Ariela Katz

The immunoscore diagnostic assay has robust prognostic value in the management of patients with colon cancer stages I-III and also may be helpful in predicting the risk of recurrence in patients with stage IV cancer, according to J&eacute;r&ocirc;me Galon, PhD, research director and head of the Laboratory of Integrative Cancer Immunology in Paris, France. In a presentation at the 33

Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018), Dr. Galon discussed the definition of the immune contexture of Immunoscore, its international validation for the risk-classification of stage I-III colon cancer, and the potential value of Immunoscore in stage IV metastatic disease.

Immunoscore Colon is a validated test that predicts the risk of relapse in early-stage and locally advanced colon cancer by measuring the host immune response at the tumor site. This risk-assessment tool provides independent and superior prognostic value, compared with the usual tumor risk parameters, and is intended to be used as an adjunct to the TNM classification to guide patients&rsquo; management.

&ldquo;Risk assessment is particularly important in order to decide when to propose an adjuvant treatment to an individual patient with early colon cancer,&rdquo; Dr. Galon said. &ldquo;Better risk stratification could improve adjuvant treatment selection to help patients avoid unnecessary toxicities without compromising outcomes.&rdquo;

According to Dr. Galon, adjuvant treatment is generally recommended for patients with stage III and high-risk stage II disease. Patients with stage II colon cancer are considered at high risk if they present with at least one of the following clinical features: lymph nodes sampling < 12, poorly differentiated tumor, vascular or lymphatic or perineural invasion, and tumor presentation with obstruction or tumor perforation and pT4 stage. However, this does not apply directly to patients with stage III disease.

Results from the international IDEA trial led to more refined risk stratification data for patients with stage III disease. The investigators determined that many patients with low-risk stage III colon cancer can receive three months of therapy instead of the standard six months.

This could allow some patients to receive a shorter duration of adjuvant therapy, leading to fewer toxicities and adverse events.

However, determining who is at high or low risk can be challenging, and there are still unmet medical needs to improve the estimation of risk-of-recurrence of patients with colon cancer. &ldquo;[There is] especially the need to identify patients in stage II who need treatment [and] patients in stage III who would be harmed by reducing treatment duration based primarily on tumor and node staging,&rdquo; Dr. Galon said.

This is in part because survival is not directly correlated to TNM stage, and clinical outcomes can vary significantly among patients within the same histological tumor stage due to other clinical and pathologic features. Therefore, patients at high risk must be identified more accurately than what is currently accomplished with TNM alone, and there is a need for a better risk-factor staging system to improve patient prognostication and optimize decisions about adjuvant therapy.

Additionally, five-year survival rates after surgical resection range widely. Patients with stage I colon cancer have about a 92 percent five-year survival rate; stage II, between 65 percent and 87 percent; stage III, between 72 percent and 53 percent; and stage IV, about 12 percent.

&ldquo;The wide ranges reflect major differences in prognosis depending upon the stage subset, tumor grading, and the other biological characteristics,&rdquo; Dr. Galon said.

The Immunoscore test could be a better way to stratify these patients accurately and assess each patient&rsquo;s needor lack thereof&mdash;for adjuvant therapy, improving survival outcomes. A large SITC-led validation study confirmed that there is a strong prognostic value in the Immunoscore assay in early-stage colon cancer.

Immunoscore demonstrated a high level of reproducibility between observers and centers (

< 0.0001). In the training set of the study, patients with a high Immunoscore had the lowest risk of recurrence at five years (14 [8 percent] patients with a high Immunoscore, 65 [19 percent] patients with an intermediate Immunoscore, and 51 [32 percent] patients with a low Immunoscore; HR for high vs. low Immunoscore, 0.20; 95 percent CI, 0.10-0.38;

Immunoscore had the highest relative contribution to identify the risk of all clinical parameters, including the TNM classification system. Immunoscore&rsquo;s ability to predict overall survival (OS) was superior to that of existing tumor risk parameters such as grade of differentiation; microsatellite instability (MSI) status; mucinous colloid type; sidedness; and venous emboli, lymphatic invasion, and perineural invasion criteria.

Additionally, Dr. Galon noted that patients with a high Immunoscore had a prolonged disease-free survival (DFS) rate regardless of their MSI status. In the training set, a significant difference in time to recurrence was also found between patients with high and intermediate Immunoscores (unadjusted HR, 0.38; 95 percent CI, 0.21-0.70;

OS at five years was achieved for 155 (82 percent) patients with a high Immunoscore, 274 (77 percent) patients with an intermediate Immunoscore, and 94 (62 percent) patients with a low Immunoscore (unadjusted HR for high vs. low Immunoscore, 0.53; 95 percent CI, 0.38-0.75;

&ldquo;These results validate the reliability of Immunoscore Colon in identifying patients with a high risk of recurrence, independently of the TNM staging system,&rdquo; Dr. Galon said. &ldquo;Prognostication by the TNM staging was improved by Immunoscore, supporting its implementation as a new component of a TNM-Immune classification of cancer.&rdquo;

In a phase III study of patients treated with adjuvant FOLFOX (folinic acid [leucovorin], fluorouracil, and oxaliplatin), the Immunoscore and CD3+ invasive margin tests were each significantly discriminant for prognosis for patients with stage III colon cancer in low-risk (T1-3N1) and high-risk (T4 or N2) subsets. When using a prior Immunoscore risk classification, higher results were associated with significantly better DFS (HR, 0.59; 95 percent CI, 0.43-0.82;

= 0.0013). A high versus low Immunoscore was also significantly associated with better three-year DFS rates among T1-3N1 patients (91percent vs. 77percent) and T4 or N2 patients (68 percent vs. 54 percent).

The study authors concluded that the Immunoscore test is prognostic in patients with stage III colon cancer and is strongly prognostic within low- and high-risk T and N subsets as defined in the IDEA study. The data underscore the limitations of TNM staging and demonstrate the prognostic potential of immune biomarkers (TABLE).

However, the Immunoscore test is not without its limits. The test is proposed from a central laboratory (HalioDx CLIA Lab) and validated only for colon cancer. However, Immunoscore could be useful in many other indications, and according to Dr. Galon, further studies are ongoing. For example, the test&rsquo;s usefulness in patients with advanced melanoma has been demonstrated, with continuing research efforts to correlate marker expression profile with clinical outcomes. The score could also serve as a useful prognostic marker in patients with rectal cancer who have undergone primary surgery. Another study examined a multivariable suppression index scoring system in patients with oral squamous cell carcinoma. The cumulative index evaluates both the tumor and stromal microcompartments at the invasive margin and incorporates those findings into the Immunoscore, providing accurate stratification, independent of stage or tumor classification.

Additionally, the proportion of patients with metastatic colon cancer who are eligible for inflammatory cell infiltration could be refined and extended by the characterization of their primary tumor immune infiltrate based on Immunoscore status. To validate the Immunoscore&rsquo;s predictive value for this use, interventional trials are needed.

Shi Q, Sobrero AF, Shields AF, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): the IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration. J Clin Oncol. 2017;35(suppl; abstr LBA1). meetinglibrary.asco.org/record/147028/abstract.

Survival rates for colorectal cancer, by stage. American Cancer Society website. cancer.org/cancer/colon-rectal-

Pag&egrave;s F, Mlecnik B, Marliot F, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391(10135):2128-2139. doi: 10.1016/S0140-6736(18)30789-X.

Sinicrope FA, Shi Q, Hermitte F, et al. Immunoscore to provide prognostic information in low- (T1-3N1) and high-risk (T4 or N2) subsets of stage III colon carcinoma patients treated with adjuvant FOLFOX in a phase III trial (NCCTG N0147; Alliance). J Clin Oncol. 2018;36(suppl; abstr 614).meetinglibrary.asco.org/record/155684/abstract.

Articles

In a presentation at the 33<sup>rd</sup> Annual Meeting &amp; Pre-Conference Programs of the Society for Immunotherapy of Cance, Dr. Galon discussed the definition of the immune contexture of Immunoscore, its international validation for the risk-classification of stage I-III colon cancer, and the potential value of Immunoscore in stage IV metastatic disease.

Immunoscore Provides Risk Assessments for All Stages of Colon Cancer

Rucaparib (Rubraca) has received a breakthrough therapy designation from the FDA for single-agent use in adult patients with

-positive metastatic castration-resistant prostate cancer (mCRPC) following at least 1 androgen receptordirected therapy and taxane-based chemotherapy.

The designation will expedite the development and review of rucaparib in this setting.

The FDA's decision is based on initial data from the ongoing phase II TRITON2 study in patients with advanced prostate cancer (NCT02952534). Data from the study will be presented at the 2018 ESMO Congress, according to a press release from&nbsp;Clovis Oncology, the manufacturer of the PARP inhibitor.

&ldquo;We hope the decision by the FDA to grant this breakthrough therapy designation for Rubraca offers encouragement to the prostate cancer community, and we will do our best to make Rubraca available to eligible prostate cancer patients as quickly as possible,&rdquo; Patrick J. Mahaffy, President and CEO of Clovis Oncology, said in the press release.

The single-arm phase II TRITON2 study is enrolling men with mCRPC with germline or somatic

1/2 mutations and evidence of a homologous recombination gene deficiency. Patients are unable to enroll if they previously received a PARP inhibitor, mitoxantrone, cyclophosphamide, or any platinum-based chemotherapy. Individuals with symptomatic and/or untreated CNS metastases are also not eligible. The study is being conducted at 106 locations and the targeted enrollment is 160 patients.

The primary endpoints are objective response rate, and prostate-specific antigen (PSA) response. Secondary outcome measures include duration of response, radiologic progression-free survival, overall survival, clinical benefit rate, time to PSA progression, and safety/tolerability. The estimated primary completion date is October 2019.

&ldquo;We are pleased the FDA has granted breakthrough therapy designation to Rubraca in mCRPC,&rdquo; Howard R. Soule, PhD, executive vice president and chief scientific officer of the Prostate Cancer Foundation, said in a statement. &ldquo;There is tremendous need for new therapeutic options in advanced prostate cancer. In particular, we are enthusiastic about the potential for targeted therapies that may provide more meaningful benefit to patients with specific genetic mutations.&rdquo;

Beyond TRITON2, the multicenter, randomized phase III TRITON3 clinical trial (NCT02975934) is comparing single-agent rucaparib with physician&rsquo;s choice of abiraterone acetate (Zytiga), enzalutamide (Xtandi), or docetaxel (Taxotere) in men with mCRPC and homologous recombination deficiency whose disease has progressed despite treatment with prior therapy.

Rucaparib has approved indications in ovarian cancer. Success with PARP inhibitors has spread to the field of breast cancer, and now, there is growing evidence of the efficacy of these agents in prostate cancer.

Celestia S. Higano, MD, discussed emerging strategies to target PARP in prostate cancer during a presentation at the New York GUTM: 10th AnnualInterdisciplinary Prostate Cancer Congress&reg; and other Genitourinary Malignancies conference, held by Physicians&rsquo; Education Resource

&ldquo;PARP is an important mediator of DNA repair as the DNA strand breaks,&rdquo; said Higano, a professor at the University of Washington School of Medicine and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle. &ldquo;And so, when we have a patient who has an underlying DNA repair problem and we inhibit PARP, we can end up with a situation where there is no DNA repair, leading to cell death.&rdquo;

PARPs, a family of multifunctional enzymes, play a critical role in base excision repair, a process through which single-strand DNA breaks are mended. In her presentation, Higano identified other key repair pathways for different types of DNA damage: homologous recombination repair and nonhomologous end joining for double-strand breaks; nucleotide excision repair and translesion synthesis for bulky adducts; and mismatch repair for nucleotide mutations, substitutions, deletions, and insertions.

In study results published in Cell in 2015, genomic testing of bone or soft tissue biopsies demonstrated that aberrations of

were observed at substantially higher frequencies (19.3% overall) in advanced prostate cancer compared with those in primary prostate cancers.

The study also determined that the frequency of DNA repair alterations increases with disease progression.

Overall, the study found that 89% of affected individuals harbored a clinically actionable DNA aberration, including 62.7% with aberrations in the androgen receptor, 65% in other cancer-related genes, and 8% with germline alterations.

Olaparib (Lynparza), the first PARP inhibitor to gain the FDA&rsquo;s approval in 2014 with an indication in recurrent ovarian cancer, is being investigated in prostate cancer under a breakthrough therapy designation based on phase II study data. In the trial, olaparib demonstrated high response rates in patients with mCRPC and DNA repair defects.

The study enrolled 50 patients who were no longer responding to standard treatments, including docetaxel, abiraterone acetate, enzalutamide, or cabazitaxel (Jevtana). Genomic sequencing was performed on tumor biopsies as a requirement of the study. Of the 49 evaluable patients, 16 (33%) had a response to the treatment with olaparib, with 12 receiving the treatment for more than 6 months.

The study concluded that the presence of defects in DNA repair genes found in biopsies of metastatic tumors was associated with a high response rate to olaparib in 14 of 16 patients, including all 7 with loss of BRCA2. &ldquo;They didn&rsquo;t really know this until after the study, but 14 out of the 16 responders had DNA repair alterations. This was a pretty small study, but it has prompted a lot of interest in researching PARP inhibitors in prostate cancers,&rdquo; said Higano.

Clovis Oncology Receives Breakthrough Therapy Designation For Rubraca&reg; (Rucaparib) For Treatment Of BRCA1/2-Mutated Metastatic Castration Resistant Prostate Cancer (MCRPC). Posted October 2, 2018. Accessed October 2, 2018. https://bit.ly/2O0Lqdq.

RobinsonD,VanAllenEM,WuYM,etal. Integrative clinical genomics of advanced prostate cancer [erratum appears in

. 2015;161(5):1215-1228. doi: 10.1016/j.cell.2015.05.001.

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

. 2015;373(18):1697-1708. doi: 10.1056/NEJMoa1506859.

Rucaparib (Rubraca) has received a breakthrough therapy designation from the FDA&nbsp;for single-agent use in adult patients with <em>BRCA1/2</em>-positive metastatic castration-resistant prostate cancer following at least 1 androgen receptor&ndash;directed therapy and taxane-based chemotherapy.

Rucaparib Granted Breakthrough Designation by FDA for mCRPC

Findings from the CHAARTED, LATITUDE, and STAMPEDE trials

showed various results for adding docetaxel (Taxotere) or abiraterone acetate (Zytiga) to androgen deprivation therapy (ADT) in prostate cancer, and this kicked off a challenging issue for clinicians: Is it better to add docetaxel, abiraterone acetate, both, or neither to their patient&rsquo;s treatment plan?

This is especially challenging considering the heterogeneous nature of prostate cancer and its subtypes. Choosing therapies for patients with metastatic hormone-sensitive prostate cancer (mHSPC) requires careful consideration of each patient&rsquo;s disease characteristics, comorbidities, treatment-related toxicities, and, to some extent, their preferences, according to Celestia S. Higano, MD.

&ldquo;Historically, the standard of care for mHSPC was, and continues to be, ADT. But now this paradigm is a bit disturbed by the fact that we have the option of adding either docetaxel or abiraterone,&rdquo; said Higano, professor in the Medical Oncology Division at the University of Washington School of Medicine in Seattle, during a presentation at New York GU&trade;: 11th Annual Interdisciplinary Prostate Cancer Congress&reg; and Other Genitourinary Malignancies.

In the CHAARTED study, which looked at ADT with or without docetaxel, volume of disease had an impact on overall survival (OS). High-volume metastatic disease was defined as the presence of visceral disease and/or more than 4 bone metastases in the study.

&ldquo;When we look at [patients with] high-volume disease in CHAARTED, we see this rather dramatic improvement in overall survival with the addition of docetaxel. But in the low-volume disease [group], we didn&rsquo;t see that, and that was confirmed when they looked at the longer-term follow-up for these patients,&rdquo; Higano said. Therefore, it seems that docetaxel does not benefit patients with low-volume disease, whereas patients with high-volume disease do benefit.

When considering the summary of disease volume and status based on the CHAARTED trial findings, and more recent data, high-volume and de novo disease are the worst factors of outcome, Higano said. High-volume disease with a de novo presentation has a median OS of about 3 years, whereas high-volume disease with recurrent or low-volume disease with de novo presentation has a median OS of close to 5.5 years. In low-volume, recurrent disease, the median OS is about 8 years.

In arm G of the STAMPEDE trial, which studied ADT with or without abiraterone acetate, there was an OS benefit for all patients because the investigators did not stratify patients by disease volume, Higano said, and they looked at patients with N1M0 disease. However, she noted that there was excellent prostate-specific antigen (PSA) control over 3 to 5 years. In a meta-analysis of patients with low-volume disease in the CHAARTED and GETUG-AFU15 studies, there was no OS benefit for adding either docetaxel or abiraterone acetate.

Another factor that should be considered is the adverse event (AE) profiles of docetaxel and abiraterone acetate. In CHAARTED and arm C of STAMPEDE, there were more cardiac-related toxicities noted with abiraterone acetate versus placebo, along with higher rates of vascular events, mainly hypertension.

For docetaxel, in terms of grade 3/4 toxicities, neutropenia was the most common (12.1%). Febrile neutropenia occurred in 6.1% of patients, while other common AEs included fatigue (4.1%) and sensory neuropathy (0.5%) (TABLE 1).

It is also important to consider treatment duration and patient age. Docetaxel is given for 6 cycles in the 2 trials, translating to a regimen of ADT plus 4 months of chemotherapy. Although abiraterone acetate is an oral agent, the median duration of treatment is 33 months, making it a continuous therapy until the patient develops castration-resistant prostate cancer, Higano said. She noted that in STAMPEDE arm G and the LATITUDE trials, which both looked at added abiraterone acetate, when the patient populations were assessed for age, the magnitude of survival benefit seemed to be greater for patients younger than 70 versus those who were 70 or older (HR, 1.54; 95% CI, 1.14-2.08; P = .005). This could be due to the fact that there tends to be more comorbidities with an older population; however, Higano cautioned that the proportion of patients younger than 70 years was fairly small in both trials.

Patients&rsquo; responses to ADT alone should also be considered before adding docetaxel and/or abiraterone acetate. In the SWOG 9346 trial, investigators assessed 1134 patients who were being treated with intermittent versus continuous ADT for 8 months. At the 7-month mark, they looked at the patients&rsquo; PSA levels and separated them into low, intermediate, and high risk.

&ldquo;Those with PSA less than or equal to 0.2 were the lowest-risk group and had a median survival of 75 months, which is dramatically different from those whose PSA [was up to a] 4, whose median survival was 44 months. High risk was those with a PSA over 4, with a median survival of 13 months,&rdquo; Higano explained.

She added that ADT alone is still a viable option for some patients. &ldquo;If you&rsquo;re in a situation where you may be wondering if ADT alone may be reasonable for a patient, you may want to give them ADT alone and see where they fall at 6 or 7 months, because at that point it&rsquo;s not too late to add abiraterone or docetaxel,&rdquo; Higano recommended. &ldquo;If they fall into the low-risk group, you might want to consider ADT alone or ADT plus abiraterone, and for intermediate- and high-risk, you could consider ADT with either abiraterone or docetaxel.&rdquo; She stressed that this was not based on level 1 evidence, but it is how she operates as a clinician. Higano also detailed some other guiding factors for therapy selection in mHSPC (TABLE 2).

Looking to the future, no head-to-head trials are set to begin that explore whether docetaxel or abiraterone acetate is a superior agent to add to ADT. However, Higano said, the real question at present is how the use of all of these agents earlier in mHSPC, or even in nonmetastatic castration-resistant disease, will impact subsequent therapies.

Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-756. doi: 10.1056/NEJMoa1503747.

Fizazi K, Tran N, Fein L, et al; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi: 10.1056/NEJMoa1704174.

James ND, Sydes MR, Clarke NW, et al; STAMPEDE investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163- 77. doi: 10.1016/S0140-6736(15)01037-5.

4. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36(11):1080- 1087. doi: 10.1200/JCO.2017.75.3657.

Gravis G, Boher JM, Chen YH, et al. Burden of metastatic castrate na&iuml;ve prostate cancer patients, to identify men more likely to benefit from early docetaxel: further analyses of CHAARTED and GETUG-AFU15 studies [published online February 20, 2018]. Eur Urol. doi: 10.1016/j.eururo.2018.02.001.

Francini E, Gray KP, Xie W, et al. Prior therapy and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC) in a hospital-based database. J Clin Oncol. 2017;35(suppl 6S; abstr 221). meetinglibrary. asco.org/record/140496/abstract.

Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol. 2006;24(24):3984-3990. doi: 10.1200/ JCO.2006.06.4246.

Findings from the CHAARTED, LATITUDE, and STAMPEDE trials&nbsp;showed various results for adding docetaxel or abiraterone acetate to androgen deprivation therapy in prostate cancer, and this kicked off a challenging issue for clinicians: Is it better to add docetaxel, abiraterone acetate, both, or neither to their patient&rsquo;s treatment plan?

Choosing Between Docetaxel or Abiraterone With ADT in Hormone-Sensitive Prostate Cancer

Patients with prostate cancer and DNA damage repair defects could be candidates for therapy involving poly (ADP-ribose) polymerase (PARP) inhibitors, and there is strong justification for activating clinical trials in this space, according to Maha Hussain, MD, the Genevieve Teuton Professor of Medicine and deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

&ldquo;Metastatic prostate cancer is very complex, with a marked inter- and intra-patient heterogeneity and diversity. Therapy development, from my perspective, must focus on the totality of the biology if we want better care for our patients. DNA repair deficiencies have emerged as a promising therapeutic target in metastatic castration-resistant prostate cancer [mCRPC],&rdquo; Hussain said during a presentation at New York GU&trade;: 11th Annual Interdisciplinary Prostate Cancer Congress&reg; and Other Genitourinary Malignancies.

She noted that there are compelling data implicating PARP-1 in the mediation of DNA repair responses to alkylating agents, cellular survival in BRCA-deficient cells, and androgen receptor (AR)-mediated prostate cancer cellular proliferation. Further, PARP-1 interacts with the androgen signaling cascade and castration-resistant tumor cells exhibit increased PARP-1 activity.

The data led to the initiation of a trial looking at the combination of temozolomide (Temodar) and veliparib (ABT-888) in patients with mCRPC, with the idea to replicate what was done preclinically. However, the overall results were not that promising, with a prostate-specific antigen (PSA) response rate of 8% based on 2 of 25 evaluable patients achieving a confirmed PSA decline of &ge;30%. In the remaining 23 patients, 13 had stable PSA and 10 had PSA progression. None of the 16 patients with measurable disease for whom data were available achieved an objective response.

Hussain noted that the reason for this lack of significant response could be that adding PARP inhibition to castration therapy provides a better tumor effect, targeting AR-signaling and the PARP pathway simultaneously. Additionally, Hussain said, there have been no predictive biomarkers to select patients for response to this regimen, but some emerging data suggested that ERG fusions could be a predictor for sensitivity to AR and PARP targeting.

In an ongoing phase II trial, investigators, led by Hussain, tested the hypotheses that targeting AR and PARP would lead to better outcomes in patients with mCRPC and that ETS fusions would serve as a predictive biomarker for the response to treatment. Every patient underwent a metastatic disease biopsy. If eligible, they were stratified either as ETS fusion&minus; positive or &minus;negative and then randomized to receive the control arm of abiraterone acetate (Zytiga) and prednisone or the experimental arm of abiraterone acetate and prednisone plus veliparib. The primary endpoint was PSA response rate.

The study was negative overall, and although there was a trend in favor of the combination treatment, this was not statistically significant. ETS fusion positivity or negativity also did not predict for a better outcome.

However, the investigators observed that in a cohort of 80 patients with adequate tissue for tumor sequencing, 20 had DNA damage repair defects, which were either homozygous or deleterious mutations. The most frequent were BRCA2 (65%), ATM (20%), BRCA1 (5%), PALB2 (5%), and RAD51B/RAD51C (5%).

&ldquo;There was a fair amount of genomic alterations, but the 1 consistent factor was that the patients had DNA repair defects and had a response as reflected by PSA, and these responses were quite deep,&rdquo; Hussain said.

PSA declines were statistically significant in patients with DNA repair defects compared with patients with wild-type disease (90% vs 56.4%, respectively; P = .007), and the measurable disease response rate was also higher for patients with DNA repair defects (87.5% vs 37.5%; P = .0009).

&ldquo;Contrary to conventional wisdom up to now, where the belief was that patients with DNA repair defects did worse, in our trial, those patients did better,&rdquo; Hussain said. &ldquo;This is a previously unknown observation that the patients who were on the abiraterone-only arm still did better compared with patients who had wild-type disease.&rdquo;

Hussain et al then performed a multivariate analysis of progression-free survival (PFS) by biomarker status that incorporated clinical factors and other molecular factors. They noted that when they controlled for these factors, DNA damage repair defect was the biomarker that predicted the best outcome to PARP inhibition therapy. The median PFS for patients with DNA damage repair defects was 14.5 months compared with 8.0 months for those with wild-type disease (P = .02).

Other molecular alterations also had a significant association with benefit from PARP therapy. Patients with a TP53, PTEN, or PIK3CA mutation all had worse outcomes; however, DNA damage repair defects were the strongest predictor (TABLE).

&ldquo;When we are designing clinical trials,&rdquo; Hussain said, &ldquo;it is very difficult for us to understand the genomic or molecular profile of the tumor because no tumor has such a unique feature that it&rsquo;s going to predict 100% response to treatment.&rdquo;

The main observation noted in this data was that patients with DNA repair defects responded to AR-targeted drugs with or without a PARP inhibitor. Another study&rsquo;s findings recently demonstrated a similar observation based on germline data, affirming that these patients with mCRPC seem to respond better than expected to AR-targeted therapy.

In the single-arm phase II TOPARP-A trial, a group of heavily pretreated patients with mCRPC were given olaparib (Lynparza) as an experimental treatment and underwent tumor sequencing.

&ldquo;Interestingly, there were 16 patients of a cohort of about 50 patients with the DNA repair defect, and 14 of the 16 responders were biomarker positive, and this translated into what I would consider meaningful clinical benefit in terms of delaying [progression] and in PFS,&rdquo; she commented.

Hussain noted that the trial showed that about 90% of mCRPC tumors harbor potentially clinically actionable molecular alterations. Several of these molecular alterations appear to be novel, and there are clinical trials starting to address some of those. However, she said that an important finding of the TOPARP trial was that over 20% of patients with mCRPC harbor DNA damage repair pathway defects, specifically in BRCA1/2, ATM, and others.

Clinically, in other cancers, these are considered the &ldquo;canonical&rdquo; DNA damage repair defects. In prostate cancer, it seems there are other potential BRCAness alterations, but Hussain posed the question of whether patients with these mutations are responsive to PARP inhibition.

The phase II BRCAAway trial is currently recruiting patients with mCRPC and DNA repair defects (NCT03012321). Patients will be entered into the study if they either have enough tissue for a biopsy or known germline mutations in BRCA1/2 or ATM. They will then be randomized to abiraterone acetate plus prednisone, olaparib alone, or the combination, with the potential to cross over after progression. Patients who have a &ldquo;noncanonical&rdquo; alteration will be entered into a single-arm cohort to see if there&rsquo;s a signal from treatment with olaparib monotherapy.

Currently, there are 6 PARP inhibitors being evaluated in prostate cancer in clinical trials. Hussain notes that further study is needed to fully understand DNA repair defects and how to target them most effectively.

Hussain M, Carducci MA, Slovin S, et al. Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Invest New Drugs. 2014;32(5):904-912. doi: 10.1007/s10637-014-0099-0.

Hussain M, Daignault S, Twardowski P, et al. Abiraterone + prednisone (Abi) +/- veliparib (Vel) for patients (pts) with metastatic castration-resistant prostate cancer (CRPC): NCI 9012 updated clinical and genomics data. J Clin Oncol. 2017;35(suppl; abstr 5001). meetinglibrary.asco.org/record/144554/ abstract.

Antonarakis ES, Lu C, Luber B, et al. Germline DNA-repair gene mutations and outcomes in men with metastatic castration-resistant prostate cancer receiving first-line abiraterone and enzalutamide [published online February 10, 2018]. Eur Urol. doi: 10.1016/j.eururo.2018.01.035.

Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-708. doi: 10.1056/NEJMoa1506859.

Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi: 10.1016/j. cell.2015.05.001.

Patients with prostate cancer and DNA damage repair defects could be candidates for therapy involving poly polymerase inhibitors, and there is strong justification for activating clinical trials&nbsp;in this space, according to Maha Hussain, MD, the Genevieve Teuton Professor of Medicine and deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Ariela Katz | Authors

Articles

Immunoscore Provides Risk Assessments for All Stages of Colon Cancer

Rucaparib Granted Breakthrough Designation by FDA for mCRPC

Choosing Between Docetaxel or Abiraterone With ADT in Hormone-Sensitive Prostate Cancer

DNA Repair Deflects Strong Targets for Prostate Cancer Therapy