS) of 5.4 months. Findings were simultaneously published in T

CheckMate-025 randomized 821 previously treated patients with advanced or metastatic clear-cell RCC in a 1:1 ratio to 3 mg/kg of intravenous (IV) nivolumab every 2 weeks or 10 mg of oral everolimus daily until progression or unacceptable toxicity. Prior treatment with one or two antiangiogenic treatment regimens for advanced or metastatic disease was required, along with evidence of disease progression within 6 months of enrollment. In that trial, OS was the primary endpoint, while secondary outcome measures included objective response rate (ORR) and progression-free survival (PFS). At a minimum follow-up of 14 months, the median OS was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93; 

 = .002). The difference was statistically significant, meeting the criteria established in the trial design of P ≤.0148. The OS benefit was observed across patient subgroups, including cohorts defined by geography, Memorial Sloan Kettering Cancer Center prognostic score, and number of prior antiangiogenic regimens.

The trial was stopped early after meeting the primary OS endpoint, and eligible patients in the everolimus cohort were allowed to cross over and receive nivolumab in an open-label extension of the study. Median PFS was 4.6 and 4.4 months in the nivolumab and everolimus arms, respectively (HR, 0.88; 95% CI, 0.75-1.03; 

 = .11). The researchers noted that there was a delayed separation of the PFS Kaplan-Meier curves. To further examine the results, they conducted an ad hoc sensitivity analysis of PFS in patients who had not progressed at 6 months. The median PFS in this cohort was 15.6 months with nivolumab versus 11.7 months with everolimus (HR, 0.64; 95% CI, 0.47-0.88).

“That was the elephant in the room,” said Hammers. “Everolimus, considered a ‘weak’ targeted therapy, and nivolumab, had similar time to PFS graphs. But starting at 9 months, there was a separation, which was driven by the response rates,” he said. Traditionally, response rates are not considered a primary endpoint, but in these patients, the response rates were very durable. “This allows us to identify the patient population that can derive the most benefit from these drugs.”

According to Hammers, toward the end of the curve for PFS, the part of the curve usually not considered for regulatory approval, a separation in PFS rates became significant. “We see that there is some lasting benefit over time, which is something that we do not fully understand yet. What we will want to know down the road, maybe 2 or 3 years from now, is are we going to see the tail end of that curve? Are there patients who are potentially cured?”

Hammers commented on the impressive response rates associated with nivolumab. “To see a response rate of 25% in a second- or third-line agent is impressive. To put that into context, the currently approved United States Food and Drug Administration (FDA) agent axitinib, indicated as second-line therapy for patients who have been previously treated with sunitinib, has a response rate around 11%.”

Perhaps the most compelling research involving PD-1 and PD-L1 inhibitors is their potential role in combination therapy. “If one immune checkpoint inhibitor works well, what about combining two different ones?” asked Hammers.

For patients with melanoma, this idea has been well documented.

In a double-blind study, CheckMate-069, the PD-1 inhibitor nivolumab plus the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor ipilimumab reduced the risk of progression or death by 60% compared with ipilimumab alone (HR, 0.40; 95% CI, 0.22-0.71; 

 <.002). With the combination, the ORR was 60% compared with 11% with ipilimumab alone in patients with BRAF wild-type melanoma.

 As a result, the FDA granted an accelerated approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a treatment for patients with 

 wild-type unresectable or metastatic melanoma.

Hammers also discussed research involving the combination of nivolumab with a VEGF pathway inhibitor. The VEGF receptor inhibitors sunitinib and pazopanib are standard of care in the treatment of patients with metastatic RCC; however, their antitumor effects are not durable.

At the European Society for Medical Oncology 2014, Amin and colleagues reported preliminary results of a phase I trial of nivolumab plus either sunitinib (S+N) or pazopanib (P+N) in patients with metastatic RCC.

 In this study, patients received either sunitinib 50 mg, 4 weeks on and 2 weeks off, or pazopanib 800 mg daily. Previously treated patients received IV nivolumab 2 mg/kg and were subsequently titrated up to 5 mg/kg IV every 3 weeks.

Overall, 7 patients were each initially treated with sunitinib plus nivolumab 2 mg/kg and 5 mg/kg, and this cohort was then expanded to an additional 19 treatment-naïve patients (total, n = 33) based on no reports of dose-limiting toxicities.

In the P+N arm, 4 dose-limiting toxicities, including elevations of ALT/AST in 3 patients and fatigue in 1 patient, were observed, leading to closure of this arm. Grade 3/4 treatment-related adverse events were reported in 27 of 33 patients (82%) and in 14 of 20 patients (70%) in the S+N and P+N groups, respectively. The researchers concluded that combination therapy with sunitinib plus nivolumab showed encouraging antitumor activity and was associated with a manageable safety profile in patients with advanced RCC. They also noted that the combination therapy resulted in responses that were higher than previously reported for monotherapy of either agent. However, they noted that the combination of pazopanib plus nivolumab was not a feasible treatment option because of dose-limiting toxicities.

The final study Hammers highlighted was a phase III study investigating atezolizumab in combination with bevacizumab versus sunitinib (NCTNCT02420821).

 The trial involves patients who have not received prior systemic active or experimental therapy, either in the adjuvant or metastatic setting.

The primary outcome is PFS, with secondary outcome measures of OS, ORR, and time-to-deterioration in patient-reported tiredness severity score.

			Hammers H. Combination checkpoint inhibition. Presented at Society of Urologic Oncology, December 2-4, 2015. Washington DC.

			Sharma P, Escudier B, McDermott DF, et al. CheckMate 025: a randomised, open-label, phase III study of nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC). Presented at European Cancer Congress; September 25-29, 2015. Vienna, Austria. Abstract LBA 3.

			Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma [published online ahead of print September 25, 2015]. 

			Hodi FS, Postow MA, Chesney J, et al. Improved clinical response in patients with advanced melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone. Presented at AACR Annual Meeting; April 18-22, 2015. Philadelphia, PA. Abstract 4214.

			Amin A, Plimack ER, Infante JR, et al. Nivolumab (N) (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib (S) or pazopanib (P) in patients (pts) with metastatic renal cell. Presented at European Society for Medical Oncology. September 26-30, 2014. Abstract 1052PD.

			A phase III, open-label, randomized study of atezolizumab in combination with bevacizumab versus sunitinib in patients with untreated advance renal cell carcinoma [IMmotion151]. https://clinicaltrials.gov/ct2/show/NCT02420821. Accessed December 28, 2015.

PD-1 and PD-L1 inhibitors, including nivolumab, atezolizumab, and avelumab, will likely play a major role as the backbone of combination therapy for patients with renal cell carcinoma (RCC).

Expert Predicts PD-1/PD-L1 Agents as Backbone of Combination Therapy in RCC

It is estimated that 20% to 30% of metastatic castration-resistant prostate cancers harbor alterations in DNA repair genes. These genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division. Alterations in DNA repair genes can lead to a failure in repair, which in turn allows subsequent mutations to accumulate. Clinical studies suggest that PARP inhibitors are highly efficacious in patients with these alternations, based on findings by Robinson, et al. Studies of PARP inhibitors in other cancers, such as breast and ovarian, also support their use in patients with this alteration.

“One could argue that PARP inhibitors should be considered as a standard of care in therapy for this subgroup of prostate cancer patients,” said Felix Feng, MD, assistant professor of Radiation Oncology, University of Michigan Health System during the 2015 Society of Urologic Oncology meeting.

PARP inhibitors are members of the poly (ADP-ribose) polymerase family of enzymes that have the repair of damaged DNA as one of their key functions. Cells have a number of different mechanisms that allow them to repair damaged DNA, including base excision repair (BER) and homologous recombination.

	PARP inhibitors have a particularly critical role in the BER pathway, binding to single-strand breaks in DNA and ultimately leading to the recruitment of DNA repair proteins to the sites of damage.

	PARP inhibitors block the activity of the PARP enzymes. As monotherapy, they have proven to be most effective against tumors with mutations in 

, tumor suppressor genes whose best-understood role is the repair of double-strand breaks in DNA.

	Robinson and colleagues found that 90% of cases harbored some kind of genetic anomaly that was clinically actionable, meaning there may be potential treatments to target that specific aberration. This suggests that clinical genomic sequencing could impact treatment decisions in a significant number of patients with disease. Previous studies have looked at the genomic landscape of clinically localized prostate cancer and found few actionable genomic alterations.

	The researchers found that nearly all the tumors had a genetic aberration known to drive cancers. The most common, found in nearly two-thirds of the patients, were aberrations in the androgen receptor. This was expected to some extent since the hallmark of castration-resistant disease is that it no longer responds to conventional androgen-blocking therapies. However, many other aberrations were found, as well.

	Fourteen percent of patients had a mutation in the 

 gene, which are already known to increase risk of breast and ovarian cancer. PARP inhibitors have already been approved in 

-positive ovarian cancer, suggesting potential for PARP inhibitors to play a role in prostate cancers with this type of aberration. In March 2015, Feng reviewed all the clinical trials involving PARP inhibitors in cancer and found 149 studies, but only 3 involved prostate cancer. By the time of the SUO meeting in December, that number had risen to 6. The defining trial of PARP inhibitors in prostate cancer was recently published by Johann De Bono,

 involving single-agent olaparib in patients with metastatic castrate resistant prostate cancer (mCRPC).

	Feng, a co-investigator in the De Bono study, said that the open-label, single-group, two-stage, multicenter phase II TOPARP-A trial examined olaparib in 50 patients with mCRPC whose disease had progressed following 1 or 2 chemotherapy regimens. Patients had an ECOG performance status of 0 to 2 and all had received prior docetaxel. Ninety-eight percent (n = 49) of patients received prior abiraterone acetate (Zytiga) or enzalutamide (Xtandi), and 58% (n = 29) had received cabazitaxel (Jevtana).

	“DNA repair defects predict response to olaparib,” stated Feng. Approximately 33% of patients responded to olaparib and those responders had a mean duration of response of about 9 months. DNA repair defects were identified in 16 of 49 patients. Among the 16, 88% had a response. Out of the 33 patients who did not exhibit a DNA repair alteration, only 2 responded.

	Feng also pointed out that PARP inhibitors have functions beyond DNA repair, namely as a regulator or modulator of transcription in the androgen receptor (AR). PARP-1 promotes oncogenic phenotypes in preclinical models of prostate cancer. Moreover, in models of advanced prostate cancer, PARP-1 enzymatic activity is enhanced, further linking PARP-1 to AR activity and disease progression.

	The role of PARP inhibitors in prostate cancer remains to be determined, but these findings suggest a viable treatment option for these patients.

	“I think there’s still a lot of questions to work out,” said Feng. These questions include what sequence or order should PARP inhibitors be administered in the course of disease progression, what combination of therapies results in the best outcome, and which biomarkers may be best predictive for response. “But nevertheless, I think that somewhere along the course of treatment for a patient with a DNA repair defect, PARP inhibitors should be strongly considered.”

				Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. 

				Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. 

				Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. 

Clinical studies suggest that PARP inhibitors are highly efficacious in patients with metastatic castration-resistant prostate cancer with these alternations in DNA repair genes. 

February 2016 | Oncology Live Urologists in Cancer Care®

First Urology of Louisville Enjoys Many Firsts in Technology and Research

Advancing Immunotherapies and Focused Ultrasound Signal a Change

In a Crowded Field, High-Intensity Focused Ultrasound Stakes a Claim

Expert Predicts PD-1/PD-L1 Agents as Backbone of Combination Therapy in RCC

Prevalence of DNA Repair Defects Key to Efficacy of PARP Inhibitors in Prostate Cancer